MSCs mediate long-term efficacy in a Crohn's disease model by sustained anti-inflammatory macrophage programming via efferocytosis

Maneesh Dave; Atul Dev; Rodrigo A Somoza; Nan Zhao; Satish Viswanath; Pooja Rani Mina; Prathyush Chirra; Verena Carola Obmann; Ganapati H Mahabeleshwar; Paola Menghini; Blythe Durbin-Johnson; Jan Nolta; Christopher Soto; Abdullah Osme; Lam T Khuat; William J Murphy; Arnold I Caplan; Fabio Cominelli

doi:10.1038/s41536-024-00347-1

MSCs mediate long-term efficacy in a Crohn's disease model by sustained anti-inflammatory macrophage programming via efferocytosis

NPJ Regen Med. 2024 Jan 20;9(1):6. doi: 10.1038/s41536-024-00347-1.

Authors

Maneesh Dave^{1

2}, Atul Dev³, Rodrigo A Somoza⁴, Nan Zhao⁵, Satish Viswanath⁶, Pooja Rani Mina³, Prathyush Chirra⁶, Verena Carola Obmann⁷, Ganapati H Mahabeleshwar⁸, Paola Menghini⁵, Blythe Durbin-Johnson⁹, Jan Nolta^{10

11}, Christopher Soto³, Abdullah Osme⁸, Lam T Khuat¹², William J Murphy^{11

12}, Arnold I Caplan⁴, Fabio Cominelli⁵

Affiliations

¹ Division of Gastroenterology and Hepatology, Department of Internal Medicine, UC Davis Medical Center, University of California Davis School of Medicine, Sacramento, CA, USA. mdave@ucdavis.edu.
² Institute for Regenerative Cures, University of California Davis School of Medicine, Sacramento, CA, USA. mdave@ucdavis.edu.
³ Division of Gastroenterology and Hepatology, Department of Internal Medicine, UC Davis Medical Center, University of California Davis School of Medicine, Sacramento, CA, USA.
⁴ Skeletal Research Center, Department of Biology, Case Western Reserve University, Cleveland, OH, USA.
⁵ Division of Gastroenterology and Liver Disease, University Hospitals, Case Western Reserve University, Cleveland, OH, USA.
⁶ Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA.
⁷ Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁸ Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
⁹ Division of Biostatistics, Department of Public Health Sciences, University of California Davis School of Medicine, Sacramento, CA, USA.
¹⁰ Institute for Regenerative Cures, University of California Davis School of Medicine, Sacramento, CA, USA.
¹¹ Division of Malignant Hematology/Cell and Marrow Transplantation, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, USA.
¹² Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA, USA.

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.

Abstract

Grants and funding