Jonathan Joseph

Background:  Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by joint stiffness, swelling, and pain, affecting approximately 1% of the global population ¹. While genetic factors like the HLA-DRB1 allele contribute to RA, environmental triggers such as smoking and obesity play a significant role, as evidenced by the low (15%) coincidence rate in identical twins ^{2 3}. The pathogenesis of RA involves an imbalance between proinflammatory Th17 cells and regulatory T cells (Tregs), where Th17-derived IL-17 overwhelms Treg suppression, leading to persistent inflammation and joint destruction ¹. Current treatments often have limitations, including side effects and refractory cases, highlighting the need for novel therapies. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach due to their immunomodulatory properties, particularly their ability to restore the Th17/Treg balance ^{2 4}. Clinical trials involving autologous MSC transplants in refractory RA patients demonstrated a significant reduction in Th17 cells (from 6.16 ± 0.80% to 4.10 ± 0.44%) and increased Treg levels (from 4.06 ± 0.80% to 8.93 ± 1.77%) within 12 months, alongside marked pain reduction ².

Objective:  This review explores the mechanisms by which MSCs and their secreted small extracellular vesicles (SEVs) modulate the Th17/Treg imbalance in RA, evaluates preclinical and clinical evidence supporting their therapeutic potential, and discusses future directions for research and application.

Search Methods: A systematic literature search was conducted using PubMed and Google Scholar (2018–2025) with keywords including “Mesenchymal stem cell mediated rheumatoid arthritis,” “Th17/Treg balance,” “small extracellular vesicles,” “MSC-derived exosomes,” “HGF and Th17 modulation,” “mitochondrial transfer,” “MSC clinical trials in RA,” and “MSC immunomodulation.”

Results:  MSCs modulate inflammation through multiple mechanisms, including the secretion of hepatocyte growth factor (HGF) ⁵, mitochondrial transfer to dysfunctional Th17 cells ⁶, and the release of SEVs containing immunoregulatory molecules like EID3 ⁷. In vitro studies show that MSC-derived HGF elevates Tregs (CD4+CD25+Foxp3+) by 40% while reducing Th17 cells (CD4+CD3+RORγt+) by 35%, effects reversible with anti-HGF antibodies ⁸. Mitochondrial transfer from MSCs to Th17 cells occurs within 4 hours, reducing IL-17 production by 50% and increasing Treg markers like FOXP3 ⁶. In vitro and mouse model studies show that MSC-derived SEVs destabilize the Th17 transcription factor RORγt, reduce IL-17 production, and promote Treg differentiation ⁷. Notably, 12% of CD4+ T cells internalized MSC-SEVs, leading to suppressed Th17 differentiation without affecting Treg pathways ⁷. Clinical trials involving autologous MSC transplants in refractory RA patients reported increased Treg levels, decreased Th17 cells, and significant pain reduction over 12 months, with no adverse effects ¹. SEVs offer additional advantages, such as easier isolation, reduced immunogenicity, and targeted delivery  ^{7 9}. In collagen-induced arthritis models, SEV treatment reduced synovial hyperplasia and serum IL-17 levels while elevating IL-10 and TGF-β, comparable to methotrexate ⁹.

Conclusion: MSCs and their SEVs represent a breakthrough in RA treatment by addressing the root cause of inflammation—the Th17/Treg imbalance. While preclinical and early clinical results are promising, further research is needed to optimize SEV production, dosing, and delivery methods. Future studies should explore the long-term efficacy and safety of MSC-based therapies and their applicability to other autoimmune diseases. These advancements could revolutionize the management of RA and similar conditions, offering hope for patients with limited treatment options.

Work Cited:

1. Frazzei, G., et al., Prevention of rheumatoid arthritis: A systematic literature review of preventive strategies in at-risk individuals. Autoimmun Rev, 2023. 22(1): p. 103217.
2. Ghoryani M, Shariati-Sarabi Z, Tavakkol-Afshari J, Ghasemi A, Poursamimi J, Mohammadi M. Amelioration of clinical symptoms of patients with refractory rheumatoid arthritis following treatment with autologous bone marrow-derived mesenchymal stem cells: A successful clinical trial in Iran. Biomedicine & Pharmacotherapy. 2019/01/01/ 2019;109:1834-1840. doi:https://doi.org/10.1016/j.biopha.2018.11.056
3. Scherer, H.U., T. Häupl, and G.R. Burmester, The etiology of rheumatoid arthritis. J Autoimmun, 2020. 110: p. 102400.
4. Harna, B., et al., Mesenchymal stromal cell therapy for patients with rheumatoid arthritis. Exp Cell Res, 2023. 423(1): p. 113468.
5. Pedrosa M, Gomes J, Laranjeira P, et al. Immunomodulatory effect of human bone marrow-derived mesenchymal stromal/stem cells on peripheral blood T cells from rheumatoid arthritis patients. J Tissue Eng Regen Med. Jan 2020;14(1):16-28. doi:10.1002/term.2958
6. Luz-Crawford P, Hernandez J, Djouad F, et al. Mesenchymal stem cell repression of Th17 cells is triggered by mitochondrial transfer. Stem Cell Research & Therapy. 2019/08/01 2019;10(1):232. doi:10.1186/s13287-019-1307-9
7. Jung S, Lee S, Kim HJ, et al. Mesenchymal stem cell-derived extracellular vesicles subvert Th17 cells by destabilizing RORγt through posttranslational modification. Experimental & Molecular Medicine. 2023/03/01 2023;55(3):665-679. doi:10.1038/s12276-023-00949-7
8. Chen QH, Wu F, Liu L, et al. Mesenchymal stem cells regulate the Th17/Treg cell balance partly through hepatocyte growth factor in vitro. Stem Cell Res Ther. Feb 28 2020;11(1):91. doi:10.1186/s13287-020-01612-y
9. Xu K, Ma D, Zhang G, et al. Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles ameliorate collagen-induced arthritis via immunomodulatory T lymphocytes. Molecular Immunology. 2021/07/01/ 2021;135:36-44. doi:https://doi.org/10.1016/j.molimm.2021.04.001