Regenerative Functions of Regulatory T Cells and Current Strategies Utilizing Mesenchymal Stem Cells in Immunomodulatory Tissue Regeneration

Overview

Journal Tissue Eng Regen Med

Date 2025 Jan 13

PMID 39804546

Authors

Jinsung Ahn

Bowon Kim

Alvin Bacero Bello

James J Moon

Yoshie Arai

Soo-Hong Lee

Affiliations

Soon will be listed here.

Abstract

Background: Regulatory T cells (Tregs) are essential for maintaining immune homeostasis and facilitating tissue regeneration by fostering an environment conducive to tissue repair. However, in damaged tissues, excessive inflammatory responses can overwhelm the immunomodulatory capacity of Tregs, compromising their functionality and potentially hindering effective regeneration. Mesenchymal stem cells (MSCs) play a key role in enhancing Treg function. MSCs enhance Treg activity through indirect interactions, such as cytokine secretion, and direct interactions via membrane proteins.

Methods: This review examines the regenerative functions of Tregs across various tissues, including bone, cartilage, muscle, and skin, and explores strategies to enhance Treg functionality using MSCs. Advanced techniques, such as the overexpression of relevant genes in MSCs, are highlighted for their potential to further enhance Treg function. Additionally, emerging technologies utilizing extracellular vesicles (EVs) and cell membrane-derived vesicles derived from MSCs offer promising alternatives to circumvent the potential side effects associated with live cell therapies. This review proposes approaches to enhance Treg function and promote tissue regeneration and also outlines future research directions.

Results And Conclusion: This review elucidates recent technological advancements aimed at enhancing Treg function using MSCs and examines their potential to improve tissue regeneration efficiency.

References

Barbi J, Pardoll D, Pan F . Treg functional stability and its responsiveness to the microenvironment. Immunol Rev. 2014; 259(1):115-39. PMC: 3996455. DOI: 10.1111/imr.12172. View

Lu J, Wang W, Li P, Wang X, Gao C, Zhang B . MiR-146a regulates regulatory T cells to suppress heart transplant rejection in mice. Cell Death Discov. 2021; 7(1):165. PMC: 8257678. DOI: 10.1038/s41420-021-00534-9. View

Gurung S, Perocheau D, Touramanidou L, Baruteau J . The exosome journey: from biogenesis to uptake and intracellular signalling. Cell Commun Signal. 2021; 19(1):47. PMC: 8063428. DOI: 10.1186/s12964-021-00730-1. View

Cosenza S, Toupet K, Maumus M, Luz-Crawford P, Blanc-Brude O, Jorgensen C . Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis. Theranostics. 2018; 8(5):1399-1410. PMC: 5835945. DOI: 10.7150/thno.21072. View

Luz-Crawford P, Kurte M, Bravo-Alegria J, Contreras R, Nova-Lamperti E, Tejedor G . Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Res Ther. 2013; 4(3):65. PMC: 3706898. DOI: 10.1186/scrt216. View

Su Y, Wang P, Weng S . The Role of Mitochondria in Immune-Cell-Mediated Tissue Regeneration and Ageing. Int J Mol Sci. 2021; 22(5). PMC: 7961648. DOI: 10.3390/ijms22052668. View

DAlessio F, Kurzhagen J, Rabb H . Reparative T lymphocytes in organ injury. J Clin Invest. 2019; 129(7):2608-2618. PMC: 6597230. DOI: 10.1172/JCI124614. View

Dai M, Sui B, Hua Y, Zhang Y, Bao B, Lin Q . A well defect-suitable and high-strength biomimetic squid type II gelatin hydrogel promoted in situ costal cartilage regeneration via dynamic immunomodulation and direct induction manners. Biomaterials. 2020; 240:119841. DOI: 10.1016/j.biomaterials.2020.119841. View

Vignali D, Collison L, Workman C . How regulatory T cells work. Nat Rev Immunol. 2008; 8(7):523-32. PMC: 2665249. DOI: 10.1038/nri2343. View

10.

English K, Ryan J, Tobin L, Murphy M, Barry F, Mahon B . Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+ regulatory T cells. Clin Exp Immunol. 2009; 156(1):149-60. PMC: 2673753. DOI: 10.1111/j.1365-2249.2009.03874.x. View

11.

Sun G, Wang Z, Ti Y, Wang Y, Wang J, Zhao J . STAT3 promotes bone fracture healing by enhancing the FOXP3 expression and the suppressive function of regulatory T cells. APMIS. 2017; 125(8):752-760. DOI: 10.1111/apm.12706. View

12.

Pang N, Zhang F, Ma X, Zhu Y, Zhao H, Xin Y . TGF-β/Smad signaling pathway regulates Th17/Treg balance during Echinococcus multilocularis infection. Int Immunopharmacol. 2014; 20(1):248-57. DOI: 10.1016/j.intimp.2014.02.038. View

13.

Schlundt C, Reinke S, Geissler S, Bucher C, Giannini C, Mardian S . Individual Effector/Regulator T Cell Ratios Impact Bone Regeneration. Front Immunol. 2019; 10:1954. PMC: 6706871. DOI: 10.3389/fimmu.2019.01954. View

14.

Julier Z, Park A, Briquez P, Martino M . Promoting tissue regeneration by modulating the immune system. Acta Biomater. 2017; 53:13-28. DOI: 10.1016/j.actbio.2017.01.056. View

15.

Liu Y, Wang L, Kikuiri T, Akiyama K, Chen C, Xu X . Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-γ and TNF-α. Nat Med. 2011; 17(12):1594-601. PMC: 3233650. DOI: 10.1038/nm.2542. View

16.

Bai X, Chen T, Li Y, Ge X, Qiu C, Gou H . PD-L1 expression levels in mesenchymal stromal cells predict their therapeutic values for autoimmune hepatitis. Stem Cell Res Ther. 2023; 14(1):370. PMC: 10729378. DOI: 10.1186/s13287-023-03594-z. View

17.

Nayer B, Tan J, Alshoubaki Y, Lu Y, Legrand J, Lau S . Local administration of regulatory T cells promotes tissue healing. Nat Commun. 2024; 15(1):7863. PMC: 11383969. DOI: 10.1038/s41467-024-51353-2. View

17.

Harrell C, Volarevic A, Djonov V, Jovicic N, Volarevic V . Mesenchymal Stem Cell: A Friend or Foe in Anti-Tumor Immunity. Int J Mol Sci. 2021; 22(22). PMC: 8622564. DOI: 10.3390/ijms222212429. View

18.

Hahm J, Kim J, Park J . Strategies to Enhance Extracellular Vesicle Production. Tissue Eng Regen Med. 2021; 18(4):513-524. PMC: 8325751. DOI: 10.1007/s13770-021-00364-x. View

19.

de Ruiter R, Wisse L, Schoenmaker T, Yaqub M, Sanchez-Duffhues G, Eekhoff E . TGF-Beta Induces Activin A Production in Dermal Fibroblasts Derived from Patients with Fibrodysplasia Ossificans Progressiva. Int J Mol Sci. 2023; 24(3). PMC: 9916423. DOI: 10.3390/ijms24032299. View