International Journal of Molecular Sciences

Editorial

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4 pages, 387 KiB

Open AccessEditorial

Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration

by Heba Abdelrazik and Alessandra Pelagalli

Int. J. Mol. Sci. 2023, 24(17), 13392; https://doi.org/10.3390/ijms241713392 - 29 Aug 2023

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Abstract

Three Special Issues, so far, have been dedicated to overall MSC prospective biology, from cell regulation to tissue regeneration [...] Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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Research

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15 pages, 9108 KiB

Open AccessArticle

Extracellular Vesicle Depletion Protocols of Foetal Bovine Serum Influence Umbilical Cord Mesenchymal Stromal Cell Phenotype, Immunomodulation, and Particle Release

by Rebecca Davies, Shannen Allen, Claire Mennan, Mark Platt, Karina Wright and Oksana Kehoe

Int. J. Mol. Sci. 2023, 24(11), 9242; https://doi.org/10.3390/ijms24119242 - 25 May 2023

Cited by 2 | Viewed by 1363

Abstract

The immunomodulatory properties of MSCs can be recreated using their extracellular vesicles (EVs). Yet, the true capabilities of the MSC EVs cannot be distinguished from contaminating bovine EVs and protein derived from supplemental foetal bovine serum (FBS). FBS EV depletion protocols can minimise [...] Read more.

The immunomodulatory properties of MSCs can be recreated using their extracellular vesicles (EVs). Yet, the true capabilities of the MSC EVs cannot be distinguished from contaminating bovine EVs and protein derived from supplemental foetal bovine serum (FBS). FBS EV depletion protocols can minimise this, but vary in terms of depletion efficiency, which can negatively impact the cell phenotype. We explore the impact of FBS EV depletion strategies, including ultracentrifugation, ultrafiltration, and serum-free, on umbilical cord MSC characteristics. Whilst a greater depletion efficiency, seen in the ultrafiltration and serum-free strategies, did not impact the MSC markers or viability, the MSCs did become more fibroblastic, had slower proliferation, and showed inferior immunomodulatory capabilities. Upon MSC EV enrichment, more particles, with a greater particle/protein ratio, were isolated upon increasing the FBS depletion efficiency, except for serum-free, which showed a decreased particle number. Whilst all conditions showed the presence of EV-associated markers (CD9, CD63, and CD81), serum-free was shown to represent a higher proportion of these markers when normalised by total protein. Thus, we caution MSC EV researchers on the use of highly efficient EV depletion protocols, showing that it can impact the MSC phenotype, including their immunomodulatory properties, and stress the importance of testing in consideration to downstream objectives. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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18 pages, 3725 KiB

Open AccessArticle

Antisense Oligonucleotides against Let-7 Enhance the Therapeutic Potential of Mesenchymal Stromal Cells

by Dae-Won Lee, Sungho Shin, Jeong-Ho Kim, Cheolju Lee, In Yong Kim and Il-Hoan Oh

Int. J. Mol. Sci. 2023, 24(10), 8639; https://doi.org/10.3390/ijms24108639 - 12 May 2023

Viewed by 1379

Abstract

Let-7 miRNAs have pleiotropic cellular functions in cell proliferation, migration, and regenerative processes. Here, we investigate whether the inhibition of let-7 miRNAs with antisense oligonucleotides (ASOs) can be a transient and safe strategy enhancing the therapeutic potential of mesenchymal stromal cells (MSCs) to [...] Read more.

Let-7 miRNAs have pleiotropic cellular functions in cell proliferation, migration, and regenerative processes. Here, we investigate whether the inhibition of let-7 miRNAs with antisense oligonucleotides (ASOs) can be a transient and safe strategy enhancing the therapeutic potential of mesenchymal stromal cells (MSCs) to overcome their limitations in cell therapeutic trials. We first identified major subfamilies of let-7 miRNAs preferentially expressed in MSCs, and efficient ASO combinations against these selected subfamilies that mimic the effects of LIN28 activation. When let-7 miRNAs were inhibited with an ASO combination (anti-let7-ASOs), MSCs exhibited higher proliferation with delayed senescence during the passaging into a culture. They also exhibited increased migration and enhanced osteogenic differentiation potential. However, these changes in MSCs were not accompanied by cell-fate changes into pericytes or the additional acquisition of stemness, but instead occurred as functional changes accompanied by changes in proteomics. Interestingly, MSCs with let-7 inhibition exhibited metabolic reprogramming characterized by an enhanced glycolytic pathway, decreased reactive oxygen species, and lower transmembrane potential in mitochondria. Moreover, let-7-inhibited MSCs promoted the self-renewal of neighboring hematopoietic progenitor cells, and enhanced capillary formation in endothelial cells. These findings together show that our optimized ASO combination efficiently reprograms the MSC functional state, allowing for more efficient MSC cell therapy. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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18 pages, 4446 KiB

Open AccessArticle

A Three-Dimensional Xeno-Free Culture Condition for Wharton’s Jelly-Mesenchymal Stem Cells: The Pros and Cons

by Benson Koh, Nadiah Sulaiman, Mh Busra Fauzi, Jia Xian Law, Min Hwei Ng, Too Lih Yuan, Abdul Ghani Nur Azurah, Mohd Heikal Mohd Yunus, Ruszymah Bt Hj Idrus and Muhammad Dain Yazid

Int. J. Mol. Sci. 2023, 24(4), 3745; https://doi.org/10.3390/ijms24043745 - 13 Feb 2023

Cited by 1 | Viewed by 2240

Abstract

Xeno-free three-dimensional cultures are gaining attention for mesenchymal stem cell (MSCs) expansion in clinical applications. We investigated the potential of xeno-free serum alternatives, human serum and human platelet lysate, to replace the current conventional use of foetal bovine serum for subsequent MSCs microcarrier [...] Read more.

Xeno-free three-dimensional cultures are gaining attention for mesenchymal stem cell (MSCs) expansion in clinical applications. We investigated the potential of xeno-free serum alternatives, human serum and human platelet lysate, to replace the current conventional use of foetal bovine serum for subsequent MSCs microcarrier cultures. In this study, Wharton’s Jelly MSCs were cultured in nine different media combinations to identify the best xeno-free culture media for MSCs culture. Cell proliferation and viability were identified, and the cultured MSCs were characterised in accordance with the minimal criteria for defining multipotent mesenchymal stromal cells by the International Society for Cellular Therapy (ISCT). The selected culture media was then used in the microcarrier culture of MSCs to determine the potential of a three-dimensional culture system in the expansion of MSCs for future clinical applications, and to identify the immunomodulatory potential of cultured MSCs. Low Glucose DMEM (LG) + Human Platelet (HPL) lysate media appeared to be good candidates for replacing conventional MSCs culture media in our monolayer culture system. MSCs cultured in LG-HPL achieved high cell yield, with characteristics that remained as described by ISCT, although the overall mitochondrial activity of the cells was lower than the control and the subsequent effects remained unknown. MSC microcarrier culture, on the other hand, showed comparable cell characteristics with monolayer culture, yet had stagnated cell proliferation, which is potentially due to the inactivation of FAK. Nonetheless, both the MSCs monolayer culture and the microcarrier culture showed high suppressive activity on TNF-α, and only the MSC microcarrier culture has a better suppression of IL-1 secretion. In conclusion, LG-HPL was identified as a good xeno-free media for WJMSCs culture, and although further mechanistic research is needed, the results show that the xeno-free three-dimensional culture maintained MSC characteristics and improved immunomodulatory activities, suggesting the potential of translating the monolayer culture into this culture system in MSC expansion for future clinical application. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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17 pages, 2628 KiB

Open AccessArticle

Paracrine and Autocrine Effects of VEGF Are Enhanced in Human eMSC Spheroids

by Irina Kozhukharova, Natalia Minkevich, Larisa Alekseenko, Alisa Domnina and Olga Lyublinskaya

Int. J. Mol. Sci. 2022, 23(22), 14324; https://doi.org/10.3390/ijms232214324 - 18 Nov 2022

Cited by 3 | Viewed by 1682

Abstract

The mechanisms underlying the therapeutic potential of MSCs are the focus of intense research. We studied human MSCs isolated from desquamated endometrium (eMSCs), which, as previously shown, have high regenerative potential in various disease models. The aim was to evaluate the role of [...] Read more.

The mechanisms underlying the therapeutic potential of MSCs are the focus of intense research. We studied human MSCs isolated from desquamated endometrium (eMSCs), which, as previously shown, have high regenerative potential in various disease models. The aim was to evaluate the role of secreted VEGF in stimulating angiogenesis and maintaining eMSC viability and migration, which is important for improving the therapeutic properties of MSCs. We compared three eMSC cultures differing in the level of VEGF secretion: 3D spheroids, monolayer eMSCs, and monolayer eMSCs with VEGF knockdown. Spheroid eMSCs produced higher amounts of VEGF and had the strongest paracrine effect on HUVEC. eMSCs with VEGF knockdown did not stimulate angiogenesis. Monolayered eMSCs expressed VEGFR1, while spheroid eMSCs expressed both VEGFR1 and VEGFR2 receptors. The knockdown of VEGF caused a significant decrease in the viability and migration of eMSCs. eMSCs from 3D spheroids enhanced proliferation and migration in response to exogenous VEGF, in contrast to monolayered eMSCs. Our results suggest that the VEGF–VEGFR1 loop appears to be autocrine-involved in maintaining the viability of eMSCs, and VEGFR2 expression enhances their response to exogenous VEGF, so the angiogenic potential of eMSC can be up- or downregulated by intrinsic VEGF signals. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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15 pages, 2239 KiB

Open AccessArticle

Preliminary Characterization of the Epigenetic Modulation in the Human Mesenchymal Stem Cells during Chondrogenic Process

by Marco Miceli, Giuseppe Maria Maruotti, Laura Sarno, Luigi Carbone, Maurizio Guida and Alessandra Pelagalli

Int. J. Mol. Sci. 2022, 23(17), 9870; https://doi.org/10.3390/ijms23179870 - 30 Aug 2022

Viewed by 1180

Abstract

Regenerative medicine represents a growing hot topic in biomedical sciences, aiming at setting out novel therapeutic strategies to repair or regenerate damaged tissues and organs. For this perspective, human mesenchymal stem cells (hMSCs) play a key role in tissue regeneration, having the potential [...] Read more.

Regenerative medicine represents a growing hot topic in biomedical sciences, aiming at setting out novel therapeutic strategies to repair or regenerate damaged tissues and organs. For this perspective, human mesenchymal stem cells (hMSCs) play a key role in tissue regeneration, having the potential to differentiate into many cell types, including chondrocytes. Accordingly, in the last few years, researchers have focused on several in vitro strategies to optimize hMSC differentiation protocols, including those relying on epigenetic manipulations that, in turn, lead to the modulation of gene expression patterns. Therefore, in the present study, we investigated the role of the class II histone deacetylase (HDAC) inhibitor, MC1568, in the hMSCs-derived chondrogenesis. The hMSCs we used for this work were the hMSCs obtained from the amniotic fluid, given their greater differentiation capacity. Our preliminary data documented that MC1568 drove both the improvement and acceleration of hMSCs chondrogenic differentiation in vitro, since the differentiation process in MC1568-treated cells took place in about seven days, much less than that normally observed, namely 21 days. Collectively, these preliminary data might shed light on the validity of such a new differentiative protocol, in order to better assess the potential role of the epigenetic modulation in the process of the hypertrophic cartilage formation, which represents the starting point for endochondral ossification. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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15 pages, 15379 KiB

Open AccessArticle

Effect of Pre-Induced Mesenchymal Stem Cell-Coated Cellulose/Collagen Nanofibrous Nerve Conduit on Regeneration of Transected Facial Nerve

by GwangWon Cho, Changjong Moon, Nagarajan Maharajan, Mary Jasmin Ang, Minseong Kim and Chul Ho Jang

Int. J. Mol. Sci. 2022, 23(14), 7638; https://doi.org/10.3390/ijms23147638 - 11 Jul 2022

Cited by 7 | Viewed by 1689

Abstract

(1) Objective: In order to evaluate the effect of a pre-induced mesenchymal stem cell (MSC)-coated cellulose/collagen nanofibrous nerve conduit on facial nerve regeneration in a rat model both in vitro and in vivo. (2) Methods: After fabrication of the cellulose/collagen nanofibrous conduit, its [...] Read more.

(1) Objective: In order to evaluate the effect of a pre-induced mesenchymal stem cell (MSC)-coated cellulose/collagen nanofibrous nerve conduit on facial nerve regeneration in a rat model both in vitro and in vivo. (2) Methods: After fabrication of the cellulose/collagen nanofibrous conduit, its lumen was coated with either MSCs or pre-induced MSCs. The nerve conduit was then applied to the defective main trunk of the facial nerve. Rats were randomly divided into three treatment groups (n = 10 in each): cellulose/collagen nanofiber (control group), cellulose/collagen nanofiber/MSCs (group I), and cellulose/collagen nanofiber/pre-induced MSCs (group II). (3) Results Fibrillation of the vibrissae of each group was observed, and action potential threshold was compared 8 weeks post-surgery. Histopathological changes were also observed. Groups I and II showed better recovery of vibrissa fibrillation than the control group. (4) Conclusions: Group II, treated with the pre-induced MSC-coated cellulose/collagen nanofibrous nerve conduit, showed the highest degree of recovery based on functional and histological evaluations. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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18 pages, 8816 KiB

Open AccessArticle

Freeze-Dried Secretome (Lyosecretome) from Mesenchymal Stem/Stromal Cells Promotes the Osteoinductive and Osteoconductive Properties of Titanium Cages

by Elia Bari, Fulvio Tartara, Fabio Cofano, Giuseppe di Perna, Diego Garbossa, Sara Perteghella, Marzio Sorlini, Delia Mandracchia, Lorella Giovannelli, Paolo Gaetani, Maria Luisa Torre and Lorena Segale

Int. J. Mol. Sci. 2021, 22(16), 8445; https://doi.org/10.3390/ijms22168445 - 06 Aug 2021

Cited by 6 | Viewed by 2263

Abstract

Titanium is one of the most frequently used materials in bone regeneration due to its good biocompatibility, excellent mechanical properties, and great osteogenic performance. However, osseointegration with host tissue is often not definite, which may cause implant failure at times. The present study [...] Read more.

Titanium is one of the most frequently used materials in bone regeneration due to its good biocompatibility, excellent mechanical properties, and great osteogenic performance. However, osseointegration with host tissue is often not definite, which may cause implant failure at times. The present study investigates the capacity of the mesenchymal stem cell (MSC)-secretome, formulated as a ready-to-use and freeze-dried medicinal product (the Lyosecretome), to promote the osteoinductive and osteoconductive properties of titanium cages. In vitro tests were conducted using adipose tissue-derived MSCs seeded on titanium cages with or without Lyosecretome. After 14 days, in the presence of Lyosecretome, significant cell proliferation improvement was observed. Scanning electron microscopy revealed the cytocompatibility of titanium cages: the seeded MSCs showed a spread morphology and an initial formation of filopodia. After 7 days, in the presence of Lyosecretome, more frequent and complex cellular processes forming bridges across the porous surface of the scaffold were revealed. Also, after 14 and 28 days of culturing in osteogenic medium, the amount of mineralized matrix detected by alizarin red was significantly higher when Lyosecretome was used. Finally, improved osteogenesis with Lyosecretome was confirmed by confocal analysis after 28 and 56 days of treatment, and demonstrating the production by osteoblast-differentiated MSCs of osteocalcin, a specific bone matrix protein. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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15 pages, 2338 KiB

Open AccessArticle

In Vitro Osteoinductivity Assay of Hydroxylapatite Scaffolds, Obtained with Biomorphic Transformation Processes, Assessed Using Human Adipose Stem Cell Cultures

by Maria Rosa Iaquinta, Elena Torreggiani, Chiara Mazziotta, Andrea Ruffini, Simone Sprio, Anna Tampieri, Mauro Tognon, Fernanda Martini and Elisa Mazzoni

Int. J. Mol. Sci. 2021, 22(13), 7092; https://doi.org/10.3390/ijms22137092 - 30 Jun 2021

Cited by 8 | Viewed by 2380

Abstract

In this study, the in vitro biocompatibility and osteoinductive ability of a recently developed biomorphic hydroxylapatite ceramic scaffold (B-HA) derived from transformation of wood structures were analyzed using human adipose stem cells (hASCs). Cell viability and metabolic activity were evaluated in hASCs, parental [...] Read more.

In this study, the in vitro biocompatibility and osteoinductive ability of a recently developed biomorphic hydroxylapatite ceramic scaffold (B-HA) derived from transformation of wood structures were analyzed using human adipose stem cells (hASCs). Cell viability and metabolic activity were evaluated in hASCs, parental cells and in recombinant genetically engineered hASC-eGFP cells expressing the green fluorescence protein. B-HA osteoinductivity properties, such as differentially expressed genes (DEG) involved in the skeletal development pathway, osteocalcin (OCN) protein expression and mineral matrix deposition in hASCs, were evaluated. In vitro induction of osteoblastic genes, such as Alkaline phosphatase (ALPL), Bone gamma-carboxyglutamate (gla) protein (BGLAP), SMAD family member 3 (SMAD3), Sp7 transcription factor (SP7) and Transforming growth factor, beta 3 (TGFB3) and Tumor necrosis factor (ligand) superfamily, member 11 (TNFSF11)/Receptor activator of NF-κB (RANK) ligand (RANKL), involved in osteoclast differentiation, was undertaken in cells grown on B-HA. Chondrogenic transcription factor SRY (sex determining region Y)-box 9 (SOX9), tested up-regulated in hASCs grown on the B-HA scaffold. Gene expression enhancement in the skeletal development pathway was detected in hASCs using B-HA compared to sintered hydroxylapatite (S-HA). OCN protein expression and calcium deposition were increased in hASCs grown on B-HA in comparison with the control. This study demonstrates the biocompatibility of the novel biomorphic B-HA scaffold and its potential use in osteogenic differentiation for hASCs. Our data highlight the relevance of B-HA for bone regeneration purposes. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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19 pages, 4046 KiB

Open AccessArticle

Superoxide Dismutase 3-Transduced Mesenchymal Stem Cells Preserve Epithelial Tight Junction Barrier in Murine Colitis and Attenuate Inflammatory Damage in Epithelial Organoids

by Lee-Jung Tak, Hae-Young Kim, Won-Kook Ham, Gaurav Agrahari, Yoojin Seo, Ji Won Yang, Eun-Joo An, Chul Hwan Bang, Min Jung Lee, Hyung-Sik Kim and Tae-Yoon Kim

Int. J. Mol. Sci. 2021, 22(12), 6431; https://doi.org/10.3390/ijms22126431 - 16 Jun 2021

Cited by 15 | Viewed by 3105

Abstract

Superoxide dismutase 3 (SOD3), also known as extracellular superoxide dismutase, is an enzyme that scavenges reactive oxygen species (ROS). It has been reported that SOD3 exerts anti-inflammatory abilities in several immune disorders. However, the effect of SOD3 and the underlying mechanism in inflammatory [...] Read more.

Superoxide dismutase 3 (SOD3), also known as extracellular superoxide dismutase, is an enzyme that scavenges reactive oxygen species (ROS). It has been reported that SOD3 exerts anti-inflammatory abilities in several immune disorders. However, the effect of SOD3 and the underlying mechanism in inflammatory bowel disease (IBD) have not been uncovered. Therefore, in the present study, we investigated whether SOD3 can protect intestinal cells or organoids from inflammation-mediated epithelial damage. Cells or mice were treated with SOD3 protein or SOD3-transduced mesenchymal stem cells (MSCs). Caco-2 cells or intestinal organoids stimulated with pro-inflammatory cytokines were used to evaluate the protective effect of SOD3 on epithelial junctional integrity. Dextran sulfate sodium (DSS)-induced colitis mice received SOD3 or SOD3-transduced MSCs (SOD3-MSCs), and were assessed for severity of disease and junctional protein expression. The activation of the mitogen-activated protein kinase (MAPK) pathway and elevated expression of cytokine-encoding genes decreased in TNF-α-treated Caco-2 cells or DSS-induced colitis mice when treated with SOD3 or SOD3-MSCs. Moreover, the SOD3 supply preserved the expression of tight junction (ZO-1, occludin) or adherence junction (E-cadherin) proteins when inflammation was induced. SOD3 also exerted a protective effect against cytokine- or ROS-mediated damage to intestinal organoids. These results indicate that SOD3 can effectively alleviate enteritis symptoms by maintaining the integrity of epithelial junctions and regulating inflammatory- and oxidative stress. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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Review

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23 pages, 801 KiB

Open AccessReview

Evaluating the Effect of Hypoxia on Human Adult Mesenchymal Stromal Cell Chondrogenesis In Vitro: A Systematic Review

by Charindu K. I. Ranmuthu, Chanuka D. S. Ranmuthu, Chalukya K. Wijewardena, Matthew K. T. Seah and Wasim S. Khan

Int. J. Mol. Sci. 2022, 23(23), 15210; https://doi.org/10.3390/ijms232315210 - 02 Dec 2022

Cited by 3 | Viewed by 1120

Abstract

Human adult mesenchymal stromal cells (MSCs) from a variety of sources may be used to repair defects in articular cartilage by inducing them into chondrogenic differentiation. The conditions in which optimal chondrogenic differentiation takes place are an area of interest in the field [...] Read more.

Human adult mesenchymal stromal cells (MSCs) from a variety of sources may be used to repair defects in articular cartilage by inducing them into chondrogenic differentiation. The conditions in which optimal chondrogenic differentiation takes place are an area of interest in the field of tissue engineering. Chondrocytes exist in vivo in a normally hypoxic environment and thus it has been suggested that exposing MSCs to hypoxia may also contribute to a beneficial effect on their differentiation. There are two main stages in which MSCs can be exposed to hypoxia, the expansion phase when cells are cultured, and the differentiation phase when cells are induced with a chondrogenic medium. This systematic review sought to explore the effect of hypoxia at these two stages on human adult MSC chondrogenesis in vitro. A literature search was performed on PubMed, EMBASE, Medline via Ovid, and Cochrane, and 24 studies were ultimately included. The majority of these studies showed that hypoxia during the expansion phase or the differentiation phase enhances at least some markers of chondrogenic differentiation in adult MSCs. These results were not always demonstrated at the protein level and there were also conflicting reports. Studies evaluating continuous exposure to hypoxia during the expansion and differentiation phases also had mixed results. These inconsistent results can be explained by the heterogeneity of studies, including factors such as different sources of MSCs used, donor variability, level of hypoxia used in each study, time exposed to hypoxia, and differences in culture methodology. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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18 pages, 1874 KiB

Open AccessReview

Harnessing Normal and Engineered Mesenchymal Stem Cells Derived Exosomes for Cancer Therapy: Opportunity and Challenges

by Mahdi Ahmadi, Monireh Mahmoodi, Maryam Shoaran, Fereshteh Nazari-Khanamiri and Jafar Rezaie

Int. J. Mol. Sci. 2022, 23(22), 13974; https://doi.org/10.3390/ijms232213974 - 12 Nov 2022

Cited by 15 | Viewed by 2221

Abstract

There remains a vital necessity for new therapeutic approaches to combat metastatic cancers, which cause globally over 8 million deaths per year. Mesenchymal stem cells (MSCs) display aptitude as new therapeutic choices for cancer treatment. Exosomes, the most important mediator of MSCs, regulate [...] Read more.

There remains a vital necessity for new therapeutic approaches to combat metastatic cancers, which cause globally over 8 million deaths per year. Mesenchymal stem cells (MSCs) display aptitude as new therapeutic choices for cancer treatment. Exosomes, the most important mediator of MSCs, regulate tumor progression. The potential of harnessing exosomes from MSCs (MSCs-Exo) in cancer therapy is now being documented. MSCs-Exo can promote tumor progression by affecting tumor growth, metastasis, immunity, angiogenesis, and drug resistance. However, contradictory evidence has suggested that MSCs-Exo suppress tumors through several mechanisms. Therefore, the exact association between MSCs-Exo and tumors remains controversial. Accordingly, the applications of MSCs-Exo as novel drug delivery systems and standalone therapeutics are being extensively explored. In addition, engineering MSCs-Exo for targeting tumor cells has opened a new avenue for improving the efficiency of antitumor therapy. However, effective implementation in the clinical trials will need the establishment of standards for MSCs-Exo isolation and characterization as well as loading and engineering methods. The studies outlined in this review highlight the pivotal roles of MSCs-Exo in tumor progression and the promising potential of MSCs-Exo as therapeutic drug delivery vehicles for cancer treatment. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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18 pages, 1165 KiB

Open AccessReview

Mechanotransduction in Mesenchymal Stem Cells (MSCs) Differentiation: A Review

by Narmadaa Raman, Siti A. M. Imran, Khairul Bariah Ahmad Amin Noordin, Wan Safwani Wan Kamarul Zaman and Fazlina Nordin

Int. J. Mol. Sci. 2022, 23(9), 4580; https://doi.org/10.3390/ijms23094580 - 21 Apr 2022

Cited by 14 | Viewed by 3302

Abstract

Mechanotransduction is the process by which physical force is converted into a biochemical signal that is used in development and physiology; meanwhile, it is intended for the ability of cells to sense and respond to mechanical forces by activating intracellular signals transduction pathways [...] Read more.

Mechanotransduction is the process by which physical force is converted into a biochemical signal that is used in development and physiology; meanwhile, it is intended for the ability of cells to sense and respond to mechanical forces by activating intracellular signals transduction pathways and the relative phenotypic adaptation. It encompasses the role of mechanical stimuli for developmental, morphological characteristics, and biological processes in different organs; the response of cells to mechanically induced force is now also emerging as a major determinant of disease. Due to fluid shear stress caused by blood flowing tangentially across the lumen surface, cells of the cardiovascular system are typically exposed to a variety of mechanotransduction. In the body, tissues are continuously exposed to physical forces ranging from compression to strain, which is caused by fluid pressure and compressive forces. Only lately, though, has the importance of how forces shape stem cell differentiation into lineage-committed cells and how mechanical forces can cause or exacerbate disease besides organizing cells into tissues been acknowledged. Mesenchymal stem cells (MSCs) are potent mediators of cardiac repair which can secret a large array of soluble factors that have been shown to play a huge role in tissue repair. Differentiation of MSCs is required to regulate mechanical factors such as fluid shear stress, mechanical strain, and the rigidity of the extracellular matrix through various signaling pathways for their use in regenerative medicine. In the present review, we highlighted mechanical influences on the differentiation of MSCs and the general factors involved in MSCs differentiation. The purpose of this study is to demonstrate the progress that has been achieved in understanding how MSCs perceive and react to their mechanical environment, as well as to highlight areas where more research has been performed in previous studies to fill in the gaps. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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22 pages, 1352 KiB

Open AccessReview

Mesenchymal Stem Cells Based Treatment in Dental Medicine: A Narrative Review

by Igor Smojver, Ivan Katalinić, Roko Bjelica, Dragana Gabrić, Vid Matišić, Vilim Molnar and Dragan Primorac

Int. J. Mol. Sci. 2022, 23(3), 1662; https://doi.org/10.3390/ijms23031662 - 31 Jan 2022

Cited by 19 | Viewed by 6703

Abstract

Application of mesenchymal stem cells (MSC) in regenerative therapeutic procedures is becoming an increasingly important topic in medicine. Since the first isolation of dental tissue-derived MSC, there has been an intense investigation on the characteristics and potentials of these cells in regenerative dentistry. [...] Read more.

Application of mesenchymal stem cells (MSC) in regenerative therapeutic procedures is becoming an increasingly important topic in medicine. Since the first isolation of dental tissue-derived MSC, there has been an intense investigation on the characteristics and potentials of these cells in regenerative dentistry. Their multidifferentiation potential, self-renewal capacity, and easy accessibility give them a key role in stem cell-based therapy. So far, several different dental stem cell types have been discovered and their potential usage is found in most of the major dental medicine branches. These cells are also researched in multiple fields of medicine for the treatment of degenerative and inflammatory diseases. In this review, we summarized dental MSC sources and analyzed their treatment modalities with particular emphasis on temporomandibular joint osteoarthritis (TMJ OA). Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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17 pages, 1456 KiB

Open AccessReview

Adipose Stromal/Stem Cell-Derived Extracellular Vesicles: Potential Next-Generation Anti-Obesity Agents

by Mariachiara Zuccarini, Patricia Giuliani, Valentina Di Liberto, Monica Frinchi, Francesco Caciagli, Vanni Caruso, Renata Ciccarelli, Giuseppa Mudò and Patrizia Di Iorio

Int. J. Mol. Sci. 2022, 23(3), 1543; https://doi.org/10.3390/ijms23031543 - 28 Jan 2022

Cited by 1 | Viewed by 2811

Abstract

Over the last decade, several compounds have been identified for the treatment of obesity. However, due to the complexity of the disease, many pharmacological interventions have raised concerns about their efficacy and safety. Therefore, it is important to discover new factors involved in [...] Read more.

Over the last decade, several compounds have been identified for the treatment of obesity. However, due to the complexity of the disease, many pharmacological interventions have raised concerns about their efficacy and safety. Therefore, it is important to discover new factors involved in the induction/progression of obesity. Adipose stromal/stem cells (ASCs), which are mostly isolated from subcutaneous adipose tissue, are the primary cells contributing to the expansion of fat mass. Like other cells, ASCs release nanoparticles known as extracellular vesicles (EVs), which are being actively studied for their potential applications in a variety of diseases. Here, we focused on the importance of the con-tribution of ASC-derived EVs in the regulation of metabolic processes. In addition, we outlined the advantages/disadvantages of the use of EVs as potential next-generation anti-obesity agents. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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18 pages, 993 KiB

Open AccessReview

Therapeutic Potential of Mesenchymal Stem Cells (MSCs) and MSC-Derived Extracellular Vesicles for the Treatment of Spinal Cord Injury

by Gang-Un Kim, Soo-Eun Sung, Kyung-Ku Kang, Joo-Hee Choi, Sijoon Lee, Minkyoung Sung, Seung Yun Yang, Seul-Ki Kim, Young In Kim, Ju-Hyeon Lim, Min-Soo Seo and Gun Woo Lee

Int. J. Mol. Sci. 2021, 22(24), 13672; https://doi.org/10.3390/ijms222413672 - 20 Dec 2021

Cited by 30 | Viewed by 5035

Abstract

Spinal cord injury (SCI) is a life-threatening condition that leads to permanent disability with partial or complete loss of motor, sensory, and autonomic functions. SCI is usually caused by initial mechanical insult, followed by a cascade of several neuroinflammation and structural changes. For [...] Read more.

Spinal cord injury (SCI) is a life-threatening condition that leads to permanent disability with partial or complete loss of motor, sensory, and autonomic functions. SCI is usually caused by initial mechanical insult, followed by a cascade of several neuroinflammation and structural changes. For ameliorating the neuroinflammatory cascades, MSC has been regarded as a therapeutic agent. The animal SCI research has demonstrated that MSC can be a valuable therapeutic agent with several growth factors and cytokines that may induce anti-inflammatory and regenerative effects. However, the therapeutic efficacy of MSCs in animal SCI models is inconsistent, and the optimal method of MSCs remains debatable. Moreover, there are several limitations to developing these therapeutic agents for humans. Therefore, identifying novel agents for regenerative medicine is necessary. Extracellular vesicles are a novel source for regenerative medicine; they possess nucleic acids, functional proteins, and bioactive lipids and perform various functions, including damaged tissue repair, immune response regulation, and reduction of inflammation. MSC-derived exosomes have advantages over MSCs, including small dimensions, low immunogenicity, and no need for additional procedures for culture expansion or delivery. Certain studies have demonstrated that MSC-derived extracellular vesicles (EVs), including exosomes, exhibit outstanding chondroprotective and anti-inflammatory effects. Therefore, we reviewed the principles and patho-mechanisms and summarized the research outcomes of MSCs and MSC-derived EVs for SCI, reported to date. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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15 pages, 948 KiB

Open AccessReview

Mesenchymal Stem Cell-Derived Extracellular Vesicle: A Promising Alternative Therapy for Osteoporosis

by Cheng-Hsiu Lu, Yi-An Chen, Chien-Chih Ke and Ren-Shyan Liu

Int. J. Mol. Sci. 2021, 22(23), 12750; https://doi.org/10.3390/ijms222312750 - 25 Nov 2021

Cited by 19 | Viewed by 3161

Abstract

Osteoporosis is the chronic metabolic bone disease caused by the disturbance of bone remodeling due to the imbalance of osteogenesis and osteoclastogenesis. A large population suffers from osteoporosis, and most of them are postmenopausal women or older people. To date, bisphosphonates are the [...] Read more.

Osteoporosis is the chronic metabolic bone disease caused by the disturbance of bone remodeling due to the imbalance of osteogenesis and osteoclastogenesis. A large population suffers from osteoporosis, and most of them are postmenopausal women or older people. To date, bisphosphonates are the main therapeutic agents in the treatment of osteoporosis. However, limited therapeutic effects with diverse side effects caused by bisphosphonates hindered the therapeutic applications and decreased the quality of life. Therefore, an alternative therapy for osteoporosis is still needed. Stem cells, especially mesenchymal stem cells, have been shown as a promising medication for numerous human diseases including many refractory diseases. Recently, researchers found that the extracellular vesicles derived from these stem cells possessed the similar therapeutic potential to that of parental cells. To date, a number of studies demonstrated the therapeutic applications of exogenous MSC-EVs for the treatment of osteoporosis. In this article, we reviewed the basic back ground of EVs, the cargo and therapeutic potential of MSC-EVs, and strategies of engineering of MSC-EVs for osteoporosis treatment. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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33 pages, 2062 KiB

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Immunomodulation and Regenerative Capacity of MSCs for Long-COVID

by Xin Ya Loke, Siti A. M. Imran, Gee Jun Tye, Wan Safwani Wan Kamarul Zaman and Fazlina Nordin

Int. J. Mol. Sci. 2021, 22(22), 12421; https://doi.org/10.3390/ijms222212421 - 17 Nov 2021

Cited by 10 | Viewed by 3611

Abstract

The rapid mutation of the SARS-CoV-2 virus is now a major concern with no effective drugs and treatments. The severity of the disease is linked to the induction of a cytokine storm that promotes extensive inflammation in the lung, leading to many acute [...] Read more.

The rapid mutation of the SARS-CoV-2 virus is now a major concern with no effective drugs and treatments. The severity of the disease is linked to the induction of a cytokine storm that promotes extensive inflammation in the lung, leading to many acute lung injuries, pulmonary edema, and eventually death. Mesenchymal stem cells (MSCs) might prove to be a treatment option as they have immunomodulation and regenerative properties. Clinical trials utilizing MSCs in treating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) have provided a basis in treating post-COVID-19 patients. In this review, we discussed the effects of MSCs as an immunomodulator to reduce the severity and death in patients with COVID-19, including the usage of MSCs as an alternative regenerative therapy in post-COVID-19 patients. This review also includes the current clinical trials in utilizing MSCs and their potential future utilization for long-COVID treatments. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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26 pages, 871 KiB

Open AccessReview

Application of Mesenchymal Stem Cells in Targeted Delivery to the Brain: Potential and Challenges of the Extracellular Vesicle-Based Approach for Brain Tumor Treatment

by Anh Duy Do, Ida Kurniawati, Chia-Ling Hsieh, Tai-Tong Wong, Yu-Ling Lin and Shian-Ying Sung

Int. J. Mol. Sci. 2021, 22(20), 11187; https://doi.org/10.3390/ijms222011187 - 17 Oct 2021

Cited by 15 | Viewed by 3647

Abstract

Treating brain tumors presents enormous challenges, and there are still poor prognoses in both adults and children. Application of novel targets and potential drugs is hindered by the function of the blood-brain barrier, which significantly restricts therapeutic access to the tumor. Mesenchymal stem [...] Read more.

Treating brain tumors presents enormous challenges, and there are still poor prognoses in both adults and children. Application of novel targets and potential drugs is hindered by the function of the blood-brain barrier, which significantly restricts therapeutic access to the tumor. Mesenchymal stem cells (MSCs) can cross biological barriers, migrate to sites of injuries to exert many healing effects, and be engineered to incorporate different types of cargo, making them an ideal vehicle to transport anti-tumor agents to the central nervous system. Extracellular vesicles (EVs) produced by MSCs (MSC-EVs) have valuable innate properties from parent cells, and are being exploited as cell-free treatments for many neurological diseases. Compared to using MSCs, targeted delivery via MSC-EVs has a better pharmacokinetic profile, yet avoids many critical issues of cell-based systems. As the field of MSC therapeutic applications is quickly expanding, this article aims to give an overall picture for one direction of EV-based targeting of brain tumors, with updates on available techniques, outcomes of experimental models, and critical challenges of this concept. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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19 pages, 2022 KiB

Open AccessReview

Mesenchymal Stem Cell Transplantation for the Treatment of Age-Related Musculoskeletal Frailty

by Elancheleyen Mahindran, Jia Xian Law, Min Hwei Ng and Fazlina Nordin

Int. J. Mol. Sci. 2021, 22(19), 10542; https://doi.org/10.3390/ijms221910542 - 29 Sep 2021

Cited by 9 | Viewed by 3544

Abstract

Projected life expectancy continues to grow worldwide owing to the advancement of new treatments and technologies leading to rapid growth of geriatric population. Thus, age-associated diseases especially in the musculoskeletal system are becoming more common. Loss of bone (osteoporosis) and muscle (sarcopenia) mass [...] Read more.

Projected life expectancy continues to grow worldwide owing to the advancement of new treatments and technologies leading to rapid growth of geriatric population. Thus, age-associated diseases especially in the musculoskeletal system are becoming more common. Loss of bone (osteoporosis) and muscle (sarcopenia) mass are conditions whose prevalence is increasing because of the change in population distribution in the world towards an older mean age. The deterioration in the bone and muscle functions can cause severe disability and seriously affects the patients’ quality of life. Currently, there is no treatment to prevent and reverse age-related musculoskeletal frailty. Existing interventions are mainly to slow down and control the signs and symptoms. Mesenchymal stem cell (MSC) transplantation is a promising approach to attenuate age-related musculoskeletal frailty. This review compiles the present knowledge of the causes and changes of the musculoskeletal frailty and the potential of MSC transplantation as a regenerative therapy for age-related musculoskeletal frailty. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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31 pages, 3178 KiB

Open AccessReview

TNF-α and IFN-γ Participate in Improving the Immunoregulatory Capacity of Mesenchymal Stem/Stromal Cells: Importance of Cell–Cell Contact and Extracellular Vesicles

by Lucero López-García and Marta E. Castro-Manrreza

Int. J. Mol. Sci. 2021, 22(17), 9531; https://doi.org/10.3390/ijms22179531 - 02 Sep 2021

Cited by 54 | Viewed by 7417

Abstract

Mesenchymal stem/stromal cells (MSCs) have an immunoregulatory capacity and have been used in different clinical protocols requiring control of the immune response. However, variable results have been obtained, mainly due to the effect of the microenvironment on the induction, increase, and maintenance of [...] Read more.

Mesenchymal stem/stromal cells (MSCs) have an immunoregulatory capacity and have been used in different clinical protocols requiring control of the immune response. However, variable results have been obtained, mainly due to the effect of the microenvironment on the induction, increase, and maintenance of MSC immunoregulatory mechanisms. In addition, the importance of cell–cell contact for MSCs to efficiently modulate the immune response has recently been highlighted. Because these interactions would be difficult to achieve in the physiological context, the release of extracellular vesicles (EVs) and their participation as intermediaries of communication between MSCs and immune cells becomes relevant. Therefore, this article focuses on analyzing immunoregulatory mechanisms mediated by cell contact, highlighting the importance of intercellular adhesion molecule-1 (ICAM-1) and the participation of EVs. Moreover, the effects of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), the main cytokines involved in MSC activation, are examined. These cytokines, when used at the appropriate concentrations and times, would promote increases in the expression of immunoregulatory molecules in the cell and allow the acquisition of EVs enriched with these molecules. The establishment of certain in vitro activation guidelines will facilitate the design of conditioning protocols to obtain functional MSCs or EVs in different pathophysiological conditions. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

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