Study of the in vitro therapeutic efficacy of preconditioned MSCs for the treatment of ARDS

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Rationale: Mesenchymal stem cells (MSCs) have demonstrated therapeutic potential in ARDS, but this has not fully translated to efficacy in clinical trials. The most efficient cell type and pre-activation method have yet to be determined. We performed in vitro potency testing by assessing the anti-inflammatory, anti-bacterial and immunomodulatory properties in three distinct MSC types, with and without an ARDS-related cytokine pre-activation strategy. Methods: Bone marrow-derived MSC (BM-MSC), and two induced pluripotent stem cell derived-MSCs (iMSCs): a wild-type (iMSC WT) and a beta 2 microglobulin-knockout (iMSC B2M KO) were preconditioned with a cocktail of IL1β, TNFα and IFNγ (Cytomix) and the conditioned media (CM) used in bacterial proliferation assays and cytokine ELISA. HLA, migration and immunosuppressive markers of MSCs were detected with flow cytometry. The cytomix-MSCs were co-cultured with activated PBMCs for 96 hours and T-cell proliferation was examined by flow. Results: MSC-preconditioning increased the levels of IL-6, IL-8 and MCP-1 secreted from all MSC types. All MSCs inhibited gram +ve and -ve bacterial proliferation, and pre-activation enhanced this against Gram-ve E. coli. MSC-preconditioning increased the expression of immigration marker CD54 and immunosuppressive marker CD200 on MSCs. All MSCs reduced CD3+ T cell proliferation. Conclusion: All MSC cell types have shown therapeutic effects in in vitro potency assays and cytomix enhanced different aspects of different cell types. The use of in vitro potency assays is crucial for the validation of MSC in ARDS. Further studies and translation to in vivo usage is needed to assess these MSCs and assays.

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