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Pharmaceutics
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Mesenchymal Stem/Stromal Cell Extracellular Vesicles: From Active Principle to Next...
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Mesenchymal Stem/Stromal Cell Extracellular Vesicles: From Active Principle to Next Generation Drug Delivery

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: 10 May 2024 | Viewed by 9756

Special Issue Editor

Dr. Margherita Pomatto

E-Mail Website
Guest Editor
Department of Medical Sciences, University of Turin, 10126 Turin, Italy
Interests: extracellular vesicles; exosomes; drug delivery; therapy; clinic; manufacturing; regenerative therapy; vaccines

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to this Special Issue focused on extracellular vesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) and their potential use in the clinic. MSCs are the most studied source of therapeutic EVs, which are increasingly emerging as a new promising cell-free therapy. EVs have unique features which make them candidates as suitable alternatives to cell therapy; these include their safety, versatile biological actions and targeting ability. Moreover, their natural role as vehicles between cells makes them the ideal delivery system, which can replace current technologies and avoid their limitations.

This Special Issue aims to provide an overview of the knowledge about the potentiality of MSC-EVs in therapeutic applications, focusing on their effect as active principle and their modification as drug vehicles. This Special Issue will summarize the latest discoveries on the application of EVs which can include their use in clinic and aspects from production to therapeutic effect, with particular interest in their use as drug carriers.

In this Special Issue, original research articles and reviews are welcome. Research areas on MSC-EVs may include (but are not limited to) the following: therapeutic effect in pathological preclinical models, methods and application as drug delivery systems, as well as their production and challenges for their clinical use.

I look forward to receiving your contributions.

Dr. Margherita Pomatto
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mesenchymal cells 
  • stem cells 
  • extracellular vesicles 
  • exosomes 
  • therapy 
  • delivery 
  • vehicle 
  • carrier 
  • drug 
  • clinic

Published Papers (5 papers)

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Research

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15 pages, 6786 KiB  
Article
Porcine Mandibular Bone Marrow-Derived Mesenchymal Stem Cell (BMSC)-Derived Extracellular Vesicles Can Promote the Osteogenic Differentiation Capacity of Porcine Tibial-Derived BMSCs
by Qun Zhao, Xing Zhang, You Li, Zhizhen He, Kang Qin, Eva Miriam Buhl, Ümit Mert, Klemens Horst, Frank Hildebrand, Elizabeth R. Balmayor and Johannes Greven
Pharmaceutics 2024, 16(2), 279; https://doi.org/10.3390/pharmaceutics16020279 - 16 Feb 2024
Viewed by 811
Abstract
Objective: Existing research suggests that bone marrow-derived mesenchymal stem cells (BMSCs) may promote endogenous bone repair. This may be through the secretion of factors that stimulate repair processes or directly through differentiation into osteoblast-progenitor cells. However, the osteogenic potential of BMSCs varies among [...] Read more.
Objective: Existing research suggests that bone marrow-derived mesenchymal stem cells (BMSCs) may promote endogenous bone repair. This may be through the secretion of factors that stimulate repair processes or directly through differentiation into osteoblast-progenitor cells. However, the osteogenic potential of BMSCs varies among different tissue sources (e.g., mandibular versus long BMSCs). The main aim of this study was to investigate the difference in osteogenic differentiation capacity between mandibular BMSCs (mBMSCs) and tibial BMSCs (tBMSCs). Materials and Methods: Bioinformatics analysis of the GSE81430 dataset taken from the Gene Expression Omnibus (GEO) database was performed using GEO2R. BMSCs were isolated from mandibular and tibial bone marrow tissue samples. Healthy pigs (n = 3) (registered at the State Office for Nature, Environment, and Consumer Protection, North Rhine-Westphalia (LANUV) 81-02.04.2020.A215) were used for this purpose. Cell morphology and osteogenic differentiation were evaluated in mBMSCs and tBMSCs. The expression levels of toll-like receptor 4 (TLR4) and nuclear transcription factor κB (NF-κB) were analyzed using quantitative polymerase chain reaction (qPCR) and Western blot (WB), respectively. In addition, mBMSC-derived extracellular vesicles (mBMSC-EVs) were gained and used as osteogenic stimuli for tBMSCs. Cell morphology and osteogenic differentiation capacity were assessed after mBMSC-EV stimulation. Results: Bioinformatic analysis indicated that the difference in the activation of the TLR4/NF-κB pathway was more pronounced compared to all other examined genes. Specifically, this demonstrated significant downregulation, whereas only 5–7 upregulated genes displayed significant variances. The mBMSC group showed stronger osteogenic differentiation capacity compared to the tBMSC group, confirmed via ALP, ARS, and von Kossa staining. Furthermore, qPCR and WB analysis revealed a significant decrease in the expression of the TLR4/NF-κB pathway in the mBMSC group compared to the tBMSC group (TLR4 fold changes: mBMSCs vs. tBMSCs p < 0.05; NF-κB fold changes: mBMSCs vs. tBMSCs p < 0.05). The osteogenic differentiation capacity was enhanced, and qPCR and WB analysis revealed a significant decrease in the expression of TLR4 and NF-κB in the tBMSC group with mBMSC-EVs added compared to tBMSCs alone (TLR4 fold changes: p < 0.05; NF-κB fold changes: p < 0.05). Conclusion: Our results indicate that mBMSC-EVs can promote the osteogenic differentiation of tBMSCs in vitro. The results also provide insights into the osteogenic mechanism of mBMSCs via TLR4/NF-κB signaling pathway activation. This discovery promises a fresh perspective on the treatment of bone fractures or malunions, potentially offering a novel therapeutic method. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cell Extracellular Vesicles: From Active Principle to Next Generation Drug Delivery)
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21 pages, 6455 KiB  
Article
Breast Milk Mesenchymal Stem Cells and/or Derived Exosomes Mitigated Adenine-Induced Nephropathy via Modulating Renal Autophagy and Fibrotic Signaling Pathways and Their Epigenetic Regulations
by Tarek Khamis, Amira Ebrahim Alsemeh, Asma Alanazi, Asmaa Monir Eltaweel, Heba M. Abdel-Ghany, Doaa M. Hendawy, Adel Abdelkhalek, Mahmoud A. Said, Heba H. Awad, Basma Hamed Ibrahim, Dina Mohamed Mekawy, Corina Pascu, Crista Florin and Ahmed Hamed Arisha
Pharmaceutics 2023, 15(8), 2149; https://doi.org/10.3390/pharmaceutics15082149 - 16 Aug 2023
Cited by 1 | Viewed by 1539
Abstract
Chronic kidney disease (CKD), a global health concern, is highly prevalent among adults. Presently, there are limited therapeutic options to restore kidney function. This study aimed to investigate the therapeutic potential of breast milk mesenchymal stem cells (Br-MSCs) and their derived exosomes in [...] Read more.
Chronic kidney disease (CKD), a global health concern, is highly prevalent among adults. Presently, there are limited therapeutic options to restore kidney function. This study aimed to investigate the therapeutic potential of breast milk mesenchymal stem cells (Br-MSCs) and their derived exosomes in CKD. Eighty adult male Sprague Dawley rats were randomly assigned to one of six groups, including control, nephropathy, nephropathy + conditioned media (CM), nephropathy + Br-MSCs, nephropathy + Br-MSCs derived exosomes (Br-MSCs-EXOs), and nephropathy + Br-MSCs + Br-MSCs-EXOs. Before administration, Br-MSCs and Br-MSCs-EXOs were isolated, identified, and labeled with PKH-26. SOX2, Nanog, and OCT3/4 expression levels in Br-MSCs and miR-29b, miR-181, and Let-7b in both Br-MSCs and Br-MSCs-EXOs were assayed. Twelve weeks after transplantation, renal function tests, oxidative stress, expression of the long non-coding RNA SNHG-7, autophagy, fibrosis, and expression of profibrotic miR-34a and antifibrotic miR-29b, miR-181, and Let-7b were measured in renal tissues. Immunohistochemical analysis for renal Beclin-1, LC3-II, and P62, Masson trichome staining, and histopathological examination of kidney tissues were also performed. The results showed that Br-MSCs expressed SOX2, Nanog, and OCT3/4, while both Br-MSCs and Br-MSCs-EXOs expressed antifibrotic miR-181, miR-29b, and Let-7b, with higher expression levels in exosomes than in Br-MSCs. Interestingly, the administration of Br-MSCs + EXOs, EXOs, and Br-MSCs improved renal function tests, reduced renal oxidative stress, upregulated the renal expression of SNHG-7, AMPK, ULK-1, Beclin-1, LC3, miR-29b, miR-181, Let-7b, and Smad-7, downregulated the renal expression of miR-34a, AKT, mTOR, P62, TGF-β, Smad-3, and Coli-1, and ameliorated renal pathology. Thus, Br-MSCs and/or their derived exosomes appear to reduce adenine-induced renal damage by secreting antifibrotic microRNAs and potentiate renal autophagy by modulating SNHG-7 expression. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cell Extracellular Vesicles: From Active Principle to Next Generation Drug Delivery)
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17 pages, 9067 KiB  
Article
Mesenchymal Stromal Cell Exosomes Mediate M2-like Macrophage Polarization through CD73/Ecto-5′-Nucleotidase Activity
by Kristeen Ye Wen Teo, Shipin Zhang, Jia Tong Loh, Ruenn Chai Lai, Hwee Weng Dennis Hey, Kong-Peng Lam, Sai Kiang Lim and Wei Seong Toh
Pharmaceutics 2023, 15(5), 1489; https://doi.org/10.3390/pharmaceutics15051489 - 13 May 2023
Cited by 10 | Viewed by 2307
Abstract
Mesenchymal stem/stromal cell (MSC) exosomes have been shown to alleviate immune dysfunction and inflammation in preclinical animal models. This therapeutic effect is attributed, in part, to their ability to promote the polarization of anti-inflammatory M2-like macrophages. One polarization mechanism has been shown to [...] Read more.
Mesenchymal stem/stromal cell (MSC) exosomes have been shown to alleviate immune dysfunction and inflammation in preclinical animal models. This therapeutic effect is attributed, in part, to their ability to promote the polarization of anti-inflammatory M2-like macrophages. One polarization mechanism has been shown to involve the activation of the MyD88-mediated toll-like receptor (TLR) signaling pathway by the presence of extra domain A-fibronectin (EDA-FN) within the MSC exosomes. Here, we uncovered an additional mechanism where MSC exosomes mediate M2-like macrophage polarization through exosomal CD73 activity. Specifically, we observed that polarization of M2-like macrophages by MSC exosomes was abolished in the presence of inhibitors of CD73 activity, adenosine receptors A2A and A2B, and AKT/ERK phosphorylation. These findings suggest that MSC exosomes promote M2-like macrophage polarization by catalyzing the production of adenosine, which then binds to adenosine receptors A2A and A2B to activate AKT/ERK-dependent signaling pathways. Thus, CD73 represents an additional critical attribute of MSC exosomes in mediating M2-like macrophage polarization. These findings have implications for predicting the immunomodulatory potency of MSC exosome preparations. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cell Extracellular Vesicles: From Active Principle to Next Generation Drug Delivery)
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16 pages, 1303 KiB  
Article
Wound-Healing Effects of Mesenchymal Stromal Cell Secretome in the Cornea and the Role of Exosomes
by Seungwon An, Khandaker Anwar, Mohammadjavad Ashraf, Hyungjo Lee, Rebecca Jung, Raghuram Koganti, Mahmood Ghassemi and Ali R. Djalilian
Pharmaceutics 2023, 15(5), 1486; https://doi.org/10.3390/pharmaceutics15051486 - 13 May 2023
Cited by 5 | Viewed by 2327
Abstract
Mesenchymal stromal/stem cells (MSCs) and their secreted factors have been shown to have immunomodulatory and regenerative effects. In this study, we investigated human bone-marrow-derived MSC secretome (MSC-S) for the treatment of corneal epithelial wounds. Specifically, we evaluated the role of MSC extracellular vesicles [...] Read more.
Mesenchymal stromal/stem cells (MSCs) and their secreted factors have been shown to have immunomodulatory and regenerative effects. In this study, we investigated human bone-marrow-derived MSC secretome (MSC-S) for the treatment of corneal epithelial wounds. Specifically, we evaluated the role of MSC extracellular vesicles (EV)/exosomes in mediating the wound-healing effects of the MSC-S. In vitro studies using human corneal epithelial cells showed that MSC-CM increased cell proliferation in HCEC and HCLE cells, while EV-depleted MSC-CM showed lower cell proliferation in both cell lines compared to the MSC-CM group. In vitro and in vivo experiments revealed that 1X MSC-S consistently promoted wound healing more effectively than 0.5X MSC-S, and MSC-CM promoted wound healing in a dose-dependent manner, while exosome deprivation delayed wound healing. We further evaluated the incubation period of MSC-CM on corneal wound healing and showed that MSC-S collected for 72 h is more effective than MSC-S collected for 48 h. Finally, we evaluated the stability of MSC-S under different storage conditions and found that after one cycle of freeze–thawing, MSC-S is stable at 4 °C for up to 4 weeks. Collectively, we identified the following: (i) MSC-EV/Exo as the active ingredient in MSC-S that mediates the wound-healing effects in the corneal epithelium, providing a measure to optimize its dosing for a potential clinical product; (ii) Treatment with EV/Exo-containing MSC-S resulted in an improved corneal barrier and decreased corneal haze/edema relative to EV/Exo-depleted MSC-S; (iii) The stability of MSC-CM for up to 4 weeks showed that the regular storage condition did not significantly impact its stability and therapeutic functions. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cell Extracellular Vesicles: From Active Principle to Next Generation Drug Delivery)
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Review

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28 pages, 1734 KiB  
Review
Emerging Roles of Mesenchymal Stem/Stromal-Cell-Derived Extracellular Vesicles in Cancer Therapy
by Andreas Nicodemou, Soňa Bernátová, Michaela Čeháková and Ľuboš Danišovič
Pharmaceutics 2023, 15(5), 1453; https://doi.org/10.3390/pharmaceutics15051453 - 10 May 2023
Cited by 3 | Viewed by 2161
Abstract
Despite the tremendous efforts of many researchers and clinicians, cancer remains the second leading cause of mortality worldwide. Mesenchymal stem/stromal cells (MSCs) are multipotent cells residing in numerous human tissues and presenting unique biological properties, such as low immunogenicity, powerful immunomodulatory and immunosuppressive [...] Read more.
Despite the tremendous efforts of many researchers and clinicians, cancer remains the second leading cause of mortality worldwide. Mesenchymal stem/stromal cells (MSCs) are multipotent cells residing in numerous human tissues and presenting unique biological properties, such as low immunogenicity, powerful immunomodulatory and immunosuppressive capabilities, and, in particular, homing abilities. Therapeutic functions of MSCs are mediated mostly by the paracrine effect of released functional molecules and other variable components, and among them the MSC-derived extracellular vesicles (MSC-EVs) seem to be one of the central mediators of the therapeutic functions of MSCs. MSC-EVs are membrane structures secreted by the MSCs, rich in specific proteins, lipids, and nucleic acids. Amongst these, microRNAs have achieved the most attention currently. Unmodified MSC-EVs can promote or inhibit tumor growth, while modified MSC-EVs are involved in the suppression of cancer progression via the delivery of therapeutic molecules, including miRNAs, specific siRNAs, or suicide RNAs, as well as chemotherapeutic drugs. Here, we present an overview of the characteristics of the MSCs-EVs and describe the current methods for their isolation and analysis, the content of their cargo, and modalities for the modification of MSC-EVs in order for them to be used as drug delivery vehicles. Finally, we describe different roles of MSC-EVs in the tumor microenvironment and summarize current advances of MCS-EVs in cancer research and therapy. MSC-EVs are expected to be a novel and promising cell-free therapeutic drug delivery vehicle for the treatment of cancer. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cell Extracellular Vesicles: From Active Principle to Next Generation Drug Delivery)
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