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Cells
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Immunoregulatory Functions of Mesenchymal Stem Cells (MSCs)
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Immunoregulatory Functions of Mesenchymal Stem Cells (MSCs)

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: 31 May 2026 | Viewed by 9373

Special Issue Editor

Prof. Dr. Joni H. Ylostalo

E-Mail Website
Guest Editor
Department of Biology, University of Mary Hardin-Baylor, 900 College Street, Box 8432, Belton, TX 76513, USA
Interests: microbiology; immunology; regenerative medicine; genetics; stem cells; 3D stem cell culture
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mesenchymal stem cells (MSCs) have drawn much interest from scientists for decades. Studies have focused on the basic characteristics and properties of MSCs and have shown that these cells can be obtained from various locations throughout the body, such as bone marrow, adipose tissue, the umbilical cord, and the synovium. Other studies have shown that MSCs can differentiate into many cells, such as osteoblasts, chondrocytes, and adipocytes, providing potential therapeutic approaches. Initially, the MSC-mediated therapeutic effects were thought to be attributed to their ability to differentiate; however, the focus has shifted to their paracrine effects and specifically to their ability to modulate immune responses. Many in vitro and in vivo studies have demonstrated the capability of MSCs to secrete factors and interact with immune cells to either suppress immune reactions or promote specific immune system-related functions.

This Special Issue aims to bring together original research and comprehensive reviews regarding the immunoregulatory functions of MSCs. Invitation extends to both basic and translational research that seeks to further the understanding of the important effects of MSCs on immune cells and systems.

Dr. Joni H. Ylostalo
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 250 words) can be sent to the Editorial Office for assessment.

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. Cells is an international peer-reviewed open access semimonthly 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 2700 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 stem cells
  • MSCs
  • immunoregulation
  • immunosuppression

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Published Papers (5 papers)

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Research

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21 pages, 4059 KB  
Article
Human Dental Pulp Stem Cells Modulate Acute Inflammation Kinetics in the AIRmax Murine Model by Sustained TNF-Alpha Suppression and Transient Homing
by Bruna de Oliveira Policiquio, Vivian Gonzaga Fonseca, Geovanna Santos Costa, Jean Gabriel de Souza, Olga Celia Martinez Ibañez, Orlando Garcia Ribeiro and Irina Kerkis
Cells 2026, 15(2), 189; https://doi.org/10.3390/cells15020189 - 20 Jan 2026
Viewed by 295
Abstract
Mesenchymal stem cells (MSCs) are multipotent adult cells that are highly valued for their immunomodulatory potential and intrinsic ability to home to inflamed sites. This study specifically utilized human dental pulp stem cells (hDPSCs), a unique MSC subtype derived from the neural crest, [...] Read more.
Mesenchymal stem cells (MSCs) are multipotent adult cells that are highly valued for their immunomodulatory potential and intrinsic ability to home to inflamed sites. This study specifically utilized human dental pulp stem cells (hDPSCs), a unique MSC subtype derived from the neural crest, due to their reported superior anti-inflammatory capacity. To rigorously test their efficacy, we employed the AIRmax murine model, which exhibits a genetically determined high-inflammatory phenotype. Acute inflammation was induced by subcutaneous injection of the polyacrylamide suspension Biogel P-100. Two hours post-induction, AIRmax mice were treated intravenously with hDPSCs. Our results demonstrate that hDPSC treatment produced significant anti-inflammatory effects evident at 24 h. The treated group showed a pronounced reduction in leukocyte migration and decreased protein extravasation in the inflammatory exudate. Crucially, hDPSCs also modulated molecular mediators, significantly decreasing the pro-inflammatory cytokine TNF-alpha and reactive oxygen species (ROS) production. Furthermore, while hDPSCs efficiently and rapidly homed to the inflammation site within 2 h, their maximal therapeutic benefits only manifested after 24 h. This suggests that their robust capacity to modulate acute inflammatory responses relies not only on rapid migration but also on a paracrine “hit-and-run” mechanism that suppresses cellular infiltration and oxidative stress over time. This study reinforces the potential of hDPSCs as a powerful, multi-target therapeutic agent for inflammatory conditions, supporting further investigation into their precise mechanisms and clinical application. Full article
(This article belongs to the Special Issue Immunoregulatory Functions of Mesenchymal Stem Cells (MSCs))
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27 pages, 3940 KB  
Article
Mesenchymal Stem Cell-Derived Extracellular Vesicles Attenuate Pro-Inflammatory Macrophage Polarization: Comparison of Matrix-Bound and Small Extracellular Vesicles
by Timofey O. Klyucherev, Maria D. Yurkanova, Daria P. Revokatova, Dmitriy A. Chevalier, Vsevolod V. Shishkov, Irina I. Vlasova, Nastasia V. Kosheleva and Peter S. Timashev
Cells 2026, 15(2), 93; https://doi.org/10.3390/cells15020093 - 6 Jan 2026
Viewed by 776
Abstract
Macrophages play a crucial role in regulating immune responses, inflammation, and tissue repair. Depending on environmental cues, they polarize into pro-inflammatory M1 or anti-inflammatory, pro-regenerative M2 phenotypes. Extracellular vesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) have emerged as key mediators of intercellular [...] Read more.
Macrophages play a crucial role in regulating immune responses, inflammation, and tissue repair. Depending on environmental cues, they polarize into pro-inflammatory M1 or anti-inflammatory, pro-regenerative M2 phenotypes. Extracellular vesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) have emerged as key mediators of intercellular communication and immune modulation. This study investigates the effects of matrix-bound vesicles (MBVs) and small extracellular vesicles (sEVs) derived from human umbilical cord MSCs (UC-MSCs) on human monocyte-derived macrophages (MDMs) in vitro. Both MBVs and sEVs reduced pro-inflammatory activation of M1 macrophages, downregulating the expression of CXCL10 and CD86 while increasing the M2 marker CD206. MBVs exerted a stronger suppressive effect on M1 MDM phenotype markers as well as on STAT1, STAT2, and IRF9 mRNA levels in M1 macrophages, indicating the inhibition of the JAK/STAT1 signaling pathway involved in the pro-inflammatory activation of macrophages. Functionally, both vesicle types enhanced phagocytosis of FITC-labeled E. coli by M1 and M0_GM macrophages, promoting a shift toward an M2-like phenotype. Moreover, MBVs and sEVs attenuated reactive oxygen species (ROS) production, with sEVs showing a more pronounced effect both on ROS generation and on the expression of NOX2 complex subunits (p47^phox, p67^phox) in M1 macrophages. These findings demonstrate that MBVs and sEVs from UC-MSCs possess distinct yet complementary immunomodulatory and antioxidant properties on MDMs, suggesting their potential as promising cell-free therapeutic agents for inflammatory and degenerative diseases. Full article
(This article belongs to the Special Issue Immunoregulatory Functions of Mesenchymal Stem Cells (MSCs))
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19 pages, 3635 KB  
Article
Bletilla Striata Polysaccharide Alleviates Neutropenia by Promoting C/EBPε-Dependent Hematopoietic Reconstitution
by Yaru Cui, Yingying Luo, Cheng Zhang, Dan Shan, Yulin Feng, Shilin Yang, Lanying Chen and Jun Yu
Cells 2025, 14(23), 1888; https://doi.org/10.3390/cells14231888 - 28 Nov 2025
Viewed by 865
Abstract
Neutropenia is a common complication in oncology patients receiving chemotherapy, and rapid regeneration of functional neutrophils is critical for effective management. Bletilla striata polysaccharide (BSP) has shown therapeutic potential, but its mechanisms and molecular targets remain unclear. Here, we demonstrate that BSP accelerates [...] Read more.
Neutropenia is a common complication in oncology patients receiving chemotherapy, and rapid regeneration of functional neutrophils is critical for effective management. Bletilla striata polysaccharide (BSP) has shown therapeutic potential, but its mechanisms and molecular targets remain unclear. Here, we demonstrate that BSP accelerates the recovery of white blood cells, particularly neutrophils, in a chemotherapy-induced neutropenia (CIN) mouse model with cyclophosphamide (CY). The regenerated neutrophils retained phagocytic activity against bacteria, and BSP treatment significantly reduced mortality in the endotoxin-induced mouse death model. Furthermore, BSP enhanced the repopulation of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow and promoted cell-cycle entry, resulting in increased frequencies of long-term hematopoietic stem cells (LT-HSCs), multipotent progenitors 2 (MPP2), and MPP3/4 subsets. Both in vitro colony formation and in vivo competitive transplantation assays confirmed that BSP reshapes hematopoietic reconstitution and corrects aberrant myeloid differentiation. PCR array analysis of HSPCs indicated that this process is mediated by C/EBPε and its downstream genes (LTF, LCN2, and ELANE). Consistently, BSP failed to support myeloid reconstitution following C/EBPε knockdown in vitro. In a C/EBPε knockout mouse model, HSPCs repopulation and regeneration were impaired, and BSP failed to promote neutrophil recovery after CY challenge or the mobilization of MPP2 and MPP3/4 subsets. The regulatory effects of BSP on C/EBPε target genes were also abolished. In conclusion, our findings identify C/EBPε as a key mediator of BSP activity, driving HSPCs repopulation and restoring hematopoietic function. These results highlight BSP as a potential therapeutic strategy for chemotherapy-induced neutropenia. Full article
(This article belongs to the Special Issue Immunoregulatory Functions of Mesenchymal Stem Cells (MSCs))
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Review

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20 pages, 3807 KB  
Review
Effects of Mesenchymal Stem Cells on Functions of Chimeric Antigen Receptor-Expressing T Lymphocytes and Natural Killer Cells
by Vladislav Volarevic, Carl Randall Harrell, Aleksandar Arsenijevic, Valentin Djonov and Ana Volarevic
Cells 2025, 14(13), 978; https://doi.org/10.3390/cells14130978 - 25 Jun 2025
Viewed by 1617
Abstract
Chimeric antigen receptor (CAR)-engineered immune cells, particularly CAR T lymphocytes and CAR natural killer (NK) cells, have revolutionized cancer immunotherapy. However, their therapeutic efficacy and safety can be influenced by the tumor microenvironment, particularly the presence of mesenchymal stem cells (MSCs). MSCs are [...] Read more.
Chimeric antigen receptor (CAR)-engineered immune cells, particularly CAR T lymphocytes and CAR natural killer (NK) cells, have revolutionized cancer immunotherapy. However, their therapeutic efficacy and safety can be influenced by the tumor microenvironment, particularly the presence of mesenchymal stem cells (MSCs). MSCs are immunomodulatory cells which can alter the function of tumor-infiltrated immune cells in both supportive and suppressive ways. Results obtained in recently conducted experimental studies demonstrate that MSCs modulate proliferation, cytotoxicity, cytokine production and anti-tumor activity in CAR-expressing immune cells in both a juxtacrine and a paracrine manner. While MSCs can enhance CAR cell viability and persistence through trophic support, they may also impair cytotoxic function and promote an immunosuppressive phenotype under certain conditions. Understanding the dualistic nature of MSCs in CAR-based immunotherapy for malignant diseases is critical for optimizing clinical outcomes. Additionally, MSCs may serve as vehicles for targeted delivery of immunomodulatory agents, and should be considered as active components in the design of next-generation CAR-based immunotherapies. Accordingly, in this review article we emphasize molecular and cellular mechanisms involved in MSC-dependent modulation of CAR-expressing immune cells, paving the way for more efficient CAR-based immunotherapy for malignant diseases. Full article
(This article belongs to the Special Issue Immunoregulatory Functions of Mesenchymal Stem Cells (MSCs))
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Other

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28 pages, 3698 KB  
Systematic Review
Mesenchymal Stem Cells as Anti-Inflammatory Agents in Chronic Kidney Disease: A Systematic Review and Meta-Analysis
by Lukman Pura, Raeni Dwi Putri, Muh. Arya Prahmana, Muhammad Palar Wijaya, Ria Bandiara, Ahmad Faried and Rudi Supriyadi
Cells 2025, 14(17), 1313; https://doi.org/10.3390/cells14171313 - 24 Aug 2025
Cited by 1 | Viewed by 5114
Abstract
Background: Chronic kidney disease (CKD) is largely driven by inflammation. Mesenchymal stem cells (MSCs) show therapeutic potential; however, their efficacy across CKD etiologies remains unclear. Methods: Comprehensive searches were conducted in PubMed, Cochrane, ScienceDirect, Scopus and Google Scholar. Effect sizes for inflammation and [...] Read more.
Background: Chronic kidney disease (CKD) is largely driven by inflammation. Mesenchymal stem cells (MSCs) show therapeutic potential; however, their efficacy across CKD etiologies remains unclear. Methods: Comprehensive searches were conducted in PubMed, Cochrane, ScienceDirect, Scopus and Google Scholar. Effect sizes for inflammation and renal function outcomes were meta-analyzed. Results: Of 2514 studies screened, 52 met inclusion criteria (49 animal studies, 3 randomized controlled trials). In animal models, MSCs significantly reduced interleukin-6 (mean difference [MD] = −155.80; 95% CI: −249.10, −62.51; p = 0.001) and tumor necrosis factor-α (TNF-α) (MD = −35.53; 95% CI: −52.75, −18.30; p < 0.0001). In patients, TNF-α reduction was not significant (MD = −0.74; 95% CI: −2.20, 0.73; p = 0.32). Serum creatinine decreased in animals (MD = −0.38; 95% CI: −0.46, −0.29; p < 0.00001), but not in patients (MD = −0.59; 95% CI: −1.92, 0.74; p = 0.39). Blood urea nitrogen decreased in animals (MD = −19.27; 95% CI: −23.50, −15.04; p < 0.00001), and glomerular filtration rate improved (standardized MD = 1.83; 95% CI: 0.51, 3.15; p = 0.007), with no change in patients. Conclusion: MSCs improve inflammation and renal function in CKD animal models; however, evidence in patients remains inconclusive. Full article
(This article belongs to the Special Issue Immunoregulatory Functions of Mesenchymal Stem Cells (MSCs))
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