Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles ameliorate collagen-induced arthritis via immunomodulatory T lymphocytes

Autor: Yang Liu, Jian Han, Dan Ma, Sumiao Liu, Jinfang Gao, Ya-Zhen Su, Liyun Zhang, Min Tian, Chun Wei, Gailian Zhang, Ke Xu
Rok vydání: 2020
Předmět:
0301 basic medicine
Immunology
Cell
Arthritis
T-Lymphocytes
Regulatory
Immunomodulation
03 medical and health sciences
Extracellular Vesicles
0302 clinical medicine
RAR-related orphan receptor gamma
Transforming Growth Factor beta
Human Umbilical Vein Endothelial Cells
Medicine
Animals
Humans
Rats
Wistar
Molecular Biology
Cells
Cultured
business.industry
Mesenchymal stem cell
Interleukin-17
Synovial Membrane
Interleukin
FOXP3
Forkhead Transcription Factors
Mesenchymal Stem Cells
T lymphocyte
Nuclear Receptor Subfamily 1
Group F
Member 3
medicine.disease
Arthritis
Experimental
Interleukin-10
Rats
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
Methotrexate
Cancer research
Th17 Cells
Female
Collagen
business
Immunosuppressive Agents
030215 immunology
Transforming growth factor
Zdroj: Molecular immunology. 135
ISSN: 1872-9142
Popis: Background Rheumatoid arthritis (RA) is an autoimmune disease for which there are currently no effective therapies. Although mesenchymal stem cells (MSCs) can prevent arthritis through immunomodulatory mechanisms, there are several associated risks. Alternatively, MSC-derived small extracellular vesicles (sEVs) can mimic the effects of MSCs, while reducing the risk of adverse events. However, few studies have examined sEVs in the context of RA. Here, we evaluate the immunomodulatory effects of human umbilical cord MSC (hUCMSC)-derived sEVs on T lymphocytes in a collagen-induced arthritis (CIA) rat model to elucidate the possible mechanism of sEVs in RA treatment. We then compare these mechanisms to those of MSCs and methotrexate (MTX). Methods The arthritis index and synovial pathology were assessed. T lymphocyte proliferation and apoptosis, Th17 and Treg proportions, and interleukin (IL)-17, IL-10, and transforming growth factor (TGF)-β expression were detected using flow cytometry. Retinoic acid receptor-related orphan receptor gamma t (RORγt) and forkhead box P3 (FOXP3), which are master transcriptional regulators of Th17 and Treg differentiation, were also assessed using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). Results sEV treatment ameliorated arthritis and inhibited synovial hyperplasia in a dose-dependent manner. These effects were mediated by inhibiting T lymphocyte proliferation and promoting their apoptosis, while decreasing Th17 cell proportion and increasing that of Treg cells in the spleen, resulting in decreased serum IL-17, and enhanced IL-10 and TGF-β expression. Transcriptionally, sEVs decreased RORγt and increased FOXP3 expression in the spleen, and decreased RORγt and FOXP3 expression in the joints. In some aspects sEVs were more effective than MSCs and MTX in treating CIA. Conclusions hUCMSC-derived sEVs ameliorate CIA via immunomodulatory T lymphocytes, and might serve as a new therapy for RA.
Databáze: OpenAIRE
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