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MiRNA Profiles of Extracellular Vesicles Secreted by Mesenchymal Stromal Cells—Can They Predict Potential Off-Target Effects?

Timo Z. Nazari-Shafti
Sebastian Neuber
Ana G. Duran
Vasileios Exarchos
Christien M. Beez
Heike Meyborg
Katrin Krüger
Petra Wolint
Johanna Buschmann
Roland Böni
Martina Seifert
Volkmar Falk
1,2,3,5,6 and
Maximilian Y. Emmert
Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, 13353 Berlin, Germany
German Centre for Cardiovascular Research, Partner Site Berlin, 13353 Berlin, Germany
Berlin Institute of Health Center for Regenerative Therapies, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
Berlin-Brandenburg School for Regenerative Therapies, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
Department of Health Sciences and Technology, ETH Zurich, 8093 Zurich, Switzerland
Clinic for Cardiovascular Surgery, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, 8091 Zurich, Switzerland
White House Center for Liposuction, 8044 Zurich, Switzerland
Institute of Medical Immunology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany
Institute for Regenerative Medicine, University of Zurich, 8044 Zurich, Switzerland
Wyss Zurich, University of Zurich and ETH Zurich, 8092 Zurich, Switzerland
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Biomolecules 2020, 10(9), 1353;
Submission received: 5 August 2020 / Revised: 6 September 2020 / Accepted: 16 September 2020 / Published: 22 September 2020


The cardioprotective properties of extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) are currently being investigated in preclinical studies. Although microRNAs (miRNAs) encapsulated in EVs have been identified as one component responsible for the cardioprotective effect of MSCs, their potential off-target effects have not been sufficiently characterized. In the present study, we aimed to investigate the miRNA profile of EVs isolated from MSCs that were derived from cord blood (CB) and adipose tissue (AT). The identified miRNAs were then compared to known targets from the literature to discover possible adverse effects prior to clinical use. Our data show that while many cardioprotective miRNAs such as miR-22-3p, miR-26a-5p, miR-29c-3p, and miR-125b-5p were present in CB- and AT-MSC-derived EVs, a large number of known oncogenic and tumor suppressor miRNAs such as miR-16-5p, miR-23a-3p, and miR-191-5p were also detected. These findings highlight the importance of quality assessment for therapeutically applied EV preparations.

1. Introduction

Mesenchymal stromal cells (MSCs) have been extensively studied in preclinical and clinical trials over the past few decades for their promising capabilities in regenerative medicine [1]. There is consensus that MSCs cannot regenerate damaged human heart tissue. However, preclinical studies showed that MSCs may provide cardioprotective effects after myocardial damage by modulating the immune response, promoting neoangiogenesis, and reducing fibrosis in the myocardial scar [2]. The therapeutic efficacy of MSCs is mainly attributed to their paracrine secretion of various growth factors, chemokines, cytokines, and extracellular vehicles (EVs) [3]. Studies in rodents and pigs showed a reduction in scar size after a single injection of MSCs after myocardial injury [4,5]. In clinical trials, the results regarding the therapeutic effect of MSCs after single treatments in patients with myocardial infarction are more inconsistent [6]. Potential issues associated with the use of MSCs include:
the difficulty in generating a consistent source of cells with a stable phenotype,
a significant first-pass effect due to entrapment of large cells in the lung and liver microvasculature, and
patient-specific comorbidities in autologous applications [7].
In addition, less than 2% of the injected human cells remain at the target site after 60 min [8]. In a porcine model of acute myocardial ischemia, intramyocardial injections resulted in a retention rate of just over 10% after 60 min [9]. Furthermore, the same study showed that less than 1% of the engrafted cells were still present four weeks after transplantation. This, in turn, means that the release time of the cardioprotective MSC secretome at the site of injury is significantly shorter than the overall process of myocardial remodeling, which prompted scientists to further investigate the secretome of MSCs, specifically MSC-derived EVs. In general, EVs are membranous nanoparticles produced by cells that are divided into three categories based on their biosynthesis: apoptotic bodies, microvesicles, and exosomes [10]. All of them are considered intercellular messengers that, when stimulated, can transmit biological signals through the blood and lymphatic system to neighboring cells and distant tissues. Proteins, messengerRNAs (mRNAs), and microRNAs (miRNAs) partially encapsulated and protected by the lipid membrane of EVs act as the biological mediators between cells. In fact, gain-of-function and loss-of-function assays have demonstrated that miRNAs transported by EVs are primarily responsible for the cardioprotective effect of MSCs [11]. MiRNAs are short nucleotide sequences of 18–22 base pairs that can bind to the 3′ untranslated region of their target mRNAs, either to interfere with their transport to the ribosome or to prevent their translation at the ribosomal site [12]. Because of their short length, miRNAs usually target more than one mRNA, making specific target prediction difficult. To date, more than 150 miRNAs have been identified in MSC-derived EVs [13]. Although there are some differences in the miRNA profile depending on the source of MSCs, a number of cardioprotective miRNAs have been identified that are commonly transported by EVs from various MSC tissue origins [14]. MiRNAs encapsulated in EVs have several functions including regulation of cell physiology, proliferation, cell differentiation, and apoptosis. For example, they can regulate the expression of members of the hypoxia-inducible factor family, which are important for the modulation of vascular sprouting in the setting of hypoxia, via the RNA interference pathway [15]. Furthermore, miRNAs can also target mRNAs that regulate fibrosis and fibroblast activation, such as tissue growth factor-beta (TGF-beta) and members of the SMAD family [16].
Since it was shown that EVs isolated from MSCs can recapitulate the cardioprotective effects of their parent cells, it was hypothesized that the use of EVs may offer significant advantages over their cellular counterparts due to a higher safety profile, lower immunogenicity, and the inability to directly induce tumors [17]. However, whereas many preclinical studies use multiple direct myocardial injections to deliver EVs, this strategy may not be optimal for many patients in clinical practice. Direct access to the heart (i.e., intracoronary or intramyocardial) is achieved either through catheter-based techniques or by cardiovascular surgery, and both methods are associated with a risk of complications. In turn, a single intramyocardial injection may not be sufficient to improve tissue remodeling after a myocardial injury due to the short half-life of EVs and patient-associated comorbidities that can reduce the intrinsic wound healing capacity seen in healthy animal subjects. As a result, several groups are currently investigating methods for intravenous application of EVs that would allow for sufficient titers of therapeutic EVs in myocardial tissues [18,19]. Despite their small size, EVs, like other lipid-based nanoparticles, undergo a significant first-pass effect with accumulation in the liver and lung tissue [19]. While several teams are currently working on targeted delivery strategies for EVs, another pharmacological component must also be considered: application of EVs over long periods translates into the systemic application of a considerable amount of miRNAs, despite their short half-life of less than 24 h [20]. In the field of cancer biology, a multitude of studies describe the role of miRNAs in cancer progression, transformation, and metastasis. In this context, miRNAs are divided into three classes:
oncogenic miRNAs,
tumor suppressor miRNAs, and
miRNAs with a dual role in cancer progression.
However, to the best of our knowledge, likely due to the limited number of preclinical trials with systemic EV applications, their miRNA cargo was not analyzed in connection with possible off-target effects. In particular, the presence or absence of pro-oncogenic miRNAs in EV preparations has not been conclusively proven. These potential risks need to be assessed for the clinical use of EVs, especially when treating patients with undetected tumors or predispositions to tumor development. The aim of the present study was therefore to characterize the miRNA cargo of EVs isolated from two clinically relevant MSC sources (i.e., cord blood (CB) and adipose tissue (AT)) and then to compare the EV miRNA cargo to well-known miRNAs involved in cancer biology.

2. Materials and Methods

2.1. Cell Isolation and Cell Culture

Human AT-derived MSCs were isolated from patients undergoing liposuction, as described previously [21]. Four donors (three female, one male, mean age 41.8 ± 9.3 years) were included in this study. None of the lipoaspirate donors were obese (body mass index was below 25 for all donors) and none of the donors reported any medical conditions at the time of liposuction. CB-derived MSCs were isolated from CB of four healthy newborns (two female, two male) at the Charité University Hospital Berlin, as described elsewhere [22]. Neither mother nor infant suffered from any medical conditions at the time of donation. All procedures were approved by the local medical ethics committees (Charité University Hospital Ethics Committee, registration number EA2/178/13; Cantonal Ethics Committee Zurich, registration number KEK-ZH 2010-0476/0) and written consent was obtained from patients or relatives. All MSCs were cultured in MesenPRO RS medium (Life Technologies, Grand Island, NY, USA, catalog no. 12747-010) containing 10% fetal bovine serum (FBS; Life Technologies, Carlsbad, CA, USA, catalog no. 10270106), 1% penicillin/streptomycin (P/S; Merck Millipore, Burlington, MA, USA, catalog no. A2213), and 2 ng/mL recombinant human fibroblast growth factor-basic (FGF-b; PeproTech, Hamburg, Germany, catalog no. 100-18C) in a humidified atmosphere of 5% carbon dioxide at 37 °C.

2.2. EV Isolation

EVs were isolated from MSC-conditioned medium using (i) sequential ultracentrifugation (UC) or (ii) the exoEasy Maxi Kit (Qiagen, Hilden, Germany, catalog no. 76064) according to the manufacturer’s instructions. Briefly, MSCs were expanded to a confluence of about 80% and washed once with Dulbecco’s phosphate-buffered saline (DPBS, Dulbecco’s phosphate-buffered saline; Life Technologies, Bleiswijk, The Netherlands, catalog no. 14190-144). The cells were switched to Dulbecco’s modified eagle medium (DMEM 1X)-GlutaMAX (Life Technologies, Paisley, United Kingdom, catalog no. 21885-025) containing 10% exosome-depleted FBS (Life Technologies, Bleiswijk, The Netherlands, catalog no. A2720803), 1% P/S, and 2 ng/mL FGF-b for 48 h, followed by a transfer to starvation medium (DMEM 1X-GlutaMAX supplemented with 1% P/S and 2 ng/mL FGF-b) for 24 h. For the isolation of EVs using sequential UC, the supernatant of approximately 3 × 107 cells at early passages (passages 5–7) was processed according to the protocol of Beez et al. [23]. For the isolation of EVs using the Qiagen kit, an MSC-conditioned medium of approximately 3 × 106 cells at early passages was collected and centrifuged at 2000× g for 15 min at 4 °C (Allegra X-15R Centrifuge, Beckman Coulter, Indianapolis, IN, USA). The supernatant was decanted and filtered using a 0.2 μm syringe filter (Sartorius, Hanover, Germany, catalog no. 16534) to remove any remaining cell debris and large aggregates. Thereafter, 8 mL of the filtered solution were mixed with 8 mL XBP buffer by gently inverting the tube. The mixture was transferred to the exoEasy spin column, centrifuged at 500× g for 1 min at room temperature (R.T) and the flow-through was discarded. Then, the bound EVs were washed with 10 mL XWP buffer and centrifuged at 5000× g for 5 min to remove residual buffer from the column. To elute EVs, 0.5 mL XE buffer was added and the column was centrifuged at 500× g for 5 min to collect the eluate, which was re-applied to the same column and centrifuged at 5000× g for 5 min. Final EV preparations were transferred to low-binding tubes (Sarstedt, Numbrecht, Germany, catalog no. 72.706.600) and stored at −80 °C until further use.

2.3. Nanoparticle Tracking Analysis (NTA) and Total Protein Analysis

Particle concentration and size distribution of EV preparations were examined using the ZetaView instrument (Particle Metrix, Inning, Germany). Particles were automatically tracked and sized based on Brownian motion and the diffusion coefficient. The NTA measurement conditions were as follows: temperature = 26.6 ± 2.2 °C, viscosity = 0.87  ± 0.04 cP, frames per second = 30, and measurement time = 75 s. Sample videos were analyzed using NTA software (ZetaView, Particle Metrix, Inning, Germany, version 8.04.02).
Total protein content of EV preparations was determined using the commercially available Bicinchoninic Acid (BCA) Protein Assay Kit with bovine serum albumin as a standard (Thermo Scientific, catalog no. 23227). Briefly, 20 µL of samples or standards were mixed with 200 µL of freshly made BCA working reagent and incubated for 30 min at 50 °C. Absorbance was measured at 560 nm with a Mithras LB940 plate reader (Berthold Technologies, Pforzheim, Germany) and analyzed with MikroWin 2000 software (Mikrotek Laborsysteme, Overath, Germany, version 4.41).

2.4. Transmission Electron Microscopy (TEM)

Isolated EV preparations were stained according to the protocol of Théry et al. [24] and morphologically evaluated at the electron microscopy (EM,) facility of the Charité—Universitätsmedizin Berlin. Briefly, 20 µL of MSC-derived EVs were first placed on formvar carbon-coated copper EM grids (Plano, Wetzlar, Germany, catalog no. G2430N) for 20 min. Then, the samples were incubated for 20 min in 4% paraformaldehyde (Electron Microscopy Sciences, Hatfield, PA, USA, catalog no. 15714), followed by 5 min in 1% glutaraldehyde (Serva, Heidelberg, Germany, catalog no. 23114). After several washing steps with water, the samples were stained for 10 min in a freshly prepared solution of 4% uranyl acetate (Serva, Heidelberg, Germany, catalog no. 77870) and 2% methylcellulose (Sigma-Aldrich, St. Louis, MO, USA, catalog no. M-6385). Imaging was performed using the Leo 906 microscope (Carl Zeiss, Oberkochen, Germany), equipped with ImageSP Viewer software (SYS-PROG, Minsk, Belarus, version

2.5. Immunofluorescence Staining and Flow Cytometry

Expression of surface molecules was measured as described before [23]. Briefly, 2 µg of MSC-derived EV protein were incubated with 15 µL of 4 μm aldehyde/sulfate latex beads (Thermo Fisher, catalog no. A37304) for 15 min at R.T. The sample volume was filled up to 1 mL with DPBS and incubated for 1 h at R.T with gentle shaking. Thereafter, samples were centrifuged for 10 min at 300× g, and after discarding the supernatant, samples were washed once with 1% fetal calf serum in DPBS (flow cytometry buffer). Next, the beads loaded with EVs were incubated with the following fluorescence-conjugated antibodies: anti-CD9/FITC (BioLegend, San Diego, CA, USA, catalog no. 312104), anti-CD63/PE (BioLegend, San Diego, CA, USA, catalog no. 353004), anti-CD73/APC (BioLegend, San Diego, CA, USA, catalog no. 344006), anti-CD81/FITC (BioLegend, San Diego, CA, USA, catalog no. 349504), anti-HLA-ABC/PE (BioLegend, catalog no. 311405), or anti-HLA-DR/APC (BioLegend, San Diego, CA, USA, catalog no. 307610), each at a dilution of 1:25 in flow cytometry buffer. After 30 min at 4 °C, the beads were washed twice with flow cytometry buffer, fixed with flow cytometry buffer supplemented with 0.5% PFA, and stored at 4 °C until measurement using a MACSQuant VYB flow cytometer (Miltenyi Biotec, Bergisch Gladbach, Germany). Beads incubated with antibodies but no EVs served as negative controls, respectively. Analysis was performed using FlowJo software (Tree Star, Ashland, OR, USA, version 10.6.1).

2.6. MiRNA Analysis

MiRNA was extracted from 200 µL of isolated EVs using the miRNeasy Mini Kit (Qiagen, Hilden, Germany, catalog no. 74104) according to the manufacturer’s instructions. The RNA quantity and purity were assessed with the Agilent 2100 Bioanalyzer system (Agilent Technologies, Waldbroon, Germany). Reverse transcription (RT) was performed using the miRCURY LNA Universal cDNA Synthesis Kit II (Exiqon-Qiagen, Hilden, Germany, catalog no. 203301). RT thermocycling parameters were as follows: 42 °C for 60 min and 95 °C for 5 min. Quantitative polymerase chain reaction (qPCR) was performed using the miRCURY LNA Universal RT microRNA PCR system (Exiqon-Qiagen, catalog no. 339340) with 752 known human miRNAs and 3 interplate calibrators and 1 spike-in miRNA as an internal control. All primer/probe sets for miRNAs were custom designed by the supplier. Three extraction controls and two cDNA synthesis controls were additionally used as indicated by the provider. Two real-time qPCR amplifications were performed for each RT reaction. Reactions were performed according to the manufacturers’ instructions using a LightCycler 480 II system (Roche, Rotkreuz, Switzerland). QPCR thermocycling conditions were as follows: 95 °C for 10 min, followed by 40 cycles at 95 °C for 10 s and 60 °C for 1 min. Melt curve analysis was performed between 60 and 95 °C at a ramp rate of 0.11 °C/s. After interpolation calibration, the examined miRNAs were classified into three categories:
miRNAs with mean corrected CT (CTcorr) values below 30.00 were considered as detected with certainty,
miRNAs with mean CTcorr values between 30.00 and 32.99 were considered as detected with uncertainty, and
miRNAs with mean CTcorr values equal or greater than 33.00 were considered as not detected.
All analyzed miRNAs and their expression values are listed in Supplementary Materials Table S1. The obtained CT values of miRNAs were normalized using the geNorm method, which calculates a normalization factor based on multiple reference miRNAs [25]. In brief, the arithmetic mean of the CT values of miRNAs that were stably expressed across all samples, namely hsa-miR-1260a, hsa-miR-125b-5p, hsa-miR-21-5p, hsa-miR-23a-3p, hsa-miR-24-3p, hsa-miR-221-3p, hsa-let-7i-5p, hsa-miR-199a-3p, and hsa-miR-100-5p, were subtracted from CTcorr values to calculate delta CT (dCT) values for every sample. In order to plot miRNA expression on heatmaps, Z-scores were determined from logarithmically transformed dCT values for each miRNA. The Z-scores were calculated as a numerical measurement of the mean value group with z = (x − μ)/σ, where x is the raw score, μ is the population mean, and σ is the population standard deviation. Finally, heatmaps of miRNAs were created with the gplots package of RStudio (version 1.3.959).

2.7. Literature Search for miRNAs

A systematic literature search was conducted for all miRNAs with a low mean CTcorr value (≤29.99) in both CB- and AT-MSC-derived EVs. Pubmed, Medline, and Scopus were used as search engines with the following search terms: “name of miRNA”, “name of miRNA” AND “heart”, “name of miRNA” AND “fibrosis”, “name of miRNA” AND “cancer”, “name of miRNA” AND “fibroblasts”, “name of miRNA” AND “endothelial cells”, “name of miRNA” AND “angiogenesis”, “name of miRNA” AND “immunomodulation”, “name of miRNA” AND “macrophages”, “name of miRNA” AND “t-cells”, and “name of miRNA” AND “immune cells”. For published miRNA targets, only studies were considered that confirmed miRNA targets by luciferase reporter assays or gain- and loss-of-function experiments. The findings are summarized in Appendix A Table A1, Table A2 and Table A3.

2.8. Statistical Analysis

GraphPad Prism (GraphPad Software, San Diego, CA, USA, versions 6.0 and 8.3.0) was used for performing data analysis and generating graphs. The statistical significance of differences in EV particle concentration, total protein amount, and surface marker expression was determined by the Mann–Whitney test; a p-value of less than 0.05 was considered significant. All miRNA data are shown as median with interquartile range, if not indicated otherwise. Data were tested with Shapiro–Wilk test for normal distribution. Statistical differences between two groups with only one variable in paired observations were determined either with the Wilcoxon matched-pairs signed rank test for non-parametric samples or with the unpaired t-test for parametric samples. Results were considered significant with * p < 0.05, ** p < 0.01, and *** p < 0.001.

3. Results

3.1. Characterization of EVs

All EVs were harvested from the supernatants of in vitro-cultured CB- and AT-MSCs, which were derived from tissues of four healthy subjects each. Although isolated from different sources, both MSC lines showed a typical spindle-shaped cell morphology under EV biogenesis conditions (Figure 1). The mean number of EV particles obtained was 7.1 ± 1.2 × 1010 per mL for CB-MSC-derived EVs and 5.5 ± 0.5 × 1010 per mL for AT-MSC-derived EVs (Figure 2A), but this difference was not significant (p = 0.057). Similarly, protein concentrations between EVs from CB- and AT-MSCs were not statistically significant (p = 0.343), with mean values of 27.9 ± 7.4 and 35.0 ± 8.7 µg/mL protein (Figure 2B). Quantitative analysis of EV diameters demonstrated an asymmetrical distribution, with a mean diameter of 132.7 ± 12.1 nm for EVs from CB-MSCs and a mean diameter of 123.9 ± 6.6 nm for EVs from AT-MSCs (Figure 2C), indicating the presence of exosomes, which are typically 40 to 150 nm in diameter [26]. Furthermore, both EV variants, which were isolated with the Qiagen kit, exhibited typical cup-like shapes as observed by TEM (Figure 3A,B). In comparison, EVs isolated by sequential UC showed a similar shape (Figure 3C,D). However, in contrast to the EVs isolated by UC, the EVs isolated by Qiagen membrane affinity columns were covered by a corona that bound larger amounts of uranyl acetate (Figure 3A,B, red triangles). EVs isolated by sequential UC have not been further examined because this manuscript focuses on EVs isolated by the Qiagen exoEasy Maxi Kit due to its excellent scalability, which is needed for the production of large EV amounts for clinical application. Next, we analyzed the isolated EV preparations for selected membrane proteins that have been associated with EVs in the past. Regardless of the cell source, it was possible to detect on all EV preparations CD9, CD63, and CD81, with CD9 exhibiting the highest normalized mean fluorescence intensities (MFIs) (Figure 4). Interestingly, all of the aforementioned markers tended to have higher values in AT-MSC-derived EVs than in CB-MSC-derived EVs, while only CD63 levels were significantly higher (p = 0.029). Figure 4 also shows that CD73 was only detected in EVs from AT-MSCs, but not from CB-MSCs. Since it was hypothesized that MSC-derived EVs do not carry human leukocyte antigens (HLAs) and are therefore less immunogenic [23], we also included HLA-ABC and HLA-DR in the flow cytometry analysis. Our data indicate that EVs from CB-MSCs did not exhibit a signal for HLA-ABC and HLA-DR (Figure 4). For EVs from AT-MSCs, HLA-ABC was also not present, while HLA-DR was detected in small amounts (Figure 4). In sum, these results indicated that the isolated EVs contained exosomes.

3.2. MiRNA Profile of CB- and AT-MSC-Derived EVs

Of the 752 miRNAs examined in this study, 117 were detected with certainty according to the guidelines of the Qiagen-Exiqon miRCURY LNA Universal RT microRNA PCR system. Based on these miRNAs, a heatmap was created (Figure 5). The grouping of donors shows a consistent clustering with only one outlier per group (CB_MSC_4 and AT-MSC_4). Interestingly, the expression profile of EV surface markers for these donors also differed from the other donors in the same group. For further analysis, all miRNAs with mean CTcorr values below 33.00 in at least one group were included. Following this, 205 miRNAs were detected in EV samples, while the majority of miRNAs (547) were not detected (Figure 6). From our analysis, 76 miRNAs were highly expressed in CB-MSC-derived EVs and 80 miRNAs were strongly expressed in AT-MSC-derived EVs with mean CTcorr values of less than 30.00. Intriguingly, among them, 66 miRNAs were found in EVs from both MSC sources. Only 10 were uniquely highly expressed in CB-MSC-derived EVs, namely let-7d-5p, miR-30a-5p, miR-106b-5p, miR-107, miR-136-5p, miR-140-3p, miR-181b-5p, miR-320b, and miR-320c, and miR-342-3p, and 14 were uniquely highly expressed in AT-MSC-derived EVs, namely miR-10b-5p, miR-29b-3p, miR-138-5p, miR-148a-3p, miR-185-5p, miR-210-3p, miR-424-3p, miR-424-5p, miR-433-3p, miR-484, miR-503-5p, miR-663b, miR-874-3p, and miR-940. Furthermore, 100 and 103 miRNAs in CB-MSC-derived EVs and AT-MSC-derived EVs, respectively, which showed mean CTcorr values of 30.00 to 32.99, were considered to be low expressed. To visualize differential miRNA expression profiles, a heatmap of all miRNAs that were significantly different in expression between CB- and AT-MSC-derived EVs was created, showing a clear clustering of CB-MSC-EV-miRNAs and AT-MSC-EV-miRNAs (Figure 7, 44 miRNAs). Overall, the differences in expression after normalization did not exceed a two-fold increase or decrease for almost all miRNAs, except for miR-10b-5p (8.23-fold higher in AT-MSC-derived EVs), miR-103a-3p (3.35-fold higher in CB-MSC-derived EVs), miR-222-5p (8.28-fold higher in AT-MSC-derived EVs), miR-376a-3p (2.45-fold higher in CB-MSC-derived EVs), miR-663a (7.68-fold higher in AT-MSC-derived EVs), and miR-1260a (2.87-fold higher in AT-MSC-derived EVs). Three miRNAs were only found to be highly expressed in AT-MSC-derived EVs, but were absent in CB-MSC-derived EVs, namely miR-148a-3p, miR-424-3p, miR-503-5p. In sum, CB- and AT-MSC-derived EVs are similar in their miRNA composition, with the exception of a small number of miRNAs.

3.3. Classification of miRNAs: Tumor Suppressor miRNAs, Oncogenic miRNAs, and Cardioprotective miRNAs

We then conducted a literature research (Figure 8) to group all 66 miRNAs found at high levels in both CB- and AT-MSC-derived EVs based on their function. As indicated in Figure 9, the majority of identified miRNAs have a well-known role as tumor suppressor. We also found many miRNAs, such as miR-103a-3p, miR-151a-5p, and miR-191-5p, which are known oncogenic miRNAs (oncomiRs). Interestingly, we also identified a large number of miRNAs (26) known to act both as oncomiRs and as tumor suppressor. The EV samples examined in this study also showed positive hits for well-known cardioprotective miRNAs, such as miR-21-3p, miR-22-3p, miR-26a-5p, and miR-125b-5p. While having cardioprotective properties, most of them are also associated with oncogenic and tumor suppressor properties. In summary, these data indicate that both CB- and AT-MSC-derived EVs not only transfer a certain set of miRNAs that are involved in one particular mechanism, but rather a multitude of miRNAs that are linked to several biochemical processes, including tumor suppression, tumorigenesis, and cardioprotection.

4. Discussion

4.1. EV Phenotype

Overall, the EVs analyzed in our study showed the expected proteins to be present in both CB- and AT-MSCs, such as the tetraspanins CD9, CD63, and CD81. The latter was present in significantly lower amounts in EVs from CB-MSCs than in EVs from AT-MSCs, an observation that was not made in other comparative studies before. The phenomenon that EVs from MSCs have only little or no HLAs present on their surface and therefore have a low immunogenicity [23] was confirmed in our study, since HLA-ABC was not found in both CB- and AT-MSC-derived EVs. Furthermore, HLA-DR was not detected in CB-MSC-derived EVs and it was only slightly above the detection level for the flow cytometry assay in AT-MSC-derived EVs. Consequently, the phenotype of the EVs might reflect the low expression of HLA molecules of the parent CB- and AT-MSCs.
It is known that the isolation method can significantly influence the composition of miRNAs in EV preparations [26,27]. To date, there is a multitude of different EVs isolation protocols available [28], and an ideal isolation method for clinical use remains to be determined. In this study, EVs were isolated using a commercially available EV isolation kit from Qiagen. In contrast to protocols using sequential UC to isolate EVs, this kit is more appropriate for scaling up the production of EVs. Initially, we performed side-to-side comparisons for the isolation of EVs using sequential UC and Qiagen membrane affinity columns. A similar comparison reported by the group of Streanska et al. [29] demonstrated that both methods lead to EVs with encapsulated miRNAs. However, they found differences in EV size and surface protein expression depending on the isolation method. While in their study, they were not able to detect the tetraspanins CD63 and CD81 using the Qiagen kit for EV isolation, we were able to detect tetraspanins such as CD9, CD63 and CD81, considered as typical EV markers. It should be noted, however, that we performed flow cytometry analysis, whereas the others used the Western blot. Furthermore, TEM analysis revealed that EVs isolated by the Qiagen kit were coated with either proteins or nucleic acids. For this experiment, EVs were incubated with uranyl acetate to stain phosphate groups of the lipid membrane. However, the presence of phosphate-rich proteins or nucleic acids in the so-called EV corona can also result in strong staining. We therefore hypothesize that the structures surrounding the EVs are most likely a mixture of proteins and nucleic acids. In line with this, the group of Varga et al. [30] has recently shown that EVs in vivo are also surrounded by a variety of different proteins that are not integrated in their own membrane. Furthermore, Jeppesen et al. [26] were able to separate a protein fraction from a pure vesicle fraction and they demonstrated that different EV isolation methods impact the EV-miRNA composition. Our data suggest that the Qiagen membrane affinity method produces EVs with an intact corona, indicating that miRNAs may also be bound to proteins in the corona. However, it cannot be conclusively determined whether the analyzed miRNAs were encapsulated, bound to co-isolated proteins, or bound within the EV protein corona. Studies that have so far investigated the therapeutic potential of EVs did not purify the EVs in their in vivo models prior to injection. Therefore, regardless of the isolation method, co-purified miRNAs will be injected together with the EV fraction. However, when EVs are used clinically, it is expected that additionally administered miRNAs could also play a role in the cardioprotective mechanism. It is therefore of importance to validate the miRNA profiles for each isolation method before conducting downstream experiments or even clinical studies. A more in depth analysis of the isolated EVs might have answered this question, but would be beyond the scope of this project.

4.2. MiRNA Profile

As mentioned above, miRNA analysis of EVs derived from CB- and AT-MSCs showed that a large number of detected miRNAs play an important role in tumor biology. Due to the multiple targets a miRNA can have, it is difficult to predict all possible targets of each miRNA. In this study, we therefore only reviewed targets that were confirmed already by other groups through in vitro assays. Since the PCR array used in our experiment focused on cellular miRNAs, which play a well-known role in cancer biology, it is not surprising that most miRNAs (547 out of 752) were not detected in the EV samples. Our data show a biological variability that is expected from human-derived samples [31]: EV samples derived from both CB- and AT-MSCs contain one outlier in terms of their surface marker configuration and their miRNA profiles (Figure 4 and Figure 7). Due to the small number of donors examined in this study, the effect of donor-specific confounding factors (e.g., gender, age, or race) on the miRNA profiles cannot be determined. Our literature search revealed that most studies focused on the therapeutic aspect of miRNAs of MSC-derived EVs. Only a few studies made the data of their miRNA arrays publicly available [32,33,34]. Additionally, the role of MSC-derived miRNAs in cancer biology has been discussed and investigated by other groups. Even here, however, only few groups made all collected data available for secondary analysis. In the case of AT-MSCs, one group has investigated the role of AT-MSC-derived EVs in the development and treatment of osteoarthritis [32,33]. In both publications, the raw data of the miRNA array were made available by the authors. A side-to-side comparison revealed that 71.0% and 73.3% of the 65 highest expressed miRNAs in both data sets were identical to the miRNAs found in our EV samples. The discrepancy could be explained by the difference in treatment of AT-MSCs at time of isolation and the isolation method itself.

4.2.1. Anti-fibrotic Signaling via Suppression of the TGF-Beta Pathway

MiRNAs were initially examined in the context of cancer biology. Target search was therefore biased and provided a greater number of miRNAs related to cancer than, for instance, to cardioprotection. However, some miRNAs with cardioprotective properties often interfere with proteins that are also regulated in cancer cells. For instance, miRNAs that advantageously modulate fibrosis and activation of fibroblasts usually target either the mRNA of proteins in the TGF-beta/SMAD-axis or promoter and receptor mRNAs that modulate cell cycle activation. Typically, miRNA-mediated suppression of TGF-beta signaling leads to decreased fibrosis in different tissues [35]. Both CB-and AT-MSC-derived EVs contain sets of miRNAs that target TGF-beta receptors directly or downstream signaling proteins such as SMAD proteins. In the context of TGF-beta signaling, SMAD2, 3, and 4 are the downstream promoters that can activate pro-fibrotic gene expression in multiple tissues including the heart [36]. MiR-16-5p (−1.03-fold change, p = 0.84), miR-23a-3p (−1.14-fold change, p = 0.99), and miR-130a-3p (−1.11-fold change, p = 0.75), which showed no difference in relative amounts for the comparison of CB-MSC-derived EVs to AT-MSC-derived EVs, all target the SMAD mRNA directly and exhibit an anti-fibrotic, and in most cancers, a tumor suppressor effect [37,38,39]. At the same time, miR-130a-3p can also act as an oncomiR in esophageal cancer by inhibiting the expression of SMAD4 [40], which incidentally leads to a tumor suppressor effect in hepatoma cells [38]. This dual role of miRNAs in cancer biology is well known and shows the complexity of gene expression regulation via RNA interference [41]. Similarly, while miR-130a-3p suppresses fibrosis in hepatic steatosis by suppressing the TGF-beta receptors 1 and 2 [37], the suppression of TGF-beta receptor 3 by miR-23b-3p and miR-27b-3p in atrial fibroblasts leads to increased fibrosis in the context of atrial fibrillation [42]. This underlines that, similar to the effect of miRNAs in cancer, a dual role of miRNAs and thus potential off-target effects can be hypothesized. It also highlights that adverse effects, such as increased fibrosis, may depend on the presence of miRNA clusters. For the EV samples investigated in the present study, both miR-23b-3p and miR-27b-3p were found with mean CTcorr values of 25.2 ± 1.4 and 25.5 ± 1.1 versus 27.4 ± 0.9 and 27.2 ± 1.1 in CB- and AT-MSC-derived EVs, respectively.

4.2.2. Role of miRNA-Mediated Mammalian Target of Rapamycin (mTOR) Suppression

The miRNA target analysis also revealed that some miRNAs found in CB- and AT-MSC-derived EVs target mTOR or mTOR-associated proteins, including miR-99b/a, miR-100-5p, miR-143-3p, miR-199a-5p/3p, and miR-199b-5p. MTOR is a protein kinase that regulates cell growth, autophagy, and cell survival [43]. Since activation of mTOR plays a crucial role in maintaining growth and inducing metastasis in many cancers, it has been intensively studied as a potential target for cancer therapy [44]. For all of the miRNAs mentioned, overexpression in cancer cell lines led to the induction of apoptosis and autophagy. Interestingly, miR-100-5p can also suppress angiogenesis by preventing cell proliferation in vascular smooth muscle cells, an effect that could counteract a potential cardioprotective effect [45]. Similarly, both miR-143-3p and miR-199a-3p can increase apoptosis during hypoxic or inflammatory injury in kidney and synovial cells, respectively [46,47]. One could therefore postulate that miRNAs that inhibit mTOR signaling are unproblematic in the context of promoting preexisting tumors at the time of EV therapy. However, further studies are needed to elucidate whether MSC-derived EVs suppress mTOR signaling and how this affects the injured heart. There is some evidence that mTOR plays an important role in the activation of cell autophagy in myocardial injuries, which can prevent cell apoptosis and necrosis in the myocardial scar [48]. In the EV samples examined in this work, at least six miRNAs were found that can target mTOR or mTOR signaling related protein mRNAs (Table A1, Table A2 and Table A3). A prolonged exposure to EVs containing these miRNAs may therefore either aggravate myocardial injury by increasing apoptosis in the early stages of myocardial infarction or improve wound healing and remodeling via autophagy.

4.2.3. OncomiRs in MSC-Derived EVs

At least six MSC-EV-miRNAs found in the present study are known oncomiRs, namely miR-24-3p, miR-92a-3p, miR-103a-3p, 151a-5p, miR-191-5p, and miR-423-3p. Remarkably, miR-24-3p and miR-423-3p were also associated with cardioprotective properties. Most of these miRNAs target proteins of the Wnt signaling pathway and/or the phosphatase and tensin homolog deleted from chromosome ten (PTEN) protein (Table A1, Table A2 and Table A3). PTEN is an intracellular membrane-bound phosphatase that hydrolyzes phosphatidylinositol (3,4,5)-trisphosphate to phosphatidylinositol (4,5)-bisphosphate and therefore reduces phosphoinositide-dependent kinase-1- and AKT-mediated activation of cell cycle progression and anti-apoptotic signaling [49]. It is a well-described tumor suppressor and often affected by mutations in various cancers. MiR-103a, for example, targets PTEN in endothelial cells and promotes proliferation and thus angiogenesis [50]. At the same time, miRNA-103a acts as an inhibitor of Wnt signaling in squamous cell carcinoma and promotes cell proliferation [51]. Similarly, the inhibition of Wnt signaling is also promoted by miR-92a and miR-221-3p, which in turn also inhibits PTEN expression in esophageal, gastric, and pancreatic cancer [52,53,54]. While Wnt signaling inhibition and PTEN inhibition are desirable targets for miR-10b-5p, miR-27b-3p, and miR-103a-3p in the context of cardioprotection [50,55,56], this may also promote progression of undetected tumors in recipients of EVs containing miRNAs.

5. Conclusions

The administration of MSC-derived EVs containing miRNAs offers a promising therapeutic approach for cardiovascular disease due to their proposed cardioprotective effects. In the present work, we have isolated EVs from two clinically relevant MSC sources, i.e., CB and AT, using membrane affinity columns and analyzed their miRNA cargo by qRT-PCR. Our data show that EVs from CB- and AT-MSCs are similar in their miRNA composition. Although a large number of miRNAs found in EVs from both MSC sources have been associated with cardioprotective properties, our literature research for known miRNA targets has revealed that they may also play a critical role in the tumor biology of various cancers. Given that EVs and miRNAs have a half-life of less than 24 h, a single administration of EVs may not be sufficient to improve tissue remodeling after a myocardial injury and multiple EV administrations would be required. However, this procedure, in turn, could lead to the accumulation of miRNAs in patients with early-stage cancers that may not have been recognized prior to treatment. Therefore, careful screening of patients for preexisting neoplasms prior to EV administration is important to reduce the risk of potential side effects that could facilitate or even worsen existing tumors. Further reports and functional studies are needed to evaluate both the therapeutic and adverse effects of EVs and their transported miRNAs, depending on the dose and duration of treatment.

Supplementary Materials

The following are available online at, Table S1: Analyzed miRNAs and their expression values.

Author Contributions

T.Z.N.-S.: conceptualization, investigation, formal analysis, writing—original draft, writing—review and editing, supervision. S.N.: investigation, formal analysis, writing—original draft, writing—review & editing. A.G.D.: investigation, formal analysis, writing—original draft. V.E.: investigation, formal analysis. H.M.: investigation. K.K.: investigation. C.M.B.: investigation, formal Analysis. P.W.: investigation. J.B.: investigation. R.B.: investigation. M.S.: writing—review and editing. V.F.: writing—review and editing, funding acquisition. M.Y.E.: conceptualization, writing—review and editing, supervision, funding acquisition. All authors have read and agreed to the published version of the manuscript.


This research was funded by institutional funds. Nazari-Shafti is a scholar in the BIH Charité Clinician Scientist Program funded by the Charité—Universitätsmedizin Berlin and the Berlin Institute of Health. Neuber was funded by the German Centre for Cardiovascular Research (FKZ 81Z0100302).


We thank the Core Facility for Electron Microscopy of the Charité—Universitätsmedizin Berlin for support in acquisition and analysis of the data.

Conflicts of Interest

The authors declare no conflict of interest.

Appendix A

Table A1. MiRNAs that are known tumor suppressors (TS). Selected miRNAs are also involved in cardioprotection (CP). Targets are given for each miRNA, with no claim to completeness. Pubmed IDs (PMIDs) are given as references when no DOI numbers are available.
Table A1. MiRNAs that are known tumor suppressors (TS). Selected miRNAs are also involved in cardioprotection (CP). Targets are given for each miRNA, with no claim to completeness. Pubmed IDs (PMIDs) are given as references when no DOI numbers are available.
[dCT ± SD]
[dCT ± SD]
Fold Differencep-ValueConfirmed Target GeneGLOBE IDCell/Tissue/Cancer TypeMiRNA ClusterBiological EffectReference
TSmiR-127-3p4.05 ± 0.244.98 ± 0.72–1.90.03BCL6fibroblastsproliferation inhibition in senescent fibroblastsdoi:10.1371/journal.pone.0080266
KMT5achondrocytesproliferation inhibition in osteoarthritisdoi:10.1016/j.bbrc.2018.06.104
MMP13chondrocytesenhances proliferation of chondrocytes in osteoarthritisdoi:10.1111/jcmm.14400
ITGA6osteosarcomatumor suppressor (cell growth, invasion)doi:10.1002/iub.1710
KIF3Bsquamous cell carcinomatumor suppressor (cell growth)doi:10.26355/eurrev_201901_16877
KIF3Bpancreatic beta cellsproliferation inhibition, diabetesdoi:10.18632/aging.101835
TS, CPmiR-30c-5p4.01 ± 0.54.84 ± 0.38–1.70.04PAI1breast cancersuppression of vasculogenesisdoi:10.1172/JCI123106
CTGFcardiac fibroblastsmiR-133cardioprotection (anti-fibrotic)doi:10.1161/CIRCRESAHA.108.182535
TGFB1, TGFBR2cardiac fibroblastssuppression of fibrosisdoi:10.1111/jcmm.13548
CTGFfibroblastssuppression of cardiac and renal fibrosisdoi:10.1016/j.jdiacomp.2015.12.011
ADAM19colorectal carcinomatumor suppressor (cell proliferation)doi:10.1371/journal.pone.0120698
SNAI1squamous cell carcinomatumor suppressor (cell proliferation)doi:10.1016/j.biopha.2017.12.095
BCL9prostate cancertumor suppressor (Wnt signaling suppression, cell proliferation)doi:10.3892/ol.2016.4161
TSmiR-99b-5p4.45 ± 0.465.45 ± 0.18–2.010.02mTOR, AKT, IGF1hepatocytespromotes hepatitis B virus replicationdoi:10.1111/cmi.12709
mTOR, AKT, IGF1gastric cancertumor suppressor (cell autophagy)doi:10.3892/ol.2018.9269
IGF1keratinocytescell proliferationdoi:10.1016/j.biopha.2015.07.013
PI2K, AKT7, mTORcervical cancertumor suppressor (cell proliferation)doi:10.1002/jcp.27645
TSmiR-376a-3p3.76 ± 0.475.05 ± 0.51–2.450.01c-MYCnon-small cell lung carcinomatumor suppressor (cell proliferation, invasion)doi:10.1002/cbin.10828
COA1, PDIA6giant cell tumormiR-127-3ptumor suppressor (cell proliferation, invasion)doi:10.1016/j.canlet.2017.08.029
NRP1breast cancertumor suppressor (tumor progression)doi:10.2147/OTT.S173416
COA1, GLE1, PDIA6giant cell tumormiR-127-3ptumor suppressor (tumor progression)doi:10.3390/cancers11122019
TSmir-376c-3p3.98 ± 0.354.85 ± 0.57–1.810.03HOXB7squamous cell carcinomatumor suppressor (cell proliferation)doi:10.1016/j.biopha.2017.04.050
BCL2, SYF2gastric cancertumor suppressor (cell proliferation)doi:10.1155/2016/9604257
CKD1neuroblastoma cellstumor suppressor (cell proliferation)doi:10.3892/ol.2018.9431
HB-EGFmedullary thyroid carcinomatumor suppressor (cell proliferation)doi:10.5114/aoms.2019.85244
TSlet-7b-5p3.03 ± 0.81.98 ± 0.362.070.04FASmacrophagesinhibits clearance of mycobacterium tuberculosisdoi:10.1093/femsle/fny040
KIAA1377squamous cell carcinomatumor suppressor (cell proliferation, invasion)doi:10.1002/cbin.11136
IGF1Rmultiple melanomatumor suppressor (cell proliferation, enhances apoptosis)doi:10.1093/abbs/gmu089
CDC25B, CDK1hepatocellular carcinomatumor suppressor (cell proliferation, metastasis)doi:10.1002/jcb.29477
TSmiR-193b-3p3.16 ± 0.452.21 ± 0.161.930.003MORC4breast cancertumor suppressor (cell proliferation, enhances apoptosis)doi:10.1002/jcb.27751
p21-AK2ovarian carcinomatumor suppressor (cell autophagy)doi:10.1016/j.biopha.2017.11.086
HDAC3brainsuppression of NFkB signaling, reduction of inflammation in brain injurydoi:10.1186/s12974-020-01745-0
CKD1, AJUBA, HEG1lung cancertumor suppressor (cell proliferation, metastasis)doi:10.1042/BSR20190634
TGFB1liverdecreases fibrosisdoi:10.1111/jcmm.14210
TSmir-143-3p3.28 ± 0.493.48 ± 0.51–1.150.6LIMK1breast cancertumor suppressor (tumor progression)PMID: 28559978
FOSL2osteosarcomatumor suppressor (cell proliferation, invasion, metastasis)doi:10.1038/s41598-017-18739-3
BMPR2bone marrow-derived MSCspromotes cartilage differentiationdoi:10.26355/eurrev_201812_16649
IGF1R, IGFBP5synovial cellspromotes inflammation and increases apoptosis in RAdoi:10.3892/etm.2018.5907
BCL2, IGF1Rsquamous cell carcinomatumor suppressor (tumor progression)doi:10.1016/j.bbrc.2019.08.075
TS, CPmiR-199a-3p1.92 ± 0.961.1 ± 0.451.820.16ITGB8ovarian carcinomatumor suppressor (chemoresistance)doi:10.3892/or.2018.6259
GRP78non-small cell lung carcinomamiR-495
(low detection)
tumor suppressor (tumor progression)doi:10.1016/j.gene.2017.03.032
DDIT4, ING4cardiomyocytesmiR-214cardioprotective (inhibit cardiomyocyte apoptosis during injury)doi:10.1152/ajpheart.00807.2015
mTORkidneyinduces injury induced apoptosisdoi:10.1002/jcb.29030
AXLosteosarcomatumor suppressor (tumor progression)PMID: 25520864
mTORendometrial endometrioid adenocarcinomatumor suppressor (cell autophagy)PMID: 31966798
KLkidneyactivation of NFkB signaling in lupus nephritisdoi:10.1016/j.molimm.2018.10.003
SMAD1prostate cancertumor suppressor (cell proliferation, invasion)doi:10.18632/oncotarget.17191
mTORhepatocellular carcinomatumor suppressor (chemosensitivity)doi:10.1186/s13046-019-1512-5
AGAP2glioma cellstumor suppressor (tumor progression)doi:10.18632/aging.102092
PTGISendothelial cellsmiR-199a-5pnitrovasodilatator resistancedoi:10.1161/CIRCULATIONAHA.117.029206
CD44hepatocellular carcinomatumor suppressor (cell proliferation)doi:10.1016/j.bbrc.2010.10.130
SOCS7, STAT3kidneysuppress renal fibrosisdoi:10.1038/srep43409
TS, CPmiR-199a-5p2.63 ± 0.922.35 ± 0.651.220.68831AA1Bmonocytesinhibits differentiationdoi:10.1189/jlb.1A0514-240R
MAP3K11non-small cell lung carcinomatumor suppressor (tumor progression)doi:10.7150/jca.29426
SNAI1papillary thyroid carcinomatumor suppressor (tumor progression)doi:10.1016/j.bbrc.2018.02.051
HIF1Ahemangioma cellstumor suppressor (cell proliferation, autophagy)doi:10.1177/0394632017749357
CCR7bladder cancertumor suppressor (metastasis)doi:10.1186/s12894-016-0181-3
ETS1breast cancertumor suppressor (cell invasion)doi:10.1111/cas.12952
CLTChepatocellular carcinomatumor suppressor (tumorigenesis)doi:10.1002/cbf.3252
PIAS3cervical cancertumor suppressor (metastasis, suppresses epithelial–mesenchymal transition)doi:10.1002/jcb.28631
ROCK1colorectal carcinomatumor suppressor (cell proliferation, metastasis)doi:10.1177/1533034618775509
ECE1spinal cord nervesinhibition of ischemia-reperfusion injurydoi:10.1007/s10571-018-0597-2
TET2osteoblastspromote differentiationdoi:10.1016/j.gene.2019.144193
DDR1brainprotect against ischemia-reperfusion injurydoi:10.1016/j.wneu.2019.07.203
DRAM1acute myeloid leukemiatumor suppressor (chemosensitivity)doi:10.1155/2019/5613417
CDH1squamous cell carcinomatumor suppressor (cell invasion)doi:10.3892/ol.2016.4602
MAP4K3hepatocellular carcinomalet-7ctumor suppressor (invasion, metastasis)doi:10.18632/oncotarget.14623
ATF6, GRP78cardiomyocytesdownregulation in myocardial hypoxic preconditioningdoi:10.1007/s13105-018-0657-6
MAP3K11esophageal cancertumor suppressor (cell proliferation)doi:10.18632/oncotarget.6752
ZEB1ovarian ectopic endometrial stromal cellinhibition of epithelial–mesenchymal transitiondoi:10.1007/s43032-019-00016-5
HIF1A, OSGIN2sarcomatumor suppressor (tumor progression)doi:10.3892/ol.2016.5320
PHLPP1colorectal carcinomatumor suppressor (chemosensitivity)doi:10.1517/14728222.2015.1057569
BIPkidneyprotect against ischemia-reperfusion injurydoi:10.1096/fj.201801821R
WNT2urothelial cellsinhibiting smooth muscle cell proliferationdoi:10.1074/jbc.M114.618694
MAGT1gliomal cellstumor suppressor (tumor progression)doi:10.1002/jcb.28791
CD44, SIRT1squamous cell carcinomatumor suppressor (repress stemness)doi:10.1080/15384101.2019.1689482
KLgastric canceroncomiR (promotes tumor progression)doi:10.1186/1471-2407-14-218
Mrz 08gliomal cellstumor suppressor (tumor progression)doi:10.26355/eurrev_201909_18858
JunBcardiomyocytespromotes apoptosis in the failing heart)doi:10.1038/s41598-018-24932-9
CAV1lungpromotes lung fibrosisdoi:10.1371/journal.pgen.1003291
NFKBovarian carcinomatumor suppressor (cell proliferation, invasion)doi:10.3892/ol.2018.9170
SIRT1, ENOSendothelial cellspromotes migration and tube formationdoi:10.1007/s00705-013-1744-1
HIF1Aprostate adeno-carcinomatumor suppressor (tumor progression)doi:10.18632/oncotarget.18315
TS, CPmiR-99a-5p4.11 ± 0.874.32 ± 0.33–1.150.49mTORurothelial carcinomatumor suppressor (cell autophagy)doi:10.2147/OTT.S114276
HOXA1smooth muscle cellscardioprotective (inhibits smooth muscle cell proliferation and atherosclerosis)doi:10.1016/j.lfs.2019.116664
mTORbladder cancertumor suppressor (cell proliferation)doi:10.1002/jcb.27318
NOX4oral cancertumor suppressor (cell proliferation, invasion, metastasis)doi:10.4149/neo_2017_503
CDC25Abreast cancertumor suppressor (tumor progression)doi:10.3390/genes11040369
TSmiR-16-5p1.76 ± 0.431.81 ± 0.33–1.030.84AKT3breast cancertumor suppressor (tumor progression)doi:10.1042/BSR20191611
SMAD3chordomatumor suppressor (cell proliferation, invasion, metastasis)doi:10.1038/s41419-018-0738-z
PIK3R1fibroblastsinhibits proliferationdoi:10.3390/ijms20051036
ANXA11hepatocellular carcinomatumor suppressor (cell proliferation, metastasis)doi:10.1186/s13046-019-1188-x
MYCNneuroblastoma cellsmiR-15a-5p,
tumor suppressor (tumor progression)doi:10.1002/1878-0261.12588
IGA2colorectal carcinomatumor suppressor (cell proliferation, invasion, metastasis)doi:10.1002/jcp.28747
SESN1myoblastsmyoblast differentiation and proliferationdoi:10.1038/s41419-018-0403-6
BACH2gingival epithelial cellsmiR-145-5pinduce apoptosisPMID: 32509061
SMAD3chondrocytespromotes osteoarthritisdoi:10.2174/1381612821666150909094712
CARMcervical cancertumor suppressor (promotes radiosensitivty)doi:10.1111/pin.12867
VEGFAMSCssuppresses osteogenic potential of MSCsdoi:10.18632/aging.103223
VEGFAbreast cancertumor suppressor (cell proliferation, invasion, autophagy)doi:10.18632/oncotarget.20398
VEGFAcolorectal carcinomatumor suppressor (cell proliferation, invasion, autophagy)doi:10.1016/j.omtn.2020.03.006
EPT1preadipocytespromotes differentiationdoi:10.1016/j.bbrc.2019.04.179
TS, CPmiR-22-3p2.52 ± 0.71.83 ± 0.311.620.09HMGB1arterial smooth muscle cellsinhibits atherosclerosisdoi:10.1159/000480212
MAPK14brainprevents Alzheimer’s diseasedoi:10.2174/1567202616666191111124516
WRNIP1small cell lung cancertumor suppressor (radiosensitivity)doi:10.1002/jcb.29032
AE1retinoblastomatumor suppressor (cell proliferation)doi:10.1016/j.biopha.2018.06.038
EIF4EBP3cervical canceroncomiR (tumuorogenesisdoi:10.7150/ijms.21645
PTENkidneysuppresses sepsis-induced kidney injurydoi:10.1042/BSR20200527
AKT3Wilm’s tumortumor suppressor (cell growth)doi:10.26355/eurrev_202006_21493
SP1hepatocellular carcinomatumor suppressor (cell proliferation, invasion, metastasis)PMID: 27904693
SIRT1peridontal stem cellsincreases proliferation and differentiationdoi:10.1002/cbin.11271
PTAFRcardiac fibroblastscardioprotective (reduces activation of cardiac fibroblasts)doi:10.26355/eurrev_202004_20869
YAP1non-small cell lung carcinomatumor suppressor (tumor progression)doi:10.1111/1759-7714.13280
DDIT4glioblastomatumor suppressor (cell proliferation)doi:10.1016/j.neulet.2020.134896
SIRT1ectopic endometrial cellsenhances proliferation and invasiondoi:10.26355/eurrev_202001_20033
FTOMSCspromotes osteogenic differentiationdoi:10.1186/s13287-020-01707-6
NFIBgastric cancertumor suppressor (tumor progression)doi:10.4149/neo_2020_190418N350
TSmiR-152-3p4.42 ± 0.665.16 ± 0.62–1.90.09SOS1glioblastomatumor suppressor (chemosensitivity)doi:10.2147/OTT.S210732
p27chronic myeloid leukemiaoncomiR (tumorigenesis)doi:10.26355/eurrev_201812_16646
KLF4prostate cancertumor suppressor (tumor progression)doi:10.1002/jcb.28984
FOXF1fibroblastspromotes cell proliferation, invasion and extracellular matrix productiondoi:10.1016/j.lfs.2019.116779
CDK8hepatocellular carcinomatumor suppressor (cell proliferation)doi:10.1016/j.prp.2019.03.034
TMEM97prostate cancertumor suppressor (tumor progression)doi:10.1186/s13148-018-0475-2
SPIN1breast cancermiR-148tumor suppressor (chemosensitivity)doi:10.1186/s13046-018-0748-9
PIK3CAbreast cancertumor suppressor (tumor progression)doi:10.3727/096504017x14878536973557
TS, CPmiR-145-5p1.55 ± 0.651.90 ± 0.37–1.280.3FLT1trophoblastpromote cell proliferation, invasiondoi:10.1016/j.lfs.2019.117008
KLF4lungpromotes chronic obstructive pulmonary diseasedoi:10.1016/j.cbi.2019.01.011
CD40cardiomyocytescardioprotection (in ischemia-reperfusion injury)doi:10.1007/s11010-017-2982-4
KLF5gastric cancertumor suppressor (tumor progression)doi:10.1002/jcp.27525
TAGLN2bladder cancertumor suppressor (cell proliferation, invasion, metastasis)doi:10.3892/ol.2018.9436
SOX2breast cancertumor suppressor (tumor progression)doi:10.1016/j.jss.2018.11.030
RHBDD1colorectal carcinomatumor suppressor (cell proliferation, invasion, metastasis)doi:10.1016/j.biocel.2019.105641
FSCN1squamous cell carcinomatumor suppressor (tumor progression)doi:10.1016/j.ymthe.2018.09.018
TPT1prolactinomatumor suppressor (chemosensitivity)doi:10.1007/s40618-018-0963-4
TGFB1vascular smooth muscle cellsinhibits proliferationdoi:10.12659/MSM.910986
TLR4melanomatumor suppressor (cell autophagy)doi:10.1002/jcb.28388
SEMA3AAT-MSCssuppresses osteogenic potential of MSCsdoi:10.1007/s11626-019-00318-7
AKAP12prostate cancertumor suppressor (chemosensitivity)doi:10.1111/jcmm.13604
SMAD2/3hepatocellular carcinomareduces extracellular matrix productiondoi:10.1016/j.bbrc.2019.11.040
MTDHsquamous cell carcinomatumor suppressor (tumor progression)doi:10.1177/1533033819850189
NRASmelanomatumor suppressor (cell proliferation, invasion, metastasis)doi:10.1002/cam4.1030
MTDHnon-small cell lung carcinomatumor suppressor (tumor progression)doi:10.1096/fj.201701237RR
TSmiR-193a-5p4.52 ± 0.674.35 ± suppressor (cell proliferation, apoptosis)doi:10.3892/ijmm.2020.4671
COL1A1colorectal carcinomatumor suppressor (inhibits epithelial–mesenchymal transition)doi:10.2147/OTT.S255485
COL1A1colorectal carcinomatumor suppressor (inhibits epithelial–mesenchymal transition)doi:10.3389/fonc.2020.00850
HOXA1breast cancertumor suppressor (tumor progression)doi:10.18632/aging.103123
HOXA7ovarian carcinomatumor suppressor (cell proliferation, apoptosis)doi:10.4149/neo_2020_190730N687
CCNE1esophageal cancertumor suppressor (tumor progression)doi:10.1007/s13402-019-00493-5
ERBB2colorectal carcinomatumor suppressor (tumor progression)doi:10.2147/CMAR.S234620
SRSF6pancreatic canceroncomiR (metastasis)PMID: 32064152
DPEP1hepatoblastomatumor suppressor (tumor progression)doi:10.1038/s41419-019-1943-0
TS, CPmiR-20a-5p4.83 ± 0.274.72 ± 0.931.080.58ABCA1artery smooth muscle cellspromotes cell proliferation and migrationdoi:10.1002/jbt.22589
PTENendothelial cellspro-angiogenic, inhibits autophagy and apoptosisdoi:10.1038/s41419-020-02745-x
ERBB2hepatocellular carcinomamiR-17-5ptumor suppressor (metastasis)doi:10.7150/thno.41365
STAT3endometrial carcinomatumor suppressor (inhibits epithelial–mesenchymal transition, invasion)PMID: 31949657
STAT3bronchial epithelial cellssuppresses apoptosisdoi:10.1016/j.mcp.2019.101499
SRCIN1osteoclastspromote proliferation and differentiationdoi:10.1002/cam4.2454
TGFB1endothelial cellsanti-angiogenicdoi:10.1002/jcp.29111
TS, CPmiR-29c-3p3.27 ± 0.922.48 ± 0.991.730.28STAT3cardiac fibroblastscardioprotection (inhibits cell proliferation)doi:10.23736/S0031-0808.20.03975-0
TNFAIP1neuroblastoma cellsoncomiR (inhibits apoptosis)doi:10.1007/s11064-020-03096-x
FOSlens epithelial cellsinhibits epithelial–mesenchymal transitiondoi:10.1016/j.biopha.2020.110290
VEGFAcolorectal carcinomatumor suppressor (inhibit angiogenesis)doi:10.1186/s13046-020-01594-y
TFAP2CT-cell acute lymphoblastic leukemiamiR-29b-3ptumor suppressor (cell proliferation)doi:10.1016/j.bbrc.2020.03.170. Epub 2020
NFATbraininhibit inflammation in Parkinson’s diseasedoi:10.1111/gtc.12764
CCNA2esophageal cancertumor suppressor (cell proliferation, migration, and invasion)doi:10.3389/fbioe.2020.00075
TRIM31hepatocellular carcinomatumor suppressor (tumor progression)doi:10.3892/or.2020.7469
FOXP1ovarian carcinomatumor suppressor (chemosensitivity)doi:10.1080/15384101.2019
TS, CPmiR-30d-5p4.70 ± 0.445.43 ± 0.631.660.09SIRT1cardiomyocytescardioprotection (inhibits hypoxia induced apoptosis)PMID: 32098921
SMAD2ovarian granulosa cellspromotes apoptosisdoi:10.3892/etm.2019.8184
NT5Eprostate cancertumor suppressor (cell proliferation, migration)doi:10.1089/cbr.2018.2457
RUNX2colon cancertumor suppressor (tumor progression)PMID: 29552759
TSmiR-320a2.51 ± 0.582.64 ± 0.20–1.090.60CXCL9synovial cellssuppress cell proliferationdoi:10.3389/fphys.2020.00441
SIRT4ovariesprevent premature ovarian insufficiencydoi:10.1016/j.omtn.2020.05.013
HIF1Aendometrial carcinomatumor suppressor (anti-angiogenic)doi:10.1016/j.yexcr.2020.112113
SMAD5bone marrow-derived MSCspromote osteogenic differentiationdoi:10.26355/eurrev_202003_20648
ANRILpapillary thyroid carcinomatumor suppressor (tumorigenesis)doi:10.1016/j.prp.2020.152856
LOX1endothelial cellsinhibit apoptosis upon low-density lipoprotein exposuredoi:10.1007/s11010-020-03688-9
CPEB1osteosarcomatumor suppressor (invasion, migration)doi:10.1002/cam4.2919
TXNRD1osteosarcomatumor suppressor (cell proliferation, migration)doi:10.1080/15384047.2019.1702405
FOXM1hepatocellular carcinomatumor suppressor (inhibits epithelial–mesenchymal transition, tumor progression)doi:10.3390/biom10010020
PBX3gastric cancertumor suppressor (tumor progression)doi:10.4251/wjgo.v11.i10.842
PKCGcancertumor suppressor (cell invasion)doi:10.1038/s41419-019-1921-6
MAFBretinapromotes diabetic retinopathydoi:10.18632/aging.101962
MAPKsynovial cellspromote apoptosis, inhibit proliferationdoi:10.26355/eurrev_201903_17228
IGFR1endometrial carcinomatumor suppressor (tumor progression)doi:10.3892/ijmm.2019.4051
TSmiR-361-5p4.82 ± 0.925.33 ± 0.31–1.430.34ITGB1cervical cancertumor suppressor (cell proliferation)doi:10.1007/s43032-019-00008-5
FOXO1chondrocytespromotes apoptosis and inhibits cell proliferationdoi:10.1186/s12920-019-0649-6
SDCBPgastric cancertumor suppressor (tumor progression)doi:10.1097/CAD.0000000000000846
WT1hepatocellular carcinomatumor suppressor (tumorigenesis)doi:10.26355/eurrev_201910_19277
ABCA1vascular smooth muscle cellsinhibits proliferationPMID: 31312370
CLDN8retinoblastomatumor suppressor (cell proliferation, promotes apoptosis)doi:10.1007/s00381-019-04199-9
VEGFAhemangioma cellstumor suppressor (anti-angiogenic)doi:10.1016/j.bbrc.2019.03.084
FOXM1cervical cancertumor suppressor (tumor progression)doi:10.1080/21691401.2019.1577883
FOXM1osteosarcomatumor suppressor (tumorigenesis)doi:10.1002/jcp.28026
SIRT1liverpromotes hepatosteatosisdoi:10.1016/j.metabol.2018.08.007
SND1glioma cellstumor suppressor (invasion, migration)doi:10.2147/OTT.S171539
MMP3, MMP9, VEGFgastric cancertumor suppressor (inhibits epithelial–mesenchymal transition, tumor progression)doi:10.1016/j.gene.2018.06.095
RQCD1breast cancertumor suppressor (invasion, migration)doi:10.17305/bjbms.2018.3399
ROCK1papillary thyroid carcinomatumor suppressor (tumor progression)doi:10.1016/j.biopha.2018.03.122
RPL22L1ovarian carcinomatumor suppressor (tumorigenesis)PMID: 31938372
FOXM1gastric cancertumor suppressor (chemoresistance)doi:10.18632/oncotarget.23513
FGFR1, MMP1breast cancertumor suppressor (cell proliferation, metastasis, metabolism)doi:10.1186/s13046-017-0630-1
FOXM1lung cancertumor suppressor (tumor progression)doi:10.4149/neo_2017_406
TWIST1glioma cellstumor suppressor (inhibits epithelial–mesenchymal transition)doi:10.3892/or.2017.5406
TSmiR-708-5p5.32 ± 0.625.41 ± 0.72–1.060.94PGE2lung cancertumor suppressor (tumorigenesis)doi:10.18632/oncotarget.27614
CTNNB1colon cancertumor suppressor (tumor progression)doi:10.1016/j.biopha.2020.110292
TLR4macrophagesimmunomodulation of controlling inflammatory factorsdoi:10.26355/eurrev_201909_19019
ZEB1osteosarcomatumor suppressor (cell proliferation, invasion)doi:10.3892/mmr.2019.10013
URGCPpancreatic ductal adenocarcinomatumor suppressor (tumor progression)doi:10.1016/j.prp.2019.01.026
TSlet-7c-5p3.67 ± 1.013.94 ± 0.38–1.210.43TGFBR1kidneychronic kidney diseasedoi:10.1155/2020/6960941
PBX3squamous cell carcinomatumor suppressor (tumor progression)doi:10.1186/s12943-020-01215-4
CMYChepatocellular carcinomatumor suppressor (cell proliferation)doi:10.1016/j.bbrc.2019.09.091
HMGA2dental pulp stem cellspromotes osteogenic differentiationdoi:10.1111/1440-1681.13059
DMP1MNFdental pulp stem cellsinhibits inflammationdoi:10.12659/MSM.909093
NAP1L1hepatocellular carcinomatumor suppressor (cell proliferation, migration)doi:10.1016/j.canlet.2018.08.024
TSlet-7e-5p4.48 ± 1.395.18 ± 0.15–1.630.28CCR7squamous cell carcinomatumor suppressor (cell proliferation, metastasis)doi:10.7150/jca.29536
FASLGendothelial progenitorsprevents deep vein thrombosisdoi:10.1016/j.thromres.2015.12.020
RCN1nasopharyngeal carcinomatumor suppressor (cell autophagy)doi:10.1152/ajpcell.00352.2019
TSlet-7g-5p4.69 ± 1.154.60 ± 0.521.070.84HMGA2glioblastomatumor suppressor (tumor progression)doi:10.1111/jcmm.14884
IGF1Rnasopharyngeal carcinomatumor suppressor (cell migration, invasion)doi:10.12659/MSM.914555
PRKCAmammary cellsregulates differentiationdoi:10.1002/jcp.27676
VSIG4glioblastomatumor suppressor (inhibits epithelial–mesenchymal transition)doi:10.3892/or.2016.5098
TS, CPlet-7i-5p1.14 ± 0.891.39 ± 0.93–1.190.72GALEglioblastomatumor suppressor (cell proliferation, metastasis)doi:10.2147/CMAR.S221585
HMGA1bladder cancertumor suppressor (cell proliferation, metastasis)doi:10.1186/s12894-019-0485-1
CCND2, E2F2cardiomyocytescardioprotection (promotes proliferation after injury)doi:10.1042/CS20181002
KLK6colon cancertumor suppressor (cell proliferation, metastasis)doi:10.3892/or.2018.6577
Table A2. MiRNAs that are known oncomiRs (O). Selected miRNAs are also involved in cardioprotection (CP). Targets are given for each miRNA, with no claim to completeness. Pubmed IDs (PMIDs) are given as references when no doi numbers are available.
Table A2. MiRNAs that are known oncomiRs (O). Selected miRNAs are also involved in cardioprotection (CP). Targets are given for each miRNA, with no claim to completeness. Pubmed IDs (PMIDs) are given as references when no doi numbers are available.
MiRNA FunctionMiRNA NameCB-MSC-EV [dCT ± SD]AT-MSC-EV [dCT ± SD]Fold Differencep-ValueConfirmed Target GeneGLOBE IDCell/Tissue/Cancer TypeMiRNA ClusterBiological EffectReference
O, CPmiR-100-5p1.11 ± 0.672.05 ± 0.28–1.90.05ANGPT2hepatocellular carcinomasuppression of angiogenesisdoi:10.1002/path.4804
p53pancreatic ductal adenocarcinomaoncomiR (promotes cell growth)doi:10.1038/s41467-018-03962-x
mTORendometrial carcinomamiR-199a-3p, miR-199b-5ptumor suppressor (cell autophagy)PMID: 31966798
mTORbreast cancertumor suppressor (anti-angiogenic)doi:10.1007/s13402-017-0335-7
mTORosteosarcomatumor suppressor (cell autophagy)doi:10.26355/eurrev_201809_15913
mTORvascular smooth muscle cellssuppression of angiogenesisdoi:10.1161/CIRCULATIONAHA.110.000323
OmiR-151a-5p4.0 ± 0.385.09 ± 0.2–2.140.007CDH1non-small cell lung carcinomaoncomiR (promotes epithelial–mesenchymal transition, proliferation, invasion)doi:10.1038/oncsis.2017.66
p53nasopharyngeal carcinomaoncomiR (promotes cell proliferation, invasion)doi:10.1042/BSR20191357
OmiR-103a-3p2.49 ± 0.644.24 ± 0.18–3.350.02APC/APC2colorectal carcinomamiR-1872
(not tested)
oncomiR (activator of Wnt signaling, cell proliferation)doi:10.1002/jcb.26357
CDK5bladder cancermiR-107oncomiR (promotes cell proliferation, invasion)doi:10.1038/emm.2015.39
CDK6AT-MSCsinhibit proliferationdoi:10.1038/srep30919
GPRC5Aprostate canceroncomiR, tumor suppressor (depending on cancer type)doi:10.1261/rna.045757.114
CDH11, NR3C1squamous cell carcinomaoncomiR (promotes cell proliferation)doi:10.26355/eurrev_202006_21505
PTENendothelial progenitor cellspromotes migration and angiogenesisdoi:10.1016/j.avsg.2019.10.048
SNRKglomerular endothelial cellspromotes NFkB/p65 activation, renal inflammation and fibrosisdoi:10.1038/s41467-019-11515-z
OmiR-191-5p3.25 ± 0.424.26 ± 0.42–2.010.02SOX4breast canceroncomiR (promotes cell proliferation)doi:10.1261/rna.060657.117
EGR1, UBE2D3hepatocellular carcinomaoncomiR (promotes cell proliferation)PMID: 31933962
EGR1osteosarcomaoncomiR (activates PI3K/AKT pathway, proliferation, invasion)doi:10.26355/eurrev_201905_17783
ENOS, MMP1, MMP9endothelial cellsantiangiogenicdoi:10.1096/fj.201601263R
OmiR-92a-3p3.05 ± 0.753.12 ± 0.26–1.050.67WNT5Achondrocytesenhance chondrogenesisdoi:10.1186/s13287-018-1004-0
PTENsquamous cell carcinomaoncomiR (promotes cell proliferation, metastasis)doi:10.3892/ijmm.2019.4258
CDH1glioma cellsoncomiR (promotes tumor progression)doi:10.3390/ijms17111799
PTENpancreatic canceroncomiR (promotes cell proliferation, invasion)doi:10.11817/j.issn.1672-7347.2020.180459
O, CPmiR-423-3p4.49 ± 0.124.47 ± (in ischemic postconditioning secreted by cardiac fibroblast-EVs)doi:10.1093/cvr/cvy231
p21CIP1, WAF1colorectal carcinomaoncomiR (promotes cell growth)doi:10.1159/000430230
PANX2glioma cellsoncomiR (promotes tumor progression)PMID: 29928399
ADIPOR2laryngeal canceroncomiR (promotes tumor progression)PMID: 25337209
O, CPmiR-21-5p-0.90 ± 0.52-0.78 ± 0.82–1.090.98FASLGhepatocellular carcinomaoncomiR (chemoresitance)doi:10.1089/dna.2018.4529
CCR7chondrosarcomatumor suppressor (tumor progression)doi:10.1080/03008207.2019.1702650
TIAM1colon cancertumor suppressor (cell proliferation, invasion, metastasis)doi:10.1159/000493457
PDCD4breast canceroncomiR (chemoresitance)doi:10.4149/neo_2018_181207N930
BCL2, TLR4macrophagesregulates mycobacterial survivaldoi:10.1002/1873-3468.13438
SET, TAF-IAlung adenocarcinomaoncomiR (promotes tumor progression)doi:10.1016/j.lfs.2019.06.014
RAB11Aneuronsneuroprotection during traumatic brain injurydoi:10.12659/MSM.915727
PTEN, PDCD4lunganti-apoptotic during ischemia-reperfusion injurydoi:10.1016/j.ejphar.2019.01.022
SOX7non-small cell lung carcinomaoncomiR (chemoresitance)doi:10.2147/OTT.S146423
TGFB1non-small cell lung carcinomaoncomiR (promotes cell proliferation)doi:10.3892/etm.2018.6752
CHL1colon adenocarcinomaoncomiR (promotes cell proliferation, invasion)doi:10.1186/s10020-018-0034-5
PTEN, PDCD4lung canceroncomiR (promotes cell proliferation, metastasis m2 polarization)doi:10.1186/s13046-019-1027-0
SMAD7non-small cell lung carcinomaoncomiR (promotes tumor progression)doi:10.2147/OTT.S172393
PI3Kcardiomyocytescardioprotection (improves contractility)doi:10.1161/CIRCRESAHA.118.312420
SPRY1jointssuppresses angiogenesis and matrix degenerationdoi:10.1186/s13075-020-2145-y
PDCD4squamous cell carcinomaoncomiR (anti-apoptotic)doi:10.3892/etm.2019.7970
MASPINendothelial cellssuppresses angiogenesis and proliferationdoi:10.1080/09168451.2018.1459179
CDKN2CmelanomaoncomiR (promotes cell proliferation)doi:10.1002/2211-5463.12819
CCL1, TIMP3neuronsinhibits neuropathic pain developmentdoi:10.1002/jcb.28920
SMAD7fibroblastspromote fibrosis in tendon injurydoi:10.1016/j.omtn.2018.11.006
FASLGcardiomyocytescardioprotection (in ischemia-reperfusion injury)doi:10.1042/BSR20190597
WWC2lung adenocarcinomaoncomiR (promotes cell proliferation, metastasis)doi:10.3233/CBM-201489
PTEN, mTORbrainprotects against seizure damagedoi:10.1016/j.eplepsyres.2018.05.001
SMAD7fibroblastsactivation of spinal fibrosisdoi:10.7150/ijbs.24074
PDCD4osteosarcomaoncomiR (promotes cell proliferation, metastasis)doi:10.3892/ijo.2017.4127
HMSH2non-small cell lung carcinomaoncomiR (chemoresitance)doi:10.1159/000481839
PTENsmooth muscle cellspromotes proliferation and remodelingdoi:10.3390/ijms20040875
MAPK10breast canceroncomiR (promotes tumor progression)doi:10.1042/BSR20181000
PTENfibroblastsprevents radiation-induced autophagydoi:10.1038/s41374-019-0323-9
CADM1tongue canceroncomiR (chemoresitance)doi:10.1007/s00109-016-1417-0
O, CPmiR-34a-5p3.49 ± 1.452.09 ± 0.842.650.23NOTCH1cardiomyocytescardiotoxicdoi:10.31083/j.rcm.2019.03.545
BCL2endothelial cellshypoxia induced autophagydoi:10.1002/jcb.29207
ZEB1cardiomyocytesaggravates hypoxia induced apoptosisdoi:10.1515/hsz-2018-0195
ACSL1hepatocytesincreases hepatic triglyceride and cholesterol levelsdoi:10.3390/ijms20184420
SIRT1kidneypromotes injury induced fibrosisdoi:10.1038/s41419-018-0527-8
SIRT1kidneypromotes injury induced fibrosisdoi:10.1016/j.bbrc.2017.12.048
DLL1osteosarcomaoncomiR (chemoresitance)doi:10.1038/srep44218
AGTR1osteosarcomaoncomiR (chemoresitance)doi:10.1186/s12885-016-3002-x
CD117osteosarcomaoncomiR (chemoresitance)doi:10.18632/oncotarget.8546
PD-L1ovarian carcinomaoncomiR (chemoresitance)doi:10.4149/neo_2019_190202N106
BCL2ovarian carcinomaoncomiR (promotes cell proliferation)doi:10.2147/OTT.S142446
OmiR-15b-5p4.41 ± 0.464.88 ± 1.04–1.380.69AKT3arteriesinhibits ateriogenesis, angiogenesisdoi:10.1161/ATVBAHA.116.308905
PAQR3gastric canceroncomiR (promotes metastasis)doi:10.3892/or.2017.5673
AXIN2hepatocellular carcinomaoncomiR (promotes cell proliferation, invasion)doi:10.3892/ol.2019.11056
RECKprostate canceroncomiR (tumorigenesis)doi:10.3892/ol.2019.11056
SEMA3Apodocytesrepressing apoptosis and inflammation in high glucose injurydoi:10.1002/jcp.28691
PDK4osteosarcomaoncomiR (promotes cell proliferation)doi:10.1016/j.bbrc.2018.08.035
BMPR1Acardiomyocytespromotes doxorubicin induced injurydoi:10.1007/s12012-018-9495-6
HPSE2breast canceroncomiR (promotes cell proliferation, metastasis)doi:10.3389/fonc.2020.00108
OmiR-17-5p5.57 ± 0.155.34 ± 0.621.100.57BAMBInasopharyngeal carcinomaoncomiR (promotes angiogenesis)doi:10.7150/jca.30757
ETV1breast cancertumor suppressor (cell proliferation)doi:10.1186/s12885-017-3674-x
RBL2, E2F4pancreatic canceroncomiR (promotes cell proliferation)doi:10.1016/j.canlet.2017.09.044
ANKHfibroblastsincreased ostegenesisdoi:10.1016/j.omtn.2019.10.003
BRCC2osteosarcomaoncomiR (promotes cell growth)doi:10.3892/or.2016.4542
NTN4breast canceroncomiR (promotes metastasis, invasion)PMID: 31933983
SKSI1osteosarcomaoncomiR (promotes epithelial–mesenchymal transition)doi:10.1002/jcb.27832
SMAD7fibroblastspromotes liver fibrosisdoi:10.1111/jcmm.14432
TGFB2cervical canceroncomiR (promotes cell proliferation)doi:10.26355/eurrev_201804_14712
E2F1granulosa cellspromotes cell proliferationdoi:10.1111/rda.13551
SMAD5myoblastsmiR-106b-5ppromotes osteogenic differentiationdoi:10.1016/j.yexcr.2016.07.010
MFN2satellite cellsmodulates mitochondrial functionPMID: 31198013
P21nasopharyngeal carcinomaoncomiR (promotes cell proliferation)doi:10.1002/cam4.863
HOXB13prostate canceroncomiR (promotes tumor progression)doi:10.1186/s12935-019-0994-8
P21astrocytesinhibits apoptosis during hypoxiadoi:10.1186/s12935-019-0994-8
CMYChepatocellular carcinomatumor suppressor (cell proliferation, invasion, metastasis)doi:10.1007/s13277-015-4355-5
VEGFAendothelial cellsmitigates endometriosisdoi:10.1007/s12038-020-00049-y
TMOD1gastric canceroncomiR (tumorigenesis)doi:10.26355/eurrev_201907_18430
SMAD7osteoblastspromotes osteogenic differentiationdoi:10.1038/emm.2014.43
RUNX3gastric canceroncomiR (promotes cell proliferation, metastasis)doi:10.1016/j.biopha.2020.110246
SOCS6gastric canceroncomiR (promotes cell proliferation)doi:10.1016/j.febslet.2014.04.036
PTENthyroid canceroncomiR (promotes cell proliferation)doi:10.4149/neo_2019_190110N29
PTEN, GAINT7hepatocellular carcinomaoncomiR (tumorigenesis)doi:10.1242/jcs.122895
PIK3R1squamous cell carcinomatumor suppressor (cell autophagy)doi:10.1007/s10620-012-2400-4
P21/PTENsmooth muscle cellspromotes hypoxia induced proliferationdoi:10.1186/s12931-018-0902-0
SMAD7nasal epithelial cellsaggravates inflammatory responsedoi:10.1186/s12860-018-0152-5
TGFB2gastric canceroncomiR (promotes cell proliferation)doi:10.18632/oncotarget.8946
HBP1breast canceroncomiR (promotes metastasis, invasion)doi:10.1007/s10549-010-0954-4
SMAD7hepatic stellate cellsactivates stellate cellsdoi:10.1038/labinvest.2015.58
O, CPmiR-21-3p5.28 ± 1.273.89 ± wound healingdoi:10.18632/aging.103610
MAT2Bbrainattenuate ischemia-reperfusion injurydoi:10.3325/cmj.2019.60.439
PTENvascular smooth muscle cellspromote migration and proliferation (pro-atherogenic)doi:10.7150/thno.37357
VEGFAgranulosa cellsinhibits autophagydoi:10.1530/REP-19-0285
TGS4retinal pigment epithelial cellsmodulates apoptosis and inflammationdoi:10.1111/1440-1681.13142
AKT, CDK2kidneyregulates metabolic alterations in acute kidney injurydoi:10.1155/2019/2821731
P53multiple cancersoncomiR (inhibit apoptosis)doi:10.1016/
PTENliver canceroncomiR (inhibit apoptosis)doi:10.2147/CMAR.S183328
HDAC1epitheliuminhibits influenca virus replicationdoi:10.3389/fcimb.2018.00175
SORBS2cardiomyocytespromoted myocardial dysfunction in sepsisdoi:10.1016/j.yjmcc.2016.03.014
HDAC1cardiomyocytescardioprotection (suppression of myocardial hypertrophy)doi:10.1093/cvr/cvu254
OmiR-663a4.43 ± 0.381.49 ± 1.067.680.02MYL9osteosarcomaoncomiR (tumorigenesis)doi:10.1177/0960327120937330
TGFB1liverreduces hepatic stellar cell activationdoi:10.1155/2020/3156267
ZBTB7AosteosarcomaoncomiR (inhibits apoptosis)doi:10.1016/j.canlet.2019.01.046
TGFB1hepatocellular carcinomatumor suppressor (cell proliferation, invasion)doi:10.1186/s12885-018-5016-z
NFIXspermatogonial stem cellspromote proliferation and inhibit apoptosisdoi:10.1016/j.omtn.2018.05.015
EMP3gallbladder canceroncomiR (tumor progression)doi:10.1016/j.canlet.2018.05.022
OmiR-664a-3p4.67 ± 1.554.77 ± 0.54–1.070.44FHL1lungProgression of chronic obstructive pulmonary diseasedoi:10.2147/COPD.S224763
FOXP3gastric canceroncomiR (tumorigenesis)doi:10.1111/cpr.12567
Table A3. MiRNAs that are known for their tumor suppressor and oncogenic potential (TS/O). Selected miRNAs are also involved in cardioprotection (CP). Targets are given for each miRNA, with no claim to completeness. Pubmed IDs (PMIDs) are given as references when no doi numbers are available.
Table A3. MiRNAs that are known for their tumor suppressor and oncogenic potential (TS/O). Selected miRNAs are also involved in cardioprotection (CP). Targets are given for each miRNA, with no claim to completeness. Pubmed IDs (PMIDs) are given as references when no doi numbers are available.
MiRNA FunctionMiRNA NameCB-MSC-EV [dCT ± SD]AT-MSC-EV [dCT ± SD]Fold Differencep-ValueConfirmed Targets GeneGLOBE IDCell/Tissue/Cancer TypeMiRNA ClusterBiological EffectReference
TS/OmiR-31-3p4.93 ± 0.565.08 ± 0.49–1.110.64RASA1colorectal carcinomaoncomiR (promotes cell proliferation, tumor progression)doi:10.1074/jbc.M112.367763
SEMA4Ccervical cancertumor suppressor (chemoresistance)doi:10.1038/s41598-019-54177-z
TIAM1colorectal carcinomamiR-21oncomiR (promotes epithelial–mesenchymal transition, invasion)doi:10.1074/jbc.M110.160069
TS/OmiR-199b-5p4.39 ± 1.53.73 ± 0.431.580.53HER2osteosarcomaoncomiR (promotes tumor progression)PMID: 30610808
STON2papillary thyroid carcinomatumor suppressor (metastasis, suppresses epithelial–mesenchymal transition)doi:10.1002/iub.1889
DYRK1A, NOTCH1, JAG1promotes pathological myocardial remodelingdoi:10.1016/j.ncrna.2016.12.002
KLK10cervical canceroncomiR (promotes cell proliferation, metastasis)doi:10.1016/j.bbrc.2018.05.165
mTORendometrial endometrial adenocarcinomamiR-100-5p, miR-199a-3ptumor suppressor (cell autophagy)PMID: 31966798
GSK3Bmonocytesinhibition of NFkB signaling, anti-inflammatorydoi:10.1007/s10753-018-0799-2
JAG1ligamentum flavum cellsinhibition of osteogenic differentiationdoi:10.1111/jcmm.13047
CAV1non-small cell lung carcinomaoncomiR (promotes cell proliferation)doi:10.1038/s41419-019-1740-9
ALK1breast cancertumor suppressor (angiogenesis)doi:10.3389/fgene.2019.01397
DDR1breast cancertumor suppressor (cell proliferation, invasion, metastasis)doi:10.3892/ol.2018.9255
BICC1oral cancermiR-101-3p
(not detected)
tumor suppressor (cell autophagy)doi:10.1016/j.mcp.2020.101567
MLKpancreatic beta cellsincreases cell proliferationdoi:10.2174/2211536605666160607082214
JAG1, DDR1colorectal carcinomatumor suppressor (cell proliferation, invasion)doi:10.1002/path.5238
PODXL, DDR1acute myeloid leukemiatumor suppressor (cell proliferation)doi:10.1002/ajh.23129
HES1medulloblastomatumor suppressor (impairs cancer stem cell function)doi:10.1371/journal.pone.0004998
ITGA3squamous cell carcinomamiR-199a-3p/5ptumor suppressor (cell proliferation)doi:10.1111/cas.13298
TS/OmiR-221-3p1.25 ± 0.670.65 ± 0.251.510.11AXIN2-miR-15b-5poncomiR (promotes cell proliferation, invasion)doi:10.3892/ol.2019.11056
THBS2squamous cell carcinomaoncomiR (promotes angiogenesis)doi:10.1007/s10456-019-09665-1
SDF1cartilageprevent cartilage degradation in osteoarthritisdoi:10.1007/s00109-017-1516-6
VASH1squamous cell carcinomaoncomiR (promotes metastasis)doi:10.1038/s41388-018-0511-x
THBS1trophoblastpromotes invasion and proliferationdoi:10.1016/j.biopha.2018.10.009
JAK3macrophagesregulates M1 to M2 transitiondoi:10.3389/fimmu.2019.03087
ARF4epithelial ovarian cancertumor suppressor (cell proliferation, metastasis)doi:10.1016/j.bbrc.2017.01.002
THBS2squamous cell carcinomaoncomiR (promotes metastasis)doi:10.1038/s41419-017-0077-5
MMP22macrophagesprevent low-density lipoprotein-induced oxidative stressdoi:10.1002/jcb.27917
EIF5A2medulloblastomatumor suppressor (cell proliferation, enhances apoptosis)doi:10.1080/09168451.2018.1553604
PTENgastric canceroncomiR (promotes tumor progression)doi:10.3727/096504016 × 14756282819385
TIMP3retinapromotes microvascular dysfunctiondoi:10.1007/s00424-020-02432-y
PARP1breast cancertumor suppressor (tumor progression)doi:10.18632/oncotarget.21561
RB1pancreatic canceroncomiR (chemoresistance)doi:10.1007/s13277-016-5445-8
JNK1, TGFBR1, ETS-1cardiac fibroblastscardioprotective (inhibits fibroblast activation)doi:10.1161/HYPERTENSIONAHA.117.10094
TS/O, CPmiR-25-3p4.52 ± 0.534.8 ± 0.13–1.210.33BTG2breast cancertumor suppressor (cell proliferation)doi:10.1186/s12943-017-0754-0
PTENretinoblastomaoncomiR (promotes tumor progression)doi:10.1016/j.biopha.2019.109111
FBXW7, DKK3glioma cellsoncomiR (promotes cell proliferation, metastasis)doi:10.3892/etm.2019.7583
BTG2breast canceroncomiR (promotes cell proliferation, metastasis)doi:10.1155/2019/7024675
SEMA4Ccervical cancertumor suppressor (suppresses EMT)doi:10.1111/cas.13104
ADAM10endothelial cellsinhibit NFkB Signaling and reduces inflammationdoi:10.3389/fimmu.2019.02205
EZH2cardiomyocytescardioprotective (inhibit cardiomyocyte apoptosis during injury)doi:10.1080/0886022X.2020.1745236
TS/OmiR-23b-3p0.73 ± 0.691.02 ± 0.26–1.230.307825SIRT1lens epithelial cellsreduces apoptosis in oxidative stressdoi:10.1002/jcb.29270
TGFBR3atrial fibroblastsmiR-27b-3ppromote atrial fibrosis in atrial fibrillationdoi:10.1111/jcmm.14211
CB1Rgastric cancermiR-130a-5p
(not detected)
tumor suppressor (cell proliferation)doi:10.2147/OTT.S181706
ANXA2pancreatic ductal adenocarcinomatumor suppressor (cell proliferation)doi:10.1159/000494468
ETS1hepatocytesdownregulate Apo(a) expressiondoi:10.1002/cbin.10896
PGC1AosteosarcomaoncomiR (promotes cell proliferation)doi:10.1038/s41419-019-1614-1
EBF3squamous cell carcinomaoncomiR (promotes cell proliferation, metastasis)doi:10.1093/abbs/gmy049
ZEB1hepatocellular carcinomatumor suppressor (suppresses epithelial–mesenchymal transition)doi:10.1016/j.gene.2018.05.061
CMETcervical cancertumor suppressor (cell proliferation, invasion, metastasis)doi:10.1038/s41598-020-60143-x
ATG12, HMGB2gastric cancertumor suppressor (chemosensitivity)doi:10.1038/cddis.2015.123
HS6ST2chondrocytesenhances matrix degradation in osteoarthritisdoi:10.1038/s41419-018-0729-0
TGIF1keratinocytesregulation of keratinocyte differentiationdoi:10.1111/exd.13119
PTENrenal canceroncomiR (promotes cell proliferation)doi:10.1371/journal.pone.0050203
TS/O, CPmiR-27b-3p2.97 ± 0.792.77 ± fibroblastsmiR-27b-3ppromote atrial fibrosis in atrial fibrillationdoi:10.1111/jcmm.14211
HOXA10colorectal carcinomaoncomiR (promotes cell invasion, metastasis)doi:10.1042/BSR20191087
CBLB, GRB2breast cancertumor suppressor (cell proliferation, chemoresistance)doi:10.1038/s41419-017-0211-4
WNT3Aatrial fibroblastscardioprotection (reduces atrial fibrosis during atrial fibrillation)doi:10.1155/2019/5703764
MARCH7endometrial carcinomatumor suppressor (cell proliferation, invasion, metastasis)doi:10.1093/abbs/gmz030
SMAD7endothelial cellssuppresses endothelial cell proliferation and migration in Kawasaki diseasedoi:10.1159/000492354
HIPK2chondrocytesinhibits apoptosis in rheumatoid arthritisdoi:10.1080/21691401.2019.1607362
PPARGthyroid canceroncomiR (chemoresistance)doi:10.1111/bcpt.13076
FZD7lung cancertumor suppressor (tumor progression)PMID: 29028088
SP7maxillary sinus membrane stem cellssuppress osteogenic differentiationdoi:10.1097/ID.0000000000000637
LIMK1colorectal carcinomatumor suppressor (cell proliferation, invasion, metastasis)PMID: 31966797
GSPT1gastric cancertumor suppressor (tumor progression)doi:10.1016/j.biopha.2019.109417
YAP1glioma cellstumor suppressor (tumorigenesis)doi:10.1139/bcb-2019-0300
ROR1gastric cancertumor suppressor (cell proliferation)doi:10.1186/s13046-015-0253-3
GSPT1non-small cell lung carcinomatumor suppressor (cell proliferation, invasion, metastasis)doi:10.2147/OTT.S196865
NRF2squamous cell carcinomatumor suppressor (tumor progression)doi:10.1007/s13577-020-00329-7
TRAF3chondrocytesinhibits IL1B-induced injurydoi:10.1016/j.intimp.2019.106052
NR5A2, CREB1breast cancertumor suppressor (chemosensitivity)doi:10.1038/cddis.2016.361
TS/O, CPmiR-24-3p0.43 ± 0.621.48 ± 0.56–2.050.091KEAP1cardiomyocytescardioprotection (in ischemia-reperfusion injury)doi:10.1155/2018/7042105
FGF11T-cellsoncomiR (immune evasion)doi:10.1002/path.4781
SOX7lung canceroncomiR (promotes metastasis, invasion)doi:10.1002/jcb.26553
SOCS6prostate canceroncomiR (promotes metastasis, invasion, proliferation)PMID: 31938287
p27KIP1papillary thyroid carcinomaoncomiR (promotes metastasis, invasion, proliferation)doi:10.26355/eurrev_201907_18327
BIMbreast canceroncomiR (chemoresistance)doi:10.1002/jcb.28568
RIPK1cardiomyocytescardioprotection (in ischemia-reperfusion injury)doi:10.1159/000495161
DEDDbladder canceroncomiR (promotes tumor progression)doi:10.3892/or.2016.5326
PRKCHLacrimal adenoid cystic carcinomatumor suppressor (tumor progression)doi:10.1371/journal.pone.0158433
MTT1hepatocellular carcinomaoncomiR (promotes cell proliferation)doi:10.1002/cbf.3213
SMAD5peridontal stem cellsinhibit osteogenic differentiationdoi:10.1002/jcp.27499
JAB1/CSN5nasopharyngeal carcinomatumor suppressor (radiosensitivity)doi:10.1038/onc.2016.147
ATG4Asmall cell lung cancertumor suppressor (chemosensitivity)doi:10.18632/oncotarget.2787
IGFBP5intervertebrate discsinduces disc degenerationdoi:10.1016/j.lfs.2020.117288
NOTCH1, DLL1endothelial cellsinhibit angiogenesis after myocardial infarctiondoi:10.3390/ijms21051733
LAMB3pancreatic ductal adenocarcinomatumor suppressor (tumor progression)doi:10.3389/fonc.2019.01499
CHD5squamous cell carcinomaoncomiR (promotes cell proliferation, chemoresistance)doi:10.2217/fon-2016-0179
FGF11fibroblastsactivation of fibrosis and proliferation in renal fibrosisdoi:10.1002/jcp.29329
TS/OmiR-23a-3p-0.14 ± 0.540.06 ± 0.95–1.140.99PNRC2renal cell carcinomaoncomiR (promotes tumor progression)doi:10.1016/j.biopha.2018.11.065
KLF3melanomaoncomiR (promotes tumor progression)doi:10.1186/s12935-019-0927-6
FGF2squamous cell carcinomatumor suppressor (cell proliferation)doi:10.1016/j.prp.2018.12.021
CHD17hepatocellular carcinomaoncomiR (promotes cell proliferation)doi:10.1007/s13105-020-00726-4
SMAD3chondrocytespromotes osteoarthritisdoi:10.1016/j.bbrc.2016.06.071
PTENgliomal cellsoncomiR (promotes cell proliferation)doi:10.1002/ar.24410
TS/O, CPmiR-130a-3p4.86 ± 0.835.01 ± 0.74–1.110.75PDE4Dcardiomyocytescardioprotection (improves cardiac cell proliferation after myocardial infarction)doi:10.1002/jcp.26327
SMAD4esophageal canceroncomiR (promotes epithelial–mesenchymal transition)doi:10.1002/cam4.1981
RAB5Bbreast cancertumor suppressor ( invasion, metastasis)doi:10.1016/j.bbrc.2018.05.018
SOX4non-small cell lung carcinomatumor suppressor (chemosensitivity)doi:10.1080/15384047.2017.1385679
SMAD4hepatoma cellstumor suppressor (invasion, metastasis)doi:10.1186/s13046-016-0296-0
SNONkidneyinhibition of renal fibrosisdoi:10.1016/j.yexmp.2019.104358
TGFBR1/2hepatic stellate cellsdecreases hepatic fibrosisdoi:10.1038/cddis.2017.10
BACH2nasopharyngeal carcinomatumor suppressor (cell autophagy)doi:10.1042/BSR20160576
TS/OmiR-15a-5p5.52 ± 2.854.42 ± osteoarthritisdoi:10.5582/bst.2016.01187
VEGFAperitoneal mesothelial cellssuppresses inflammation and fibrosisdoi:10.1002/jcp.27660
WNT3Aendometrial carcinomatumor suppressor (cell growth)PMID: 29164582
CXCL10chronic myeloid leukemiatumor suppressor (cell autophagy), metastasisPMID: 28979704
MYCNneuroblastoma cellsmiR-15b-5p, miR-16-5ptumor suppressor (tumor progression)doi:10.1002/1878-0261.12588
PTHrPchondrocytespromotes osteoarthritisdoi:10.1155/2019/3904923
FASNarteriesalleviates atherosclerosis and vascular inflammationdoi:10.1042/BSR20181852
PHLPP2gastric canceroncomiR (chemoresistance)doi:10.4149/neo_2020_190904N861
TP53INP1cervical canceroncomiR (anti-apoptotic)doi:10.26355/eurrev_201910_19129
BDNFhepatocellular carcinomatumor suppressor (cell proliferation)doi:10.1007/s13277-015-4427-6
TGFB3, VEGFretinal endothelial cellspromote endothelial cell tight junction formationdoi:10.1016/j.visres.2017.07.007
VEGFAendometrial mesenchymal stem cellspromote endometriosisPMID: 27608888
HOXA3thyroid cancertumor suppressor (tumor progression)doi:10.1089/hum.2018.109
TS/O, CPmiR-181a-5p5.5 ± 0.686.54 ± 0.7–1.090.9PBX1ligamentspromotes osteogenesisdoi:10.7150/thno.44309
CBLBesophageal cancertumor suppressor (chemosensitivity)doi:10.2147/CMAR.S251264
E2F7non-small cell lung carcinomaoncomiR (tumor progression)doi:10.2147/CMAR.S240964
SIRT1cardiomyocytespromotes apoptosis in hypoxic injurydoi:10.1080/09168451.2020.1750943
KLF17prostate canceroncomiR (promotes epithelial–mesenchymal transition)PMID: 32195032
PDGFRAendothelial cellsanti-angiogenesisdoi:10.1002/cbf.3472
AKT3gastric adenocarcinomatumor suppressor (cell proliferation, apoptosis)doi:10.1098/rsob.190095
p53cardiomyocytescardioprotection (reduces high glucose induced apoptosis)doi:10.1538/expanim.19-0058
ATG7hepatocellular carcinomaoncomiR (inhibits autophagy)doi:10.1002/jcb.29064
TS/OmiR-106a-5p5.19 ± 0.765.42 ± 1.07–1.170.97HK2squamous cell carcinomatumor suppressor (cell proliferation, invasion, metastasis)doi:10.1007/s11010-020-03840-5
STAT3endothelial cellsallelviates atherosclerosis and vascular inflammationdoi:10.3892/mmr.2020.11147
RBM24prostate canceroncomiR (tumor progression)doi:10.2147/OTT.S246274
TGFBR2colorectal carcinomaoncomiR (chemoresistance)PMID: 31949649
ARHGAP24ovarian carcinomaoncomiR (cell proliferation, invasion)doi:10.1016/j.lfs.2020.117296
TGFBR2palatepromotes cleft palate formationdoi:10.1016/j.yexcr.2019
TS/OmiR-125a-5p2.3 ± 0.542.64 ± 0.22–1.270.27FUT4osteosarcomatumor suppressor (tumor progression)doi:10.3389/fgene.2020.00672
LIN28Bovarian carcinomatumor suppressor (cell proliferation, metastasis)doi:10.3892/mmr.2020.11223
MACC1hepatocellular carcinomamiR-34atumor suppressor (cell proliferation, metastasis)doi:10.4149/neo_2020_191019N1062
FNDC3Bcolorectal carcinomamiR-217oncomiR (cell proliferation, invasion)doi:10.2147/OTT.S226520
HK2lunginhibits glycolysis and improved pulmonary arterial hypertensiondoi:10.18632/aging.103163
TRAF6macrophagespromotes M2 polarizationdoi:10.1007/s10753-020-01231-y
GALNT7cervical cancertumor suppressor (cell proliferation, invasion)doi:10.1186/s12935-020-01209-8
VEGFAtrophoblastsuppresses migration and proliferationdoi:10.1016/j.bbrc.2020.02.137
GAB2breast cancertumor suppressor (cell proliferation, invasion)doi:10.3934/mbe.2019347
SIRT7non-small cell lung carcinomatumor suppressor (radioresistance)doi:10.3233/CBM-190381
TAZovarian carcinomatumor suppressor (inhibits epithelial–mesenchymal transition)doi:10.3233/CBM-190381
TS/O, CPmiR-125b-5p−1.36 ± 0.51−1.21 ± 0.36–1.110.58p53, BAK1cardiomyocytescardioprotection (inhibits apoptosis in ischemia-reperfusion injury)doi:10.7150/thno.28021
p53, BNIP3cardiomyocytescardioprotection (inhibits apoptosis in ischemia-reperfusion injury)doi:10.1161/CIRCRESAHA.118.312758
SMAD7cardiomyocytescardiotoxic (increase hypoxia induced injury signaling)doi:10.3892/ijmm.2018.3496
BAK1, KLF13cardiomyocytescardioprotection (inhibits apoptosis in ischemia-reperfusion injury)doi:10.1016/j.yjmcc.2017.11.003
EIF5A2melanomatumor suppressor (cell proliferation, metastasis)doi:10.1186/s13046-020-01599-7
BTG2lung adenocarcinomaoncomiR (cell proliferation, migration and promotes epithelial–mesenchymal transition)doi:10.26355/eurrev_202004_20841
PAK3prenatal folliclesinhibits steroidogenesisdoi:10.1016/j.metabol.2020.154241
BACE1neuronsattenuate neurotoxicitydoi:10.1016/j.jns.2020.116793
TRIB2squamous cell carcinomatumor suppressor (tumor progression)doi:10.1042/BSR20193172
PDK1cervical cancertumor suppressor (tumorigenesis)doi:10.1155/2020/4351671
NLRC5cardiomyocytescardioprotection (inhibits apoptosis in ischemia-reperfusion injury)doi:10.3892/etm.2019.8309
STAT3embryonic stem cellstumor suppressor (tumorigenesis)doi:10.7150/jca.33696
TRAF6skeletal musclerelieves skeletal muscle atrophydoi:10.21037/atm.2019.08.39
HK2bladder cancertumor suppressor (tumor progression)doi:10.1007/s13577-019-00285-x
(not tested)
inhibit proliferationdoi:10.1016/j.ejphar.2019.172659
TXNRD1hepatocellular carcinomatumor suppressor (cell proliferation, invasion, metastasis)doi:10.1186/s12935-019-0919-6
TRAF6chondrocytesanti-inflammatory in the setting of osteoarthritisdoi:10.1038/s41598-019-42601-3
TS/O, CPmiR-19a-3p3.07 ± 0.623.29 ± 1.04–1.160.99PTENbrainalleviates ischemia-reperfusion injury-induced apoptosisdoi:10.1016/j.neuroscience.2020.04.020
IGFBP3brainalleviates ischemia-reperfusion injurydoi:10.1186/s40659-020-00280-9
FASrectal cancertumor suppressor (induces apoptosis)doi:10.1177/1533033820917978
PIK3IP1hepatocellular carcinomatumor suppressor (cell proliferation)doi:10.7150/jca.37748
FOXF2colorectal carcinomatumor suppressor (inhibits epithelial–mesenchymal transition)doi:10.3748/wjg.v26.i6.627
IGFBP3ovarian carcinomaoncomiR (tumor progression)doi:10.1002/mc.23113
SOCS3synovial cellspromote cell proliferation10.1002/jcb.28442
PTENosteosarcomaoncomiR (chemoresistance)doi:10.3892/ol.2018.9592
PFN1hepatocellular carcinomaoncomiR (tumor progression)doi:10.1016/j.prp.2018.12.012
PTENhepatocellular carcinomaoncomiR (chemoresistance, metastasis)doi:10.1016/j.biopha.2018.06.097
PITX1gastric canceroncomiR (tumor progression)doi:10.1159/000489590
TSC1osteoblastsmediates dexamethasone resistancedoi:10.18632/oncotarget.23326
SMAD2/4prostate cancertumor suppressor (invasion, metastasis)doi:10.3892/or.2017.6096
TGFBR2cardiac fibroblastsmiR-19b-3pcardioprotection: anti-fibroticdoi:10.1038/srep24747
TS/O, CPmiR-19b-3p3.29 ± 0.353.07 ± 0.811.160.47NRP1gastric cancertumor suppressor (tumor progression)doi:10.1186/s12935-020-01257-0
CCDC6cholangiosarcomaoncomiR (promotes proliferation, epithelial–mesenchymal transition)doi:10.1016/
HIF1Aendothelial cellsanti-angiogenic after hypoxiadoi:10.1096/fj.201902434R
BACE1brainmiR-16-5pprevent amyloid beta induced apoptosisdoi:10.1097/WNR.0000000000001379
TNFAIP3endothelial cellspro-inflammatory in the setting of meningitisdoi:10.3390/pathogens8040268
HOXA9non-small cell lung carcinomaoncomiR (promotes proliferation, migration, invasion)doi:10.2147/OTT.S216320
PTENpancreatic canceroncomiR (cell proliferation)doi:10.21037/atm.2019.04.61
GRK6chondrocytesreduces inflammation and matrix degradationdoi:10.1007/s11010-019-03563-2
PTENmuscle cellsosteogenic differentiationdoi:10.1002/cbin.11133
TS/O CPmiR-214-3p2.19 ± 1.041.96 ± 0.591.170.99PTENcardiomyocytescardioprotection: inhibiting autophagy in sepsisdoi:10.1155/2020/1409038
ATMlungreduce radiation induced pulmonary injurydoi:10.1089/ars.2019.7965
CENPMhepatocellular carcinomatumor supressor (tumor progression)doi:10.1093/jb/mvaa073
PLAGL2colorectal carcinomatumor suppressor (cell proliferation)doi:10.18632/aging.103233
LIVINcolorectal carcinomatumor supressor (tumor progression)doi:10.1080/21655979.2020
IL17myocardiumcardioprotective (anti-fibrotic)doi:10.3389/fcell.2020.00243
WNT23vascular smooth muscle cellsinhibits cell proliferationdoi:10.26355/eurrev_202003_20696
ABCB1, XIAPretinoblastomaoncomiR (chemoresistance)doi:10.2147/OTT.S235862
PSMD10papillary thyroid carcinomatumor suppressor (tumor progression)doi:10.1002/jcp.29557
TWIST1endometrial carcinomatumor suppressor (inhibit epithelial–mesenchymal transition)doi:10.2147/OTT.S181037
LHX6ovarian carcinomaoncomiR (tumorigenesis)doi:10.3390/cancers11121917
ST6GAL1breast canceroncomiR (cell proliferation, inhibit apoptosis)doi:10.1007/s10616-019-00352-z
FOXP3breast canceroncomiR (cell proliferation)doi:10.26355/eurrev_201910_19156
HDGFpancreatic cancertumor suppressor (chemosensitivity)doi:10.2147/OTT.S222703
BIRC5breast cancertumor suppressor (cell proliferation)doi:10.26355/eurrev_201909_18856
NLRC5myocardiumcardioprotection: anti-fibroticdoi:10.1042/CS20190203
CTNNB1preadipocytespromote differentiationdoi:10.3390/ijms20081816
TS/OmiR-222-3p2.34 ± 1.601.61 ± 0.571.660.50PUMAnon-small cell lung carcinomaoncomiR (cell proliferation, inhibit apoptosis)doi:10.1177/1533033820922558
PDCD10ovarian carcinomatumor suppressor (inhibit epithelial–mesenchymal transition)doi:10.7150/thno.43198
GILZairway epithelial cellsameliorates glucocorticoid induced inhibition of cell repairdoi:10.1080/10799893.2020.1742739
IGF1bone marrow-derived MSCspromote osteogenic differentiationdoi:10.1016/j.diabres.2020.108121
TMP2renal clear cell carcinomaoncomiR (tumor progression)doi:10.3233/CBM-190264
IRF2, INPP4Bacute myeloid leukemiatumor suppressor (cell proliferation)doi:10.1016/j.mcp.2020.101513
CDKN1Bsquamous cell carcinomaoncomiR (tumorigenesis)doi:10.1111/jop.12986
PPP2R2Alarge B-cell lymphomaoncomiR (cell proliferation, inhibit apoptosis)doi:10.1177/1533033819892256
GAS5, PTENcolorectal carcinomaoncomiR (promotes cell proliferation, migration, invasion)doi:10.1016/j.omtn.2019.06.009
PDE3Aendothelial cellsmiR-27a-3ppromote vascular integritydoi:10.1007/s12035-018-1446-5
TIMP3osteosarcomaoncomiR (promote metastasis and invasion)doi:10.2147/OTT.S175745
PTENpapillary thyroid carcinomaoncomiR (inhibit apoptosis)doi:10.18632/oncotarget.23336
TS/O, CPmiR-26a-5p3.75 ± 0.544.06 ± 0.72–1.240.53RANBP9braininhibit injury induced apoptosisdoi:10.1016/j.acthis.2020.151571
TLR4kidneyprotect against diabetic nephropathydoi:10.1074/jbc.RA120.012522
HMGA2hepatocellular carcinomatumor suppressor (cell proliferation, promote apoptosis)doi:10.2147/CMAR.S237752
CTGFmacrophagesmodulates TLR signaling upon activationdoi:10.1042/BSR20192598
CREB1renal cell carcinomamiR-27a-3p, miR-221-3ptumor suppressor (cell proliferation, promote apoptosis)doi:10.1038/s41598-020-63403-y
DYRK1Abraininhibit development Alzheimer’s diseasedoi:10.2174/1567202617666200414142637
WNT5Agastric cancertumor suppressor (cell proliferation)doi:10.2147/OTT.S241199
ADAM17cardiomyocytescardioprotection (inhibit apoptosis)doi:10.1007/s10863-020-09829-5
COL10A1gastric cancertumor suppressor (cell proliferation, migration, and invasion)doi:10.26355/eurrev_202002_20170
HOXA5osteosarcomaoncomiR (promotes cell proliferation, migration)doi:10.2147/OTT.S232100
PTENmyocardiumcardioprotection (inhibits apoptosis in ischemia-reperfusion injury)doi:10.1590/1414-431 × 20199106
PTGS2jointsalleviate osteoarthritisdoi:10.1016/j.intimp.2019.105946
AURKAhepatocellular carcinomatumor suppressor (chemosensitivity)doi:10.1177/1533033819851833
WNT5Apapillary thyroid carcinomatumor suppressor (cell proliferation, migration, and invasion)doi:10.2147/OTT.S205994
PTENmyocardiumcardioprotection (inhibits apoptosis in ischemia-reperfusion injury)doi:10.26355/eurrev_201908_18661
PTENsynovial cellspromote cell proliferation and inhibit apoptosisdoi:10.1042/BSR20182192
TS/O, CPmiR-27a-3p1.87 ± 0.981.80 ± 0.881.050.96SLIT2endothelial cellspromotes apoptosis, autophagy during inflammationdoi:10.1016/j.jss.2020.05.102
SP7preosteoblastspromotes differentiationdoi:10.3892/mmr.2020.11246
TAB3kidneypromotes apoptosis during kidney injurydoi:10.1080/09168451.2020.1792760
PDL1macrophagesoncomiR (promotes immune evasion of breast cancer)doi:10.1111/jcmm.15367
BNIP3pancreatic canceroncomiR (inhibits apoptosis)doi:10.3892/ijmm.2020.4632
SMURF2lunganti-fibrotic after bleomycin exposurePMID: 32538751
TGFBR1cardiomyocytescardioprotection (inhibits apoptosis in ischemia-reperfusion injury)doi:10.1155/2020/2016259
FBXW7cervical canceroncomiR (tumor progression)doi:10.2147/CMAR.S234897
ICOSlung adenocarcinomatumor suppressor (promotes antitumor immunity)doi:10.1111/1759-7714.13411
NOVAgastric canceroncomiR (promotes epithelial–mesenchymal transition)doi:10.3892/mmr.2020.10949
BNIP3cardiomyocytescardioprotection (inhibits apoptosis in ischemia-reperfusion injury)doi:10.1016/j.omtn.2019.11.017
TS/O, CPmiR-29a-3p2.50 ± 0.871.64 ± 0.661.820.19E2F1ovarian carcinomaoncomiR (promotes epithelial–mesenchymal transition)doi:10.18632/aging.103388
PTENaortapromotes development of aortic aneurysmsdoi:10.1002/jcp.29746
DRP1myocardiumcardioprotection (prevent myocardial hypertrophy)doi:10.2174/0929866527666200416144459
COL4A2hepatocellular carcinomatumor suppressor (cell proliferation, migration, and invasion)doi:10.1039/c9mt00266a
COL5A1breast cancertumor suppressor (cell proliferation, migration)doi:10.1016/j.lfs.2019.117179
TNFR1endothelial cellsreduces TNF-alpha injury responsedoi:10.1016/j.omtn.2019.10.014
TS/O, CPmiR-30b-5p5.04 ± 1.104.56 ± 0.621.400.62KIF18Aprostate canceroncomiR (radioresistance)doi:10.1089/cbr.2019.3538.
MYBL2medulloblastomatumor suppressor (cell proliferation, promotes apoptosis)doi:10.1136/jim-2020-001354
CAMK2Ddermal papilla cellsinhibits proliferationdoi:10.1186/s12864-020-06799-1
ASPP2breast canceroncomiR (cell proliferation, migration, and invasion)doi:10.1155/2020/7907269
PTAFRmyocardiumcardioprotection: anti-fibroticdoi:10.26355/eurrev_202004_20869
PPARGC1AHuh-7 cellsregulate lipid metabolismdoi:10.1186/s12944-020-01261-3
CTNNB1cardiomyocytescardiotoxic (increased apoptosis during myocardial injury)doi:10.23736/S00264806.20.06565-9
AVENcardiomyocytescardiotoxic (increased apoptosis during myocardial injury)doi:10.1186/s11658-019-0187-4
TS/O, CPmiR-31-5p1.42 ± 0.462.24 ± 0.74–1.760.15YAPcolorectal carcinomatumor suppressor (cell proliferation, metastasis, chemosensitivity)doi:10.1016/j.yexcr.2020.112176
FLOT1renal clear cell carcinomatumor suppressor (cell proliferation, promote apoptosis)doi:10.2147/OTT.S254634
HOXA7trophoblastinhibit proliferationdoi:10.1111/jog.14344
PEX5hepatocellular carcinomaoncomiR (radioresistance)doi:10.7150/thno.42371
TNS1colon adenocarcinomaoncomiR (tumor progression)doi:10.18632/aging.103096
PKCGcardiomyocytescardioprotective, inhibit cardiomyocyte hypertrophydoi:10.26355/eurrev_202002_20351
PAN3cardiomyocytescardioprotective: attenuates doxorubicin induced cardiotoxicitydoi:10.1016/j.yjmcc.2020.02.009
ETBR, VEGFAendothelial cellsanti-angiogenicdoi:10.1016/j.lfs.2020.117306
MEGEA3hepatocellular carcinomaoncomiR (chemoresistance, cell proliferation)doi:10.1016/j.omtn.2019.10.035
LATS2colorectal carcinomaoncomiR (chemoresistance)doi:10.3390/cancers11101576
MLH1renal cell carcinomaoncomiR (chemoresistance)doi:10.1002/ijc.32543
VEGFAgliomal cellstumor suppressor (anti-angiogenic)doi:10.1002/ijc.32483
TS/OmiR-365a-3p3.99 ± 0.844.34 ± 0.67–1.270.43ABCC4gastric cancertumor suppressor (tumor progression)doi:10.2147/OTT.S245557
ADAM10colorectal carcinomatumor suppressor (cell proliferation, migration)doi:10.7150/jca.42731
CRELpancreatic cancertumor suppressor (tumor progression)doi:10.1016/j.canlet.2019.03.025
TET1hepatocellular carcinomatumor suppressor (tumor progression, invasion)doi:10.4149/neo_2018_171119N752
USP33lung canceroncomiR (tumorigenesis)doi:10.1186/s12935-018-0563-6
TS/OmiR-93-5p5.04 ± 0.595.43 ± 0.62–1.310.39MAP3K2hepatocellular carcinomaoncomiR (tumor progression)doi:10.1038/s41388-020-01401-0
RGMBsquamous cell carcinomaoncomiR (migration and invasion)doi:10.7150/jca.43854
FOXA1colorectal carcinomaoncomiR (radioresistance)doi:10.1186/s13046-019-1507-2
AHNAKgastric canceroncomiR (promotes epithelial–mesenchymal transition)doi:10.1186/s12935-019-1092-7
PD-L1colorectal carcinomatumor suppressor (tumor progression)doi:10.1002/cbin.11323
FOXK2cervical canceroncomiR (tumor progression)doi:10.1007/s43032-020-00140-7
CASC2chondrocytesinhibits apoptosis in osteoarthritisdoi:10.1186/s12891-019-3025-y
MMP2gliomal cellstumor suppressor (cell proliferation, migration)doi:10.26355/eurrev_201911_19446
TS/Olet-7a-5p2.46 ± 0.962.79 ± 0.46–1.260.40SMAD2chondrocytespromotes hypertrophic differentiationdoi:10.1152/ajpcell.00039.2020
SAMD2lens epithelial cellsinhibits proliferation, migration and invasionPMID: 32345785
DUSP7breast cancertumor suppressor (chemoresistance)doi:10.2147/CMAR.S238513
BCLXLlung cancertumor suppressor (cell autophagy)doi:10.1016/j.omto.2019.08.010
BCL2L1lung cancertumor suppressor (induce apoptosis)doi:10.3389/fonc.2019.00808
EGFRbreast canceroncomiR (chemoresistance)doi:10.1002/iub.2075
HMGA2kidneypromotes diabetic nephropathydoi:10.3892/mmr.2019.10057


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Figure 1. Cord blood (CB)- and adipose tissue mesenchymal stromal cells (AT-MSCs) maintain their spindle-shaped morphology under extracellular vesicles (EV) biogenesis conditions. MSCs were expanded to a confluence of about 80%, washed with Dulbecco’s phosphate-buffered saline and cultivated for 48 h in exosome-depleted medium. Then, the cells were switched to starvation medium for 24 h to derive the conditioned medium for EV isolation. Representative bright-field images of cell morphology of CB-MSCs (A) and AT-MSCs (B) were taken by phase-contrast microscopy at the time of EV isolation. Bars, 200 µm.
Figure 1. Cord blood (CB)- and adipose tissue mesenchymal stromal cells (AT-MSCs) maintain their spindle-shaped morphology under extracellular vesicles (EV) biogenesis conditions. MSCs were expanded to a confluence of about 80%, washed with Dulbecco’s phosphate-buffered saline and cultivated for 48 h in exosome-depleted medium. Then, the cells were switched to starvation medium for 24 h to derive the conditioned medium for EV isolation. Representative bright-field images of cell morphology of CB-MSCs (A) and AT-MSCs (B) were taken by phase-contrast microscopy at the time of EV isolation. Bars, 200 µm.
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Figure 2. Particle number, protein amount and size distribution of EVs isolated from CB- and AT-MSCs. Particle concentration (A) and size distribution (C) of EV preparations were measured by nanoparticle tracking analysis. Protein content (B) was determined by the bicinchoninic acid assay. In (AC), the results are mean values ± standard deviation (SD) obtained from four different donors per cell type.
Figure 2. Particle number, protein amount and size distribution of EVs isolated from CB- and AT-MSCs. Particle concentration (A) and size distribution (C) of EV preparations were measured by nanoparticle tracking analysis. Protein content (B) was determined by the bicinchoninic acid assay. In (AC), the results are mean values ± standard deviation (SD) obtained from four different donors per cell type.
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Figure 3. Identification of EV-like structures via transmission electron microscopy. CB- and AT-MSC-derived EVs shown in (A,B) were isolated using the Qiagen exoEasy Maxi Kit, and CB- and AT-MSC-derived EVs shown in (C,D) were isolated using sequential ultracentrifugation. All EVs exhibit the expected cup-like shape, an artefact of the fixation method. In (A,B), EVs are covered with phosphate-rich matter, and red triangles indicate structures in which covered EVs were detected. In (C,D), exemplary EVs are indicated by blue triangles. In (AD), enlarged regions of selected EVs are shown on that top right.
Figure 3. Identification of EV-like structures via transmission electron microscopy. CB- and AT-MSC-derived EVs shown in (A,B) were isolated using the Qiagen exoEasy Maxi Kit, and CB- and AT-MSC-derived EVs shown in (C,D) were isolated using sequential ultracentrifugation. All EVs exhibit the expected cup-like shape, an artefact of the fixation method. In (A,B), EVs are covered with phosphate-rich matter, and red triangles indicate structures in which covered EVs were detected. In (C,D), exemplary EVs are indicated by blue triangles. In (AD), enlarged regions of selected EVs are shown on that top right.
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Figure 4. CB- and AT-MSC-derived EVs display a distinct surface marker profile. Detection of the surface marker proteins CD9, CD63, CD73, CD81, HLA-ABC, and HLA-DR using flow cytometry on EV preparations. The data are presented as means ± SD of normalized mean fluorescence intensities (MFIs), which were calculated as the ratio of the geometric MFI of EV samples (beads + EVs + antibodies) to control samples (beads + antibodies). Statistical analysis was performed by the Mann-Whitney test with * p < 0.05. ND indicates not detected. EVs from four different donors per cell type were included.
Figure 4. CB- and AT-MSC-derived EVs display a distinct surface marker profile. Detection of the surface marker proteins CD9, CD63, CD73, CD81, HLA-ABC, and HLA-DR using flow cytometry on EV preparations. The data are presented as means ± SD of normalized mean fluorescence intensities (MFIs), which were calculated as the ratio of the geometric MFI of EV samples (beads + EVs + antibodies) to control samples (beads + antibodies). Statistical analysis was performed by the Mann-Whitney test with * p < 0.05. ND indicates not detected. EVs from four different donors per cell type were included.
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Figure 5. Heatmap and dendrograms of all microRNAs (miRNAs) detected with certainty according to the guidelines of the Qiagen-Exiqon miRCURY LNA Universal RT microRNA PCR system. Sample IDs are shown on the x-axis. Samples with similar miRNA expression are clustered together. The heatmap was generated by RStudio and 2dCT was used for data input. Z-scores of more than zero indicate a higher expression of miRNAs in one sample compared to the others; Z-scores of less than zero indicate the opposite.
Figure 5. Heatmap and dendrograms of all microRNAs (miRNAs) detected with certainty according to the guidelines of the Qiagen-Exiqon miRCURY LNA Universal RT microRNA PCR system. Sample IDs are shown on the x-axis. Samples with similar miRNA expression are clustered together. The heatmap was generated by RStudio and 2dCT was used for data input. Z-scores of more than zero indicate a higher expression of miRNAs in one sample compared to the others; Z-scores of less than zero indicate the opposite.
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Figure 6. Venn diagram of miRNAs found in CB- and AT-MSC-derived EVs. In total, 752 miRNAs were analyzed and categorized according to mean CTcorr values. High miRNA expression means CTcorr value ≤ 29.99; low miRNA expression means CTcorr value = 30.00–32.99. Five hundred and forty-seven miRNAs were not detected in EVs from CB-MSCs or in EVs from AT-MSCs (mean CTcorr value ≥ 33.00).
Figure 6. Venn diagram of miRNAs found in CB- and AT-MSC-derived EVs. In total, 752 miRNAs were analyzed and categorized according to mean CTcorr values. High miRNA expression means CTcorr value ≤ 29.99; low miRNA expression means CTcorr value = 30.00–32.99. Five hundred and forty-seven miRNAs were not detected in EVs from CB-MSCs or in EVs from AT-MSCs (mean CTcorr value ≥ 33.00).
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Figure 7. Heatmap and dendrograms of miRNAs that were significantly changed in AT-MSC-derived EVs compared to CB-MSC-derived EVs. Sample IDs are shown on the x-axis. Samples with similar miRNA expression are clustered together. The heatmap was generated by RStudio and 2dCT was used for data input. Z-scores of more than zero indicate a higher expression of miRNAs in one sample compared to the others; Z-scores of less than zero indicate the opposite.
Figure 7. Heatmap and dendrograms of miRNAs that were significantly changed in AT-MSC-derived EVs compared to CB-MSC-derived EVs. Sample IDs are shown on the x-axis. Samples with similar miRNA expression are clustered together. The heatmap was generated by RStudio and 2dCT was used for data input. Z-scores of more than zero indicate a higher expression of miRNAs in one sample compared to the others; Z-scores of less than zero indicate the opposite.
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Figure 8. Diagram of literature search rules applied for all miRNAs with a low mean CTcorr value (≤ 29.99) in both CB- and AT-MSC-derived EVs. Search terms were “name of miRNA”, “name of miRNA” AND “heart”, “name of miRNA” AND “cancer”, “name of miRNA” AND “fibrosis”, “name of miRNA” AND “endothelial cells”, “name of miRNA” AND “angiogenesis”, “name of miRNA” AND “immunomodulation”, “name of miRNA” AND “macrophages”, “name of miRNA” AND “t-cells”, and “name of miRNA” AND “immune cells”.
Figure 8. Diagram of literature search rules applied for all miRNAs with a low mean CTcorr value (≤ 29.99) in both CB- and AT-MSC-derived EVs. Search terms were “name of miRNA”, “name of miRNA” AND “heart”, “name of miRNA” AND “cancer”, “name of miRNA” AND “fibrosis”, “name of miRNA” AND “endothelial cells”, “name of miRNA” AND “angiogenesis”, “name of miRNA” AND “immunomodulation”, “name of miRNA” AND “macrophages”, “name of miRNA” AND “t-cells”, and “name of miRNA” AND “immune cells”.
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Figure 9. Venn diagram of selected miRNAs based on their function. Gray, tumor suppressor miRNAs; yellow, oncogenic miRNAs; red, cardioprotective miRNAs. With the exception of miR-1260a, all miRNAs with a low mean CTcorr value (≤29.99) in both CB- and AT-MSC-derived EVs were included. MiR-1260a could not be included, as no targets were described in the literature so far. Further details on these miRNAs are given in Table A1, Table A2 and Table A3.
Figure 9. Venn diagram of selected miRNAs based on their function. Gray, tumor suppressor miRNAs; yellow, oncogenic miRNAs; red, cardioprotective miRNAs. With the exception of miR-1260a, all miRNAs with a low mean CTcorr value (≤29.99) in both CB- and AT-MSC-derived EVs were included. MiR-1260a could not be included, as no targets were described in the literature so far. Further details on these miRNAs are given in Table A1, Table A2 and Table A3.
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Nazari-Shafti, T.Z.; Neuber, S.; Duran, A.G.; Exarchos, V.; Beez, C.M.; Meyborg, H.; Krüger, K.; Wolint, P.; Buschmann, J.; Böni, R.; et al. MiRNA Profiles of Extracellular Vesicles Secreted by Mesenchymal Stromal Cells—Can They Predict Potential Off-Target Effects? Biomolecules 2020, 10, 1353.

AMA Style

Nazari-Shafti TZ, Neuber S, Duran AG, Exarchos V, Beez CM, Meyborg H, Krüger K, Wolint P, Buschmann J, Böni R, et al. MiRNA Profiles of Extracellular Vesicles Secreted by Mesenchymal Stromal Cells—Can They Predict Potential Off-Target Effects? Biomolecules. 2020; 10(9):1353.

Chicago/Turabian Style

Nazari-Shafti, Timo Z., Sebastian Neuber, Ana G. Duran, Vasileios Exarchos, Christien M. Beez, Heike Meyborg, Katrin Krüger, Petra Wolint, Johanna Buschmann, Roland Böni, and et al. 2020. "MiRNA Profiles of Extracellular Vesicles Secreted by Mesenchymal Stromal Cells—Can They Predict Potential Off-Target Effects?" Biomolecules 10, no. 9: 1353.

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