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Advanced Therapy Using Human Mesenchymal Stem Cells (MSCs) and MSC Extracellular Vesicles

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 20 April 2026 | Viewed by 12377

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Special Issue Editors

Dr. Tong Ming Liu

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Guest Editor

Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
Interests: MSC and iPSC medium development; critical quality attributes (CQAs) of MSC manufacturing; mesenchymal stem cell stemness and ageing; gene therapy and cell therapy of human mesenchymal stem cells (hMSCs) for bone and cartilage regeneration; bone and cartilage disease modeling; drug screening and gene correction via iPSCs; immortalization of hMSCs

Dr. Xiaoman Luo

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Guest Editor

Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
Interests: bioceramics; material-induced osteoinduction; biomaterials for orthopaedics; bioengineering; bone and cartilage regeneration; mesenchymal stem cell for bone and cartilage regeneration; bone and cartilage disease modeling; biological evaluation of implantable devices; animal models

Special Issue Information

Dear Colleagues,

Human mesenchymal stem cells (MSCs) are one of the most used stem cells for clinical applications. So far, MSCs have been used in over 1500 clinical trials to treat over 30 diseases. However, MSC applications are being greatly affected by several limitations, such as limited lifespan, gradual loss of MSC stemness during in vitro expansion, cell rejection during transplant etc. Extracellular vesicles (EVs), particularly exosomes, are small membrane-bound particles secreted by cells. EVs carry various bioactive molecules such as proteins, lipids, mRNAs, and miRNAs, which contribute to their therapeutic effects. MSC-derived EVs are considered to mediate many of the therapeutic effects previously attributed to MSCs themselves, offering a cell-free alternative in regenerative medicine. Due to the advantages of MSC-EVs in cell-free approaches, i.e., their scalability and safety, MSC-EVs have been used for anti-inflammatory effects, tissue repair, neurological disorders, and cancer therapy.

Advanced therapy using MSCs and MSC-EVs is an emerging field for enhanced regenerative medicine and cell-based/free therapy. These approaches leverage the biological properties of MSCs and their secreted EVs to treat various conditions, including tissue injuries, inflammation, and degenerative diseases.

This Special Issue of the International Journal of Molecular Sciences titled “Advanced Therapy Using Human Mesenchymal Stem Cells (MSCs) and MSC Extracellular Vesicles” will include a selection of scientific contributions aimed at presenting the development and applications using MSCs and MSC-EVs, including cell therapy, gene therapy, EV characterization/standardization and application, manufacturing and scale-up, and mechanistic understanding to address personalized and regenerative medicine approaches.

Original research, review articles, preclinical studies, short communications, and letters on all topics in these research fields are invited.

This Special Issue is now open for submissions. If you are interested in contributing your work, please send a tentative title or short abstract to the Guest Editor or Editorial Office.

Dr. Tong Ming Liu
Dr. Xiaoman Luo
Guest Editors

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

mesenchymal stem cells
extracellular vesicles
MSCs
MSC-EVs
regenerative medicine

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Published Papers (7 papers)

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Research

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19 pages, 3716 KB

Open AccessArticle

Anti-Inflammatory and Angiogenic Effects of Stem Cell Secretome

by Shawn P. Grogan, Grant Stinebaugh and Darryl D. D’Lima

Int. J. Mol. Sci. 2026, 27(5), 2325; https://doi.org/10.3390/ijms27052325 - 1 Mar 2026

Viewed by 774

Abstract

Mesenchymal stem cells (MSCs) exert biological effects in part through their secretome which includes extracellular vesicles. In this study, we isolated and characterized the secretome from clinically relevant stem cell lines: human embryonic stem cell–derived mesenchymal stem cell line (ES-MSCs) and Infrapatellar fat pad derived MSC (IPFP-MSC) cultured in xeno-free medium. We assessed the biological activity of concentrated cell secretome or isolated fractions of extracellular vesicles (EVs) on cell proliferation, microvascular formation, and cartilage degradation in a human osteoarthritic (OA) ex vivo model. Serum-free conditioned medium from ES-MSC (N = 1) or IPFP-MSC (N = 2) monolayer cultures were concentrated by ultrafiltration to generate concentrated conditioned medium (CCM). Size exclusion chromatography was used to fractionate extracellular vesicles (EVs). Vesicle size, concentration, morphology, and surface markers were characterized by nanoparticle tracking analysis, transmission electron microscopy, and flow cytometry. Biological activity was evaluated by treating human umbilical vein endothelial cells (HUVECs), IPFP-MSCs, and ES-MSCs with CCM and EVs at defined particle concentrations. Endothelial network formation was tested in fibrin gels with different cell and secretome combinations. For analysis of cartilage degradation, human cartilage explants (N = 4; 3.5 mm in diameter) were harvested from patients undergoing total knee arthroplasty and subjected to IL-1β stimulation to induce an OA phenotype. Explants were treated with varying doses from CCM or EVs. Release of glycosaminoglycan in the medium and RNA analysis of catabolic genes were used as readouts. Secretome preparations yielded on average approximately 50 billion vesicles per mL with a similar particle size distribution between 50–200 nm in ES-MSC and IPFP-MSC cultures. Transmission electron microscopy confirmed vesicle morphology and flow cytometry confirmed expression of exosomal surface markers (CD9, CD63, CD81). Functionally, CCM and EVs enhanced proliferation in a dose-dependent manner. Endothelial networks formed by HUVECs in fibrin were stabilized over 7 days by CCMs, most notably by hypoxic ES-MSC CCM relative to no CCM treatment (control). In the OA cartilage model, IL-1β stimulation increased glycosaminoglycan release, whereas ES-MSC CCM treatment and EV treatment reduced glycosaminoglycan release and ES-MSC CCM reduced gene expression of IL-1β, MMP-1, and MMP-3. We isolated and characterized the concentrated secretome and the isolated vesicle-enriched fractions from xeno-free ES-MSC and IPFP-MSC and demonstrated bioactivity in promoting cell proliferation, modulating endothelial network formation, and mitigating cartilage degradation in osteoarthritic tissue. These findings support the bioactivity and therapeutic potential of stem cell–derived secretomes for OA. Full article

(This article belongs to the Special Issue Advanced Therapy Using Human Mesenchymal Stem Cells (MSCs) and MSC Extracellular Vesicles)

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18 pages, 2664 KB

Open AccessArticle

The Protective Role of Curcumin in Osteoarthritis: Establishing Mitochondrial Homeostasis Through Autophagy Induction and Apoptosis Inhibition

by Kavitha Raja, Rajashree Patnaik, Dineshwary Suresh, Riah Varghese, Adam Eid, Thomas Nau, Yajnavalka Banerjee and Nerissa Naidoo

Int. J. Mol. Sci. 2026, 27(2), 609; https://doi.org/10.3390/ijms27020609 - 7 Jan 2026

Viewed by 700

Abstract

Osteoarthritis (OA) is a progressive joint disorder affecting over 250 million people globally and is characterized by chronic pain and disability. Among its key pathogenic mechanisms are mitochondrial dysfunction and elevated reactive oxygen species (ROS), often triggered by inflammatory mediators such as lipopolysaccharide (LPS). This study evaluates the protective effects of curcumin on mitochondrial function, autophagy, and apoptosis in an in vitro model of OA. Human bone marrow-derived mesenchymal stem cells (BMSCs) were differentiated into chondrocytes using MesenCult™-ACF medium. Differentiation was confirmed by histological staining for Type II Collagen, Alcian Blue, and Toluidine Blue. LPS was used to induce an OA-like inflammatory response. Mitochondrial membrane potential (ΔΨm) was assessed using Rhodamine 123 staining. Autophagy and apoptosis were evaluated using Acridine orange and propidium iodide staining, respectively. Western blotting was performed to analyze the expression of pro-caspase-3, Bcl-2, Beclin-1, LC3-I/II, and GAPDH. LPS significantly impaired mitochondrial function, limited autophagy, and enhanced apoptotic signaling (reduced pro-caspase-3). Curcumin (25 µM and 100 µM) restored ΔΨm, increased Beclin-1 and LC3-II, and maintained pro-caspase-3 expression, with Bcl-2 showing a non-monotonic response (higher at 25 µM than at 100 µM). Curcumin exerted cytoprotective effects in inflamed chondrocytes by stabilizing ΔΨm, promoting autophagy, and attenuating apoptotic activation, supporting its multi-target therapeutic potential in OA. Full article

(This article belongs to the Special Issue Advanced Therapy Using Human Mesenchymal Stem Cells (MSCs) and MSC Extracellular Vesicles)

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23 pages, 3798 KB

Open AccessArticle

The Impact of IFN-γ Licensing on Mesenchymal Stromal Cells’ Mediated Immunoregulation and HLA Class II Expression: Emerging Evidence from In Vitro Results

by Panagiotis Mallis, Theofanis Chatzistamatiou, Evangelia Gkatzoflia, Hava Zdrava, Eirini-Faidra Sarri, Efstathios Michalopoulos, Alexandros Spyridonidis and Catherine Stavropoulos-Giokas

Int. J. Mol. Sci. 2025, 26(19), 9436; https://doi.org/10.3390/ijms26199436 - 26 Sep 2025

Viewed by 1346

Abstract

Mesenchymal stromal cells (MSCs) exert their immunoregulatory properties after licensing by inflammatory signaling cues, e.g., interferon (IFN)-γ. However, MSCs licensing by IFN-γ may result in increased expression of human leukocyte antigen (HLA) class II, which is related to rapid cell elimination, impairment of their immunosuppressive properties, and patient sensitization. The aim of this study was to evaluate the impact of IFN-γ on mediated immunoregulation and HLA class II expression. In this study, Wharton’s jelly (WJ) MSCs were isolated from human umbilical cords. Well-defined WJ-MSCs were submitted to IFN-γ exposure, and after 96 h, evaluation of biomolecule secretion and HLA class II expression was performed. Typing of HLA alleles using a next-generation sequencing (NGS) platform was performed. IFN-γ-primed WJ-MSCs secreted a high amount of immunoregulatory biomolecules, while elevated expression of HLA-DRB1 was observed. Analyses the NGS results showed the possibility of WJ-MSCs cluster formation based on their frequency of detected HLA alleles and immunoregulatory potential. Taking into consideration that IFN-γ-primed WJ-MSCs express HLA class II alleles, it is suggested that the HLA histocompatibility between allogeneic donor and recipient should be strongly considered to acquire the most beneficial outcome for the MSCs therapeutic strategy. Full article

(This article belongs to the Special Issue Advanced Therapy Using Human Mesenchymal Stem Cells (MSCs) and MSC Extracellular Vesicles)

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21 pages, 4205 KB

Open AccessArticle

Safety Evaluation and Biodistribution of Fetal Umbilical Cord Mesenchymal Stem Cells-Derived Small Extracellular Vesicles in Sprague Dawley Rats

by Illayaraja Krishnan, Ubashini Vijakumaran, Ng Min Hwei, Law Jia Xian, Mohd Rafizul Mohd Yusof, Thavachelvi Thangarajah, Tan Geok Chin, Yin Ping Wong, Anusha Kalyanasundaram, Zalina Mahmood, Shathiya Rajamanickam, Baskar Subramani and Yogeswaran Lokanathan

Int. J. Mol. Sci. 2025, 26(14), 6806; https://doi.org/10.3390/ijms26146806 - 16 Jul 2025

Cited by 2 | Viewed by 2183

Abstract

Umbilical cord mesenchymal stem cells (UCMSCs)-derived small extracellular vehicles (sEVs) are reported to offer therapeutic effects in regenerative medicine, but they lack safety and biodistribution profiles to support smooth translation at the clinical stage and regulatory requirements. Our study aimed to determine the safety and biodistribution profile in a healthy animal model before application in the metabolic syndrome model. Method: Healthy male Sprague Dawley (SD) rats were given an intravenous (IV) injection of normal saline (control group) or pooled fetal UCMSCs-derived sEVs (treated group) every three weeks for 90 days. Morbidity and mortality observation (daily), physical measurements (weekly), selected serum biochemistry (every three weeks), and hematology (every three weeks) were performed for 90 days. Acute toxicity (on day 14) and sub-chronic toxicity (on day 90) were assessed for gross necropsy, relative organ weight, and histopathological assessment of lungs, liver, spleen, kidney, and lymph nodes. Separately, a biodistribution study was conducted with the sEVs preparations labeled with PKH26 fluorescent dye, given intravenously to the rats. The organs were harvested 24 h post-injection. There were no drastic changes in either group’s morbidity or mortality, physical, hematological, and biochemistry evaluation. The histopathological assessment concluded moderate (focal) inflammation in the treated group’s kidneys and signs of recovery from the inflammation and vascular congestion in the liver. A biodistribution study revealed a higher accumulation of sEVs in the spleen. Multiple IV injections of the pooled fetal UCMSCs-derived sEVs in healthy male SD rats were deemed safe. The sEVs were abundantly distributed in the spleen 24 h post-injection. Full article

(This article belongs to the Special Issue Advanced Therapy Using Human Mesenchymal Stem Cells (MSCs) and MSC Extracellular Vesicles)

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22 pages, 5741 KB

Open AccessArticle

The Therapeutic Potential of Exosomes vs. Matrix-Bound Nanovesicles from Human Umbilical Cord Mesenchymal Stromal Cells in Osteoarthritis Treatment

by Timofey O. Klyucherev, Maria A. Peshkova, Daria P. Revokatova, Natalia B. Serejnikova, Nafisa M. Fayzullina, Alexey L. Fayzullin, Boris P. Ershov, Yana I. Khristidis, Irina I. Vlasova, Nastasia V. Kosheleva, Andrey A. Svistunov and Peter S. Timashev

Int. J. Mol. Sci. 2024, 25(21), 11564; https://doi.org/10.3390/ijms252111564 - 28 Oct 2024

Cited by 14 | Viewed by 5117

Abstract

Osteoarthritis (OA) is a degenerative joint disease with limited therapeutic options, where inflammation plays a critical role in disease progression. Extracellular vesicles (EV) derived from mesenchymal stromal cells (MSC) have shown potential as a therapeutic approach for OA by modulating inflammation and alleviating degenerative processes in the joint. This study evaluated the therapeutic effects for the treatment of OA of two types of EV—exosomes and matrix-bound nanovesicles (MBV)—both derived from the human umbilical cord MSC (UC-MSC) via differential ultracentrifugation. Different phenotypes of human monocyte-derived macrophages (MDM) were used to study the anti-inflammatory properties of EV in vitro, and the medial meniscectomy-induced rat model of knee osteoarthritis (MMx) was used in vivo. The study found that both EV reduced pro-inflammatory cytokines IL-6 and TNF-α in MDM. However, exosomes showed superior results, preserving the extracellular matrix (ECM) of hyaline cartilage, and reducing synovitis more effectively than MBVs. Additionally, exosomes downregulated inflammatory markers (TNF-α, iNOS) and increased Arg-1 expression in macrophages and synovial fibroblasts, indicating a stronger anti-inflammatory effect. These results suggest UC-MSC exosomes as a promising therapeutic option for OA, with the potential for modulating inflammation and promoting joint tissue regeneration. Full article

(This article belongs to the Special Issue Advanced Therapy Using Human Mesenchymal Stem Cells (MSCs) and MSC Extracellular Vesicles)

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Review

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21 pages, 4087 KB

Open AccessReview

Bridging Osteoimmunology and Regenerative Therapy: The Role of MSCs and Extracellular Vesicles

by Itziar Álvarez-Iglesias, Alice Colombo, Luis Gil-de-Gómez, Daniel García-Sánchez, Alberto González-González and Flor M. Pérez-Campo

Int. J. Mol. Sci. 2026, 27(3), 1155; https://doi.org/10.3390/ijms27031155 - 23 Jan 2026

Viewed by 674

Abstract

Bone homeostasis and regeneration depend on tightly regulated interactions between skeletal cells and the immune system within the bone microenvironment. Disruption of this crosstalk by ageing, chronic inflammation, or systemic disease contributes to osteoporosis, inflammatory bone loss, and impaired fracture healing. Osteoimmunology has reframed bone biology as an immune-regulated process, highlighting mesenchymal stem cells (MSCs) as central coordinators of bone-immune communication. Beyond their differentiation capacity, MSCs act primarily through paracrine mechanisms, releasing a secretome composed of soluble factors and extracellular vesicles (EVs) that modulate immune responses, regulate osteoblast and osteoclast activity, promote angiogenesis, and support extracellular matrix remodelling. MSC-derived EVs have emerged as key nanoscale mediators that transfer bioactive cargo to target cells in a context-dependent manner, enabling precise regulation of osteoimmune processes. This review summarises current knowledge on the role of MSCs in osteoimmunology, with a focus on how their secretome and EVs integrate immune modulation with bone regeneration. We discuss the mechanisms underlying MSC-mediated regulation of innate and adaptive immune cells, examine emerging cell-free therapeutic strategies based on secretome and EV delivery, and outline the main challenges that must be addressed to advance these approaches towards clinical application. Full article

(This article belongs to the Special Issue Advanced Therapy Using Human Mesenchymal Stem Cells (MSCs) and MSC Extracellular Vesicles)

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23 pages, 1463 KB

Open AccessReview

Acute Lung Injury Induced by Hyperbaric Oxygen or Other External Factors, with a Focus on Exosomes

by Jing Shi, Houyu Zhao, Chenyang Yan, Ping Zhu, Qi Zhu, Wei Ding, Longfei Wang, Yunpeng Zhao, Yue Wang and Yiqun Fang

Int. J. Mol. Sci. 2026, 27(2), 836; https://doi.org/10.3390/ijms27020836 - 14 Jan 2026

Viewed by 780

Abstract

Acute lung injury (ALI) is in part precipitated by hyperbaric oxygen or other mechanical insults. It constitutes the fundamental pathological process underlying acute respiratory distress syndrome (ARDS). The manifestation of the condition is characterized by an uncontrolled inflammatory response and alveolar edema, consequent to the disruption of the alveolar–capillary barrier. This phenomenon is associated with elevated morbidity and mortality rates. The current therapeutic interventions for ALI are not well researched or articulated. However, recent studies have indicated that stem cells may possess therapeutic potential in the context of ALI. The present study demonstrates that these exosome preparations have the capacity to significantly ameliorate radiographic findings, histological parameters, and vascular permeability in murine models of ALI. Concurrently, they attenuate the inflammatory response to a certain extent. The present review commences with an examination of the pathogenic mechanisms and manifestations of pulmonary injury induced by hyperbaric oxygen or other external factors. The subsequent sections of the text provide detailed accounts of the latest advances in exosome-based therapies for mitigating such injury, including their mechanisms of action and future translational prospects. While exosome-based treatments have demonstrated considerable advancement in preclinical research, numerous challenges must be surmounted before their widespread implementation in clinical settings can be realized, underscoring the necessity for sustained research in this domain. Full article

(This article belongs to the Special Issue Advanced Therapy Using Human Mesenchymal Stem Cells (MSCs) and MSC Extracellular Vesicles)

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