Allogeneic mesenchymal stem cells derived extracellular vesicles as a superior immunosuppressant in murine arthritis therapy

Runci Wang^1,2, Yi Liu², Songtao Shi¹

Affiliation:

1. Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA 19104, USA

2. Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PRC

The authors declare no conflict of interest.

Background/Purpose:

Mesenchymal stem cells (MSCs) are creating promising new options for autoimmune disorders. MSCs utilize multiple mechanisms to modulate immune cells, and extracellular vesicles (EVs) have recently been recognized as important intercellular mediators, in this study we tested whether EVs derived from allogeneic MSCs would have therapeutic potential in comparison with their parent cells in murine collagen-induced arthritis model.

Methods:

At the time of primary immunization with type II collagen, DBA/1 mice were systemically infused with PBS (sham), EVs derived from 1*10^6 allogeneic BMMSCs, and 1*10^6 allogeneic bone marrow MSCs (BMMSCs) as control. Therapeutic efficacy was determined by arthritis activity, joint histology, and _CT imaging. Serum cytokine level, as well as T cell phenotypes in blood, spleen and draining lymph nodes were analyzed. Na•ve CD4+ T cells were isolated and co-cultured with BMMSCs or EVs to assess activation and differentiation.

Results:

EVs outperformed BMMSCs in three aspects: clinically, EVs treated mice had delayed onset and milder arthritis score; histologically, with decreased joint inflammation, pannus formation, collagen disruption, IL-17+ cells infiltration, as well as _CT visual socre; and immunologically, with lower serum IL-6 and IL-17, as well as decreased Th17 and activated CD4+ T cells in the circulation and lymphoid organs. When co-cultured in vitro and compared with BMMSCs, EVs decreased Ca²⁺ release upon CD3/28 stimulation and greatly suppressed na•ve T cells activation, and suppressed Th17 differentiation.

Conclusion:

Collectively, these data demonstrated the outstanding therapeutic efficacy of EVs derived from allogeneic MSCs, and provided a new strategy for stem cell-based immunotherapy.

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