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Pharmaceutics
Special Issues
Mesenchymal Stem Cell-Derived Extracellular Vesicles as Therapeutics
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Mesenchymal Stem Cell-Derived Extracellular Vesicles as Therapeutics

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

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 17772

Special Issue Editors

Dr. Enrico Ragni

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Guest Editor
Laboratorio di Biotecnologie Applicate All'Ortopedia, IRCCS Ospedale Galeazzi–Sant’Ambrogio, Via Cristina Belgioioso 173, 20157 Milan, Italy
Interests: regenerative medicine; mesenchymal stromal cells; osteoarthritis; extracellular vesicles; miRNA
Special Issues, Collections and Topics in MDPI journals
Dr. Carlotta Perucca Orfei

E-Mail Website
Guest Editor
Laboratorio di Biotecnologie Applicate all'Ortopedia, IRCCS Istituto Ortopedico Galeazzi, I-20161 Milano, Italy
Interests: regenerative medicine; mesenchymal stromal cells; tendinopathies; extracellular vesicles; miRNA

Special Issue Information

Dear Colleagues,

Mesenchymal stromal cells (MSCs) have gained attention in the field of regenerative medicine. MSCs’ differentiation potential together with their paracrine properties has made them a crucial option for tissue healing and repair. MSCs’ paracrine properties rely on the release of soluble factors and extracellular vesicles (EVs) such as exosomes and microvesicles. EVs’ origin is mainly endosomal, and they shuttle a cargo defined by several active molecules such as miRNA, mRNA, lipids and proteins that are transferred from their original cells to target cells. In the last decade, EVs have been postulated as crucial players for the therapeutic effect of MSCs in several in vitro and in vivo disease models. Moreover, a number of clinical trials using MSC-EVs have been started covering cancer, neurological diseases, diabetes and COVID-19. Hence, MSC-EVs may be envisioned as a cell-free therapy in regenerative medicine and all those diseases where tissue healing is needed. Nevertheless, a deep characterization of the cargo fingerprint associated with the MSC source and an explanation of MSCs’ properties are still largely missing. Therefore, the aim of this Special Issue is to collect reports from in vitro to clinical trials aimed at shedding light on MSC-EV features at both the physiological and molecular levels.

Dr. Enrico Ragni
Dr. Carlotta Perucca Orfei
Guest Editors

Manuscript Submission Information

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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 stromal cells
  • extracellular vesicles
  • regenerative medicine
  • miRNA
  • lipids
  • cytokines

Related Special Issue

Published Papers (6 papers)

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Research

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18 pages, 1841 KiB  
Article
Joint Tissue Protective and Immune-Modulating miRNA Landscape of Mesenchymal Stromal Cell-Derived Extracellular Vesicles under Different Osteoarthritis-Mimicking Conditions
by Enrico Ragni, Carlotta Perucca Orfei, Federico Sinigaglia and Laura de Girolamo
Pharmaceutics 2022, 14(7), 1400; https://doi.org/10.3390/pharmaceutics14071400 - 2 Jul 2022
Cited by 2 | Viewed by 1759
Abstract
In regenerative medicine related to orthopedic conditions, mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs) have been proposed as innovative clinical options. The definition of EV-shuttled signals and their modulation under orthopedic settings, such as osteoarthritis (OA), is crucial for MSC-related research, [...] Read more.
In regenerative medicine related to orthopedic conditions, mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs) have been proposed as innovative clinical options. The definition of EV-shuttled signals and their modulation under orthopedic settings, such as osteoarthritis (OA), is crucial for MSC-related research, both for basic science and for use in clinical settings, either as therapeutics or as producers of cell-free products such as EVs or secretome. The objective of this work is to compare the literature available on high-throughput EV-miRNA data obtained from adipose-derived MSCs (ASCs) in standard conditions or cultured in high levels of IFNγ, low-level inflammatory conditions mimicking OA synovial fluid (SF), and OA-SF. The first result was that both IFNγ and low-level inflammatory treatment led to an increase, whereas SF led to a reduction in EV release. Second, more than 200 EV-miRNAs were found to be shared across the different conditions. After a bioinformatics search through experimentally validated and OA-related targets, pathways and tissues, several miRNAs resulted in the restoration of cartilage and synovium stability and the homeostasis of inflammatory cells, including macrophages, promoting their switch towards an M2 anti-inflammatory phenotype. Third, IFNγ and especially SF culturing were able to modulate the overall EV-miRNA fingerprint, although the main molecular messages related to OA resulted conserved between treatments with the majority of modulations within 2-fold range. In conclusion, ASC EV-miRNAs may be modulated in their overall landscape by OA-related culturing conditions albeit resulted largely stable in their specific OA-protective signals allowing for a faster clinical translation of these new cell-free therapies for joint diseases. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cell-Derived Extracellular Vesicles as Therapeutics)
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15 pages, 3867 KiB  
Article
Human Osteochondral Explants as an Ex Vivo Model of Osteoarthritis for the Assessment of a Novel Class of Orthobiologics
by Chiara Giannasi, Laura Mangiavini, Stefania Niada, Andrea Colombo, Elena Della Morte, Valeria Vismara, Andrea Ambrosanio, Paolo Savadori, Sara Casati, Giuseppe M. Peretti and Anna Teresa Brini
Pharmaceutics 2022, 14(6), 1231; https://doi.org/10.3390/pharmaceutics14061231 - 10 Jun 2022
Cited by 1 | Viewed by 1991
Abstract
Osteoarthritis (OA) is a highly prevalent joint disease still lacking effective treatments. Its multifactorial etiology hampers the development of relevant preclinical models to evaluate innovative therapeutic solutions. In the last decade, the potential of Mesenchymal Stem Cell (MSC) secretome, or conditioned medium (CM), [...] Read more.
Osteoarthritis (OA) is a highly prevalent joint disease still lacking effective treatments. Its multifactorial etiology hampers the development of relevant preclinical models to evaluate innovative therapeutic solutions. In the last decade, the potential of Mesenchymal Stem Cell (MSC) secretome, or conditioned medium (CM), has emerged as an alternative to cell therapy. Here, we investigated the effects of the CM from adipose MSCs (ASCs), accounting for both soluble factors and extracellular vesicles, on human osteochondral explants. Biopsies, isolated from total knee replacement surgery, were cultured without additional treatment or with the CM from 106 ASCs, both in the absence and in the presence of 10 ng/mL TNFα. Tissue viability and several OA-related hallmarks were monitored at 1, 3 and 6 days. Specimen viability was maintained over culture. After 3 days, TNFα induced the enhancement of matrix metalloproteinase activity and glycosaminoglycan release, both efficiently counteracted by CM. The screening of inflammatory lipids, proteases and cytokines outlined interesting modulations, driving the attention to new players in the OA process. Here, we confirmed the promising beneficial action of ASC secretome in the OA context and profiled several bioactive factors involved in its progression, in the perspective of accelerating an answer to its unmet clinical needs. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cell-Derived Extracellular Vesicles as Therapeutics)
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15 pages, 4931 KiB  
Article
Therapeutic Potential of Exosomes Derived from Diabetic Adipose Stem Cells in Cutaneous Wound Healing of db/db Mice
by Hsiang-Hao Hsu, Aline Yen Ling Wang, Charles Yuen Yung Loh, Ashwin Alke Pai and Huang-Kai Kao
Pharmaceutics 2022, 14(6), 1206; https://doi.org/10.3390/pharmaceutics14061206 - 6 Jun 2022
Cited by 13 | Viewed by 2547
Abstract
(1) Background: Diabetes impairs angiogenesis and wound healing. Paracrine secretion from adipose stem cells (ASCs) contains membrane-bound nano-vesicles called exosomes (ASC-Exo) but the functional role and therapeutic potential of diabetic ASC-Exo in wound healing are unknown. This study aims to investigate the in [...] Read more.
(1) Background: Diabetes impairs angiogenesis and wound healing. Paracrine secretion from adipose stem cells (ASCs) contains membrane-bound nano-vesicles called exosomes (ASC-Exo) but the functional role and therapeutic potential of diabetic ASC-Exo in wound healing are unknown. This study aims to investigate the in vivo mechanistic basis by which diabetic ASC-Exo enhance cutaneous wound healing in a diabetic mouse model. (2) Methods: Topically applied exosomes could efficiently target and preferentially accumulate in wound tissue, and the cellular origin, ASC or dermal fibroblast (DFb), has no influence on the biodistribution pattern of exosomes. In vivo, full-thickness wounds in diabetic mice were treated either with ASC-Exo, DFb-Exo, or phosphate-buffered saline (PBS) topically. ASC-Exo stimulated wound healing by dermal cell proliferation, keratinocyte proliferation, and angiogenesis compared with DFb-Exo and PBS-treated wounds. (3) Results: Diabetic ASC-Exo stimulated resident monocytes/macrophages to secrete more TGF-β1 and activate the TGF-β/Smad3 signaling pathway. Fibroblasts activated by TGF-β1containing exosomes from ASCs initiate the production of TGF-β1 protein in an autocrine fashion, which leads to more proliferation and activation of fibroblasts. TGF-β1 is centrally involved in diabetic ASC-Exo mediated cellular crosstalk as an important early response to initiating wound regeneration. (4) Conclusions: The application of diabetic ASC-Exo informs the potential utility of a cell-free therapy in diabetic wound healing. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cell-Derived Extracellular Vesicles as Therapeutics)
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21 pages, 6256 KiB  
Article
Human Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Ameliorated Insulin Resistance in Type 2 Diabetes Mellitus Rats
by Seng Kar Yap, Kian Leong Tan, Nor Yasmin Abd Rahaman, Nur Fazila Saulol Hamid, Der Jiun Ooi, Yin Sim Tor, Qi Hao Daniel Looi, Li Kar Stella Tan, Chee Wun How and Jhi Biau Foo
Pharmaceutics 2022, 14(3), 649; https://doi.org/10.3390/pharmaceutics14030649 - 16 Mar 2022
Cited by 23 | Viewed by 3593
Abstract
Human umbilical cord mesenchymal stem cell-derived small extracellular vesicle (hUC-MSCs-sEVs) therapy has shown promising results to treat diabetes mellitus in preclinical studies. However, the dosage of MSCs-sEVs in animal studies, up to 10 mg/kg, was considered high and may be impractical for future [...] Read more.
Human umbilical cord mesenchymal stem cell-derived small extracellular vesicle (hUC-MSCs-sEVs) therapy has shown promising results to treat diabetes mellitus in preclinical studies. However, the dosage of MSCs-sEVs in animal studies, up to 10 mg/kg, was considered high and may be impractical for future clinical application. This study aims to investigate the efficacy of low-dose hUC-MSCs-sEVs treatment on human skeletal muscle cells (HSkMCs) and type 2 diabetes mellitus (T2DM) rats. Treatment with hUC-MSCs-sEVs up to 100 μg/mL for 48 h showed no significant cytotoxicity. Interestingly, 20 μg/mL of hUC-MSCs-sEVs-treated HSkMCs increased glucose uptake by 80–90% compared to untreated cells. The hUC-MSCs-sEVs treatment at 1 mg/kg improved glucose tolerance in T2DM rats and showed a protective effect on complete blood count. Moreover, an improvement in serum HbA1c was observed in diabetic rats treated with 0.5 and 1 mg/kg of hUC-MSCs-sEVs, and hUC-MSCs. The biochemical tests of hUC-MSCs-sEVs treatment groups showed no significant creatinine changes, elevated alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels compared to the normal group. Histological analysis revealed that hUC-MSCs-sEVs relieved the structural damage to the pancreas, kidney and liver. The findings suggest that hUC-MSCs-sEVs could ameliorate insulin resistance and exert protective effects on T2DM rats. Therefore, hUC-MSCs-sEVs could serve as a potential therapy for diabetes mellitus. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cell-Derived Extracellular Vesicles as Therapeutics)
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Review

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39 pages, 6152 KiB  
Review
Practical Considerations for Translating Mesenchymal Stromal Cell-Derived Extracellular Vesicles from Bench to Bed
by Pauline Po Yee Lui and Yung Tim Leung
Pharmaceutics 2022, 14(8), 1684; https://doi.org/10.3390/pharmaceutics14081684 - 12 Aug 2022
Cited by 10 | Viewed by 2519
Abstract
Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have shown potential for the treatment of tendon and ligament injuries. This approach can eliminate the need to transplant live cells to the human body, thereby reducing issues related to the maintenance of cell [...] Read more.
Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have shown potential for the treatment of tendon and ligament injuries. This approach can eliminate the need to transplant live cells to the human body, thereby reducing issues related to the maintenance of cell viability and stability and potential erroneous differentiation of transplanted cells to bone or tumor. Despite these advantages, there are practical issues that need to be considered for successful clinical application of MSC-EV-based products in the treatment of tendon and ligament injuries. This review aims to discuss the general and tissue-specific considerations for manufacturing MSC-EVs for clinical translation. Specifically, we will discuss Good Manufacturing Practice (GMP)-compliant manufacturing and quality control (parent cell source, culture conditions, concentration method, quantity, identity, purity and impurities, sterility, potency, reproducibility, storage and formulation), as well as safety and efficacy issues. Special considerations for applying MSC-EVs, such as their compatibility with arthroscopy for the treatment of tendon and ligament injuries, are also highlighted. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cell-Derived Extracellular Vesicles as Therapeutics)
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23 pages, 1223 KiB  
Review
Effects of BMSC-Derived EVs on Bone Metabolism
by Xuchang Zhou, Hong Cao, Jianming Guo, Yu Yuan and Guoxin Ni
Pharmaceutics 2022, 14(5), 1012; https://doi.org/10.3390/pharmaceutics14051012 - 8 May 2022
Cited by 31 | Viewed by 4484
Abstract
Extracellular vesicles (EVs) are small membrane vesicles that can be secreted by most cells. EVs can be released into the extracellular environment through exocytosis, transporting endogenous cargo (proteins, lipids, RNAs, etc.) to target cells and thereby triggering the release of these biomolecules and [...] Read more.
Extracellular vesicles (EVs) are small membrane vesicles that can be secreted by most cells. EVs can be released into the extracellular environment through exocytosis, transporting endogenous cargo (proteins, lipids, RNAs, etc.) to target cells and thereby triggering the release of these biomolecules and participating in various physiological and pathological processes. Among them, EVs derived from bone marrow mesenchymal stem cells (BMSC-EVs) have similar therapeutic effects to BMSCs, including repairing damaged tissues, inhibiting macrophage polarization and promoting angiogenesis. In addition, BMSC-EVs, as efficient and feasible natural nanocarriers for drug delivery, have the advantages of low immunogenicity, no ethical controversy, good stability and easy storage, thus providing a promising therapeutic strategy for many diseases. In particular, BMSC-EVs show great potential in the treatment of bone metabolic diseases. This article reviews the mechanism of BMSC-EVs in bone formation and bone resorption, which provides new insights for future research on therapeutic strategies for bone metabolic diseases. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cell-Derived Extracellular Vesicles as Therapeutics)
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