Dave, ManeeshManeeshDaveDev, AtulAtulDevSomoza, Rodrigo ARodrigo ASomozaZhao, NanNanZhaoViswanath, SatishSatishViswanathMina, Pooja RaniPooja RaniMinaChirra, PrathyushPrathyushChirraObmann, Verena CarolaVerena CarolaObmannMahabeleshwar, Ganapati HGanapati HMahabeleshwarMenghini, PaolaPaolaMenghiniDurbin-Johnson, BlytheBlytheDurbin-JohnsonNolta, JanJanNoltaSoto, ChristopherChristopherSotoOsme, AbdullahAbdullahOsmeKhuat, Lam TLam TKhuatMurphy, William JWilliam JMurphyCaplan, Arnold IArnold ICaplanCominelli, FabioFabioCominelli2024-10-262024-10-262024-01-20https://boris-portal.unibe.ch/handle/20.500.12422/173661Mesenchymal 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.en600 - Technology::610 - Medicine & healtharticle10.48350/1919523824554310.1038/s41536-024-00347-1