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Mesenchymal Stem/Stromal Cells: Mechanisms and Applications in Tissue Regeneration

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 June 2026 | Viewed by 7898

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Special Issue Editor

Dr. Daiva Bironaite

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Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, LT-08410 Vilnius, Lithuania
Interests: cell death; survival mechanisms; intracellular signaling pathways; oxidative stress; adult human mesenchymal stem/stromal cells; tissue regeneration
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Special Issue Information

Dear Colleagues,

Mesenchymal stem/stromal cells (MSCs) have emerged as a cornerstone of regenerative medicine due to their multipotency, immunomodulatory properties, and ability to promote tissue repair. This Special Issue, “Mesenchymal Stem/Stromal Cells: Mechanisms and Applications in Tissue Regeneration”, brings together cutting-edge research and comprehensive reviews on the biology, therapeutic potential, and translational challenges of MSCs. Key topics include the molecular mechanisms underlying MSC differentiation, their interactions with the immune system, and their role in modulating the microenvironment for tissue repair in model systems in vitro and in vivo. The issue also explores innovative approaches for enhancing MSC efficacy, including genetic modifications, biomaterial scaffolds, and extracellular vesicle-based therapies. Additionally, clinical applications in the regeneration of musculoskeletal, cardiovascular, and other tissues are discussed, alongside emerging regulatory and manufacturing considerations. By integrating fundamental insights with translational advancements, this Special Issue provides a holistic perspective on the evolving landscape of MSC-based therapies and their future in regenerative medicine.

Dr. Daiva Bironaite
Guest Editor

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Keywords

MSC isolation, identification, and viability
MSC differentiation mechanisms
extracellular environment modifications
intracellular signalling systems
cytotoxicity investigations
tissue regeneration mechanisms

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Published Papers (7 papers)

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Research

Jump to: Review

19 pages, 4129 KB

Open AccessArticle

Cardiosphere-Derived Cells from Not Dilated and Dilated Human Myocardium Exhibit Enhanced Metabolic Potential Compared with Conventional Cardiac Mesenchymal Stem/Stromal Cells

by Daiva Bironaite and Rokas Mikšiūnas

Int. J. Mol. Sci. 2026, 27(3), 1303; https://doi.org/10.3390/ijms27031303 - 28 Jan 2026

Viewed by 354

Abstract

Dilated cardiomyopathy (DCM) is a major contributor to heart failure and cardiac transplantation. This study investigated the metabolic potential of human myocardium-derived mesenchymal stem/stromal cells (hmMSCs) and subsequently cardiac sphere-derived cells (SDCs) obtained from healthy (non-dilated) and pathological (dilated) myocardial tissues. hmMSCs were isolated using the explant outgrowth method and expanded in monolayer culture. Small round cells loosely attached on hmMSCs were harvested and cultivated as cardiac spheroids for 1–3 days, subsequently obtaining SDCs. The cell morphology, proliferation rate, mitochondrial activity, and intracellular calcium levels were analyzed using flow cytometry, Seahorse metabolic assays, and spectrophotometry, while expression of cell progenitor and cardiac commitment genes were analyzed by quantitative PCR. Both healthy and pathological SDCs demonstrated significantly enhanced mitochondrial function—reflected by increased maximal respiration, ATP production, and coupling efficiency—along with reduced steady-state intracellular calcium levels compared with hmMSCs. SDCs from both healthy and dilated myocardium showed marked upregulation of several cardiac progenitor and lineage-commitment genes relative to hmMSCs. SDCs derived from both healthy and dilated myocardiums possess a more favorable metabolic, progenitor and cardiac commitment profile than conventional hmMSCs. hmMSCs and SDCs from dilated myocardium retain residual metabolic potential, which may be further enhanced under 3D culture conditions. Full article

(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells: Mechanisms and Applications in Tissue Regeneration)

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22 pages, 6540 KB

Open AccessArticle

The Role of Gap Junctions in MSC-EA.hy926 (An Endothelial Cell Model) Crosstalk Under Hypoxic Stress: Regulation of the Angiogenic Response

by Mariia Ezdakova, Diana Matveeva and Margarita Lobanova

Int. J. Mol. Sci. 2025, 26(22), 11239; https://doi.org/10.3390/ijms262211239 - 20 Nov 2025

Viewed by 970

Abstract

Effective communication between multipotent mesenchymal stromal cells (MSCs) and endothelial cells (ECs) plays a critical role in the regulation of angiogenesis, especially under conditions of hypoxia. In addition to paracrine stimulation, direct intercellular contacts play an important role in the angiogenic interaction between MSCs and ECs, making them an important target for modulating vascular network restoration under ischemic conditions. The aim of this study was to determine the contribution of gap junctions (GJs) to the angiogenic response of MSCs and the EA.hy926 cell line (an Endothelial Cell Model) under acute hypoxic stress. In a cell co-culture model at 0.1% O₂ using a specific GJ inhibitor (carbenoxolone), molecular, cellular, and functional tests were performed: assessment of viability, proliferation, migration, secretion of angiogenic mediators, and expression of crucial genes. GJ blockade was accompanied by decreases in the proliferation and migration activity and angiogenic potential of the conditioned medium in in vitro and in ovo tests. These data highlight the importance of the GJ in coordinating the angiogenic response in conditions of acute hypoxia and can be used to develop protocols for regenerative medicine. Full article

(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells: Mechanisms and Applications in Tissue Regeneration)

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27 pages, 3715 KB

Open AccessArticle

Safety and Regenerative Properties of Immortalized Human Mesenchymal Stromal Cell Secretome

by Maxim Karagyaur, Alexandra Primak, Nataliya Basalova, Anna Monakova, Anastasia Tolstoluzhinskaya, Maria Kulebyakina, Elizaveta Chechekhina, Mariya Skryabina, Olga Grigorieva, Vadim Chechekhin, Tatiana Yakovleva, Victoria Turilova, Elena Shagimardanova, Guzel Gazizova, Maksim Vigovskiy, Konstantin Kulebyakin, Veronika Sysoeva, Uliana Dyachkova, Stalik Dzhauari, Kirill Bozov, Vladimir Popov, Zhanna Akopyan, Anastasia Efimenko, Natalia Kalinina and Vsevolod Tkachuk Show full author list Hide full author list

Int. J. Mol. Sci. 2025, 26(19), 9322; https://doi.org/10.3390/ijms26199322 - 24 Sep 2025

Cited by 1 | Viewed by 1413

Abstract

The secretome of mesenchymal stromal cells (MSCs) can efficiently stimulate regeneration and therefore is a tempting remedy for “cell-free cellular therapy”. However, the usage of primary MSC cultures as secretome producers for translation studies has obvious obstacles, including the rapid aging of MSC cultures, the need for a large number of verified donors, and donor-to-donor variability of secretome content. MSCs immortalization makes it possible to overcome those limitations and to obtain secretome-producing cultures with a prolonged lifetime. However, the efficacy and safety of such secretomes are critical issues that limit their usage as therapeutic agents. In this study, we tested in large detail how the immortalization of MSC cultures affects the content, biological activity and safety of their secretome. MSCs immortalization via the overexpression of human TERT gene does not significantly alter the qualitative and quantitative composition of their secretome or its activity according to the results of proteomic analysis, ELISA, qPCR and functional tests in vitro. Moreover, we have demonstrated that the secretome of immortalized MSCs does not contain detectable amounts of telomerase and does not possess any transforming activity. Altogether, our data suggest that immortalized MSC cultures may become a reliable source for obtaining standardized active secretome in large-scale quantities for clinical use. Full article

(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells: Mechanisms and Applications in Tissue Regeneration)

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15 pages, 3236 KB

Open AccessArticle

Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviated the Inflammatory Response in Mice Infected with the Influenza Virus A (H1N1)

by Hui Xiao, Xiao Yu, Yiding Dong, Shilong Bao, Xiaoting Meng, Jia Zhao and Zhiyong Dong

Int. J. Mol. Sci. 2025, 26(18), 8839; https://doi.org/10.3390/ijms26188839 - 11 Sep 2025

Viewed by 1316

Abstract

Influenza A virus (H1N1) infection poses a significant global public health challenge and imposes a substantial economic burden. Numerous studies have shown that excessive immune activation and dysregulated inflammatory responses following influenza virus infection are the primary causes of disease progression and mortality. Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) exhibit potent anti-inflammatory effects. Therefore, this study aims to investigate the effects of extracellular vesicles derived from human umbilical cord mesenchymal stem cells (hUCMSC-EVs) on pulmonary inflammatory responses in mice infected with the influenza A virus (H1N1). The study first established a mouse influenza virus infection model by intranasal inoculation of the influenza A virus (H1N1), followed by treatment with hUCMSC-EVs (70 μg) administered via tail vein injection for four consecutive days. The results showed that compared with the H1N1 group, after treatment with hUCMSC-EVs, pulmonary edema was reduced, inflammatory cell infiltration in the lungs was significantly decreased, and the expression levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) proteins in serum and lung tissue were significantly reduced. Therefore, this study suggests that the protective effect of hUCMSC-EVs against lung damage caused by influenza A virus (H1N1) infection may be related to the reduction in inflammatory cytokine levels of TNF-α, IL-1β, and IL-6, thereby alleviating pulmonary inflammation. Full article

(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells: Mechanisms and Applications in Tissue Regeneration)

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Review

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15 pages, 1905 KB

Open AccessReview

Mitochondria-Targeted Biophysical Priming of Autologous Biologics for Skin Regeneration and Wound Repair

by Geun-Ho Kang, Kilyong Lee, Chang Hwan Jeon, Seong Kyoung Kim and SungHoon Cho

Int. J. Mol. Sci. 2026, 27(5), 2201; https://doi.org/10.3390/ijms27052201 - 26 Feb 2026

Viewed by 372

Abstract

Skin aging, photoaging, and chronic wounds are increasingly recognized to be driven by mitochondria-centered mechanisms characterized by oxidative stress, defective mitophagy, and impaired bioenergetics in cutaneous cells. Autologous biologics, including platelet-rich plasma, stromal vascular fraction, bone marrow aspirate concentrate, and mesenchymal stromal/stem cell–derived products, are widely used for skin rejuvenation and wound repair. Recent studies have suggested that many of these effects are mediated by mitochondrial mechanisms, including metabolic reprogramming, redox modulation, and intercellular mitochondrial transfer. Concurrently, biophysical modalities such as red/near-infrared photobiomodulation (PBM), low-intensity pulsed ultrasound, mechanical stimulation, and nanoengineered cues can modulate mitochondrial function in skin-relevant cells. In this review, we integrate these lines of evidence to introduce the concept of mitochondria-targeted biophysical priming of autologous biologics for dermatological applications. We summarize the mitochondrial biology in skin pathology, evaluate these biologics as mitochondria-active therapies, and outline ex vivo priming implementation using PBM, ultrasound, or mechanical stimulation. Finally, we discuss key regulatory considerations that support clinical translation. Full article

(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells: Mechanisms and Applications in Tissue Regeneration)

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23 pages, 2400 KB

Open AccessReview

Clinical Insights into Mesenchymal Stem Cell Applications for Spinal Cord Injury

by Matthew Shkap, Daria Namestnikova, Elvira Cherkashova, Daria Chudakova, Arthur Biktimirov, Konstantin Yarygin and Vladimir Baklaushev

Int. J. Mol. Sci. 2025, 26(24), 12139; https://doi.org/10.3390/ijms262412139 - 17 Dec 2025

Viewed by 1438

Abstract

This review examines the safety and clinical efficacy of mesenchymal stem/stromal cells (MSCs)-based therapies in patients with spinal cord injury (SCI). The analysis covers 26 clinical studies conducted on patients with varying degrees of the post-SCI neurological deficit. The review highlights the methodology of trials, the source of MSCs, the dosage of cells administered, transplantation methods, patient inclusion criteria, and the methods of evaluating the effectiveness of the therapy. MSC transplantation in SCI was safe and feasible in all the studies summarized in our review. All studies conducted have demonstrated varying degrees of patient improvement and reduction in the severity of neurological deficits. However, further controlled randomized studies on larger numbers of patients are needed to better evaluate the therapeutic efficacy of MS transplantation. The prospects of the enhancement of the efficacy of the SCI cell therapy with MSCs, including their transplantation with other types of stem cells, administration of MSC-derived exosomes, genetic modification of MSCs, use of the MSC- and other-stem-cell-based tissue-engineered scaffolds, and combination of cell therapy with neuromodulation, are discussed. Full article

(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells: Mechanisms and Applications in Tissue Regeneration)

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35 pages, 1409 KB

Open AccessReview

Ex Vivo Preconditioning as a Useful Tool for Modification of the Extracellular Matrix of Multipotent Mesenchymal Stromal Cells

by Elena Andreeva, Olga Zhidkova, Diana Matveeva, Aleksandra Gornostaeva, Margarita Lobanova and Ludmila Buravkova

Int. J. Mol. Sci. 2025, 26(13), 6301; https://doi.org/10.3390/ijms26136301 - 30 Jun 2025

Viewed by 1689

Abstract

Cell technologies have provided promising tools for modulating the properties of multipotent mesenchymal stem/stromal cells (MSCs) to meet the needs of cell therapy as well as tissue engineering and regenerative medicine (TERM). Ex vivo preconditioning is directed at enhancing the engraftment of MSCs and activating their secretory activity, primarily the production of soluble mediators. The present review aims to highlight the underestimated effect of the most accepted preconditioning approaches on the modification of the important set of insoluble molecules secreted by MSCs into extracellular space—the extracellular matrix (ECM). A thorough review of the published literature was performed, with particular emphasis on ECM-related data. The analysis of data on ECM changes showed that most of the applied preconditioning methods—hypoxia, inflammatory priming, pharmacological agents, 3D culture, and scaffolds—generally stimulate ECM production, increase the deposition of growth factors, promote alignment, and increase ECM stiffness. There are already preliminary results demonstrating the successful application of preconditioned ECM for promoting angiogenesis, targeted stromal lineage differentiation, and other therapeutic goals. The prospects for further research in this area are discussed. Full article

(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells: Mechanisms and Applications in Tissue Regeneration)

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