Mesenchymal stem cells ameliorate inflammation in an experimental model of Crohn's disease via the mesentery

Dave, M.; Dev, A.; Somoza, R. A.; Zhao, N.; Viswanath, S.; Mina, P. R.; Chirra, P.; Obmann, V. C.; Mahabeleshwar, G. H.; Menghini, P.; Johnson, B. D.; Nolta, J. A.; Soto, C.; Osme, A.; Khuat, L. T.; Murphy, W.; Caplan, A. I.; Cominelli, F.

doi:10.1101/2023.05.22.541829

bioRxiv · 10.1101/2023.05.22.541829

Mesenchymal stem cells ameliorate inflammation in an experimental model of Crohn's disease via the mesentery

Dave, M.·Dev, A.·Somoza, R. A.·Zhao, N.·Viswanath, S.·Mina, P. R.·Chirra, P.·Obmann, V. C.·Mahabeleshwar, G. H.·Menghini, P.·Johnson, B. D.·Nolta, J. A.·Soto, C.·Osme, A.·Khuat, L. T.·Murphy, W.·Caplan, A. I.·Cominelli, F.

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Abstract

ObjectiveMesenchymal stem cells (MSCs) are novel therapeutics for treatment of Crohns disease. However, their mechanism of action is unclear, especially in disease-relevant chronic models of inflammation. Thus, we used SAMP-1/YitFc, a chronic and spontaneous murine model of small intestinal inflammation, to study the therapeutic effect and mechanism of human bone marrow-derived MSCs (hMSC). DesignhMSC immunosuppressive potential was evaluated through in vitro mixed lymphocyte reaction, ELISA, macrophage co-culture, and RT-qPCR. Therapeutic efficacy and mechanism in SAMP were studied by stereomicroscopy, histopathology, MRI radiomics, flow cytometry, RT-qPCR, small animal imaging, and single-cell RNA sequencing (Sc-RNAseq). ResultshMSC dose-dependently inhibited naive T lymphocyte proliferation in MLR via PGE2 secretion and reprogrammed macrophages to an anti-inflammatory phenotype. hMSC promoted mucosal healing and immunologic response early after administration in SAMP model of chronic small intestinal inflammation when live hMSCs are present (until day 9) and resulted in complete response characterized by mucosal, histological, immunologic, and radiological healing by day 28 when no live hMSCs are present. hMSC mediate their effect via modulation of T cells and macrophages in the mesentery and mesenteric lymph nodes (mLN). Sc-RNAseq confirmed the anti-inflammatory phenotype of macrophages and identified macrophage efferocytosis of apoptotic hMSCs as a mechanism of action that explains their long-term efficacy. ConclusionhMSCs result in healing and tissue regeneration in a chronic model of small intestinal inflammation. Despite being short-lived, exert long-term effects via macrophage reprogramming to an anti-inflammatory phenotype. Data Transparency StatementSingle-cell RNA transcriptome datasets are deposited in an online open access repository Figshare (DOI: https://doi.org/10.6084/m9.figshare.21453936.v1)

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Dave, M., Dev, A., Somoza, R. A., Zhao, N., Viswanath, S., Mina, P. R., Chirra, P., Obmann, V. C., Mahabeleshwar, G. H., Menghini, P., Johnson, B. D., Nolta, J. A., Soto, C., Osme, A., Khuat, L. T., Murphy, W., Caplan, A. I., Cominelli, F.. 2023-05-24. Mesenchymal stem cells ameliorate inflammation in an experimental model of Crohn's disease via the mesentery. https://doi.org/10.1101/2023.05.22.541829

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