1. MSCs mediate long-term efficacy in a Crohn’s disease model by sustained anti-inflammatory macrophage programming via efferocytosis
- Author
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Dave, Maneesh, Dev, Atul, Somoza, Rodrigo A, Zhao, Nan, Viswanath, Satish, Mina, Pooja Rani, Chirra, Prathyush, Obmann, Verena Carola, Mahabeleshwar, Ganapati H, Menghini, Paola, Durbin-Johnson, Blythe, Nolta, Jan, Soto, Christopher, Osme, Abdullah, Khuat, Lam T, Murphy, William J, Caplan, Arnold I, and Cominelli, Fabio
- Subjects
Medical Biotechnology ,Medical Physiology ,Biomedical and Clinical Sciences ,Inflammatory Bowel Disease ,Stem Cell Research - Nonembryonic - Human ,Crohn's Disease ,Regenerative Medicine ,Stem Cell Research ,Autoimmune Disease ,Digestive Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Oral and gastrointestinal ,Inflammatory and immune system ,Medical biotechnology ,Medical physiology - Abstract
Mesenchymal stem cells (MSCs) are novel therapeutics for the treatment of Crohn's disease. However, their mechanism of action is unclear, especially in disease-relevant chronic models of inflammation. Thus, we used SAMP-1/YitFc (SAMP), a chronic and spontaneous murine model of small intestinal inflammation, to study the therapeutic effects and mechanism of action of human bone marrow-derived MSCs (hMSC). hMSC dose-dependently inhibited naïve T lymphocyte proliferation via prostaglandin E2 (PGE2) secretion and reprogrammed macrophages to an anti-inflammatory phenotype. We found that the hMSCs promoted mucosal healing and immunologic response early after administration in SAMP when live hMSCs are present (until day 9) and resulted in a complete response characterized by mucosal, histological, immunologic, and radiological healing by day 28 when no live hMSCs are present. hMSCs 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 that explains their long-term efficacy. Taken together, our findings show that hMSCs result in healing and tissue regeneration in a chronic model of small intestinal inflammation and despite being short-lived, exert long-term effects via sustained anti-inflammatory programming of macrophages via efferocytosis.
- Published
- 2024