Intraperitoneally Delivered Mesenchymal Stem Cells Alleviate Experimental Colitis Through THBS1-Mediated Induction of IL-10-Competent Regulatory B Cells

Abstract

Mesenchymal stem cells (MSCs) show promising therapeutic potential in treating inflammatory bowel disease (IBD), and intraperitoneal delivery of MSCs have become a more effective route for IBD treatment. However, the underlying mechanisms are still poorly understood. Here, we found that intraperitoneally delivered MSCs significantly alleviated experimental colitis. Depletion of peritoneal B cells, but not macrophages, clearly impaired the therapeutic effects of MSCs. Intraperitoneally delivered MSCs improved IBD likely by boosting the IL-10-producing B cells in the peritoneal cavity, and a single intraperitoneal injection of MSCs could significantly prevent disease severity in a recurrent mouse colitis model, with lower proinflammation cytokines and high level of IL-10. The gene expression profile revealed that thrombospondin-1 (THBS1) was dramatically upregulated in MSCs after coculture with peritoneal lavage fluid from colitis mice. Knockout of THBS1 expression in MSCs abolished their therapeutic effects in colitis and the induction of IL-10-producing B cells. Mechanistically, THBS1 modulates the activation of transforming growth factor-β (TGF-β), which combines with TGF-β receptors on B cells and contributes to IL-10 production. Blocking the interaction between THBS1 and latent TGF-β or inhibiting TGF-β receptors (TGF-βR) significantly reversed the THBS1-mediated induction of IL-10-producing B cells and the therapeutic effects on colitis. Collectively, our study revealed that intraperitoneally delivered MSCs secreted THBS1 to boost IL-10+Bregs and control the progression and recurrence of colitis, providing new insight for the prevention and treatment of IBD.

Bone marrow mesenchymal stromal cells support regeneration of intestinal damage in a colitis mouse model, independent of their CXCR4 expression

“…In addition, is has been previously shown that i.p. delivered MSCs can alleviate the symptoms of experimental colitis in mice through induction of regulatory B Cells 50 . Although this mechanism is unlikely to be involved in our immune‐deficient mouse model, it underlines the fact that multiple mechanisms may be involved in the immune modulating and regenerative effects of MSCs.…”

“…delivered MSCs can alleviate the symptoms of experimental colitis in mice through induction of regulatory B Cells. 50 Although this mechanism is unlikely to be involved in our immune‐deficient mouse model, it underlines the fact that multiple mechanisms may be involved in the immune modulating and regenerative effects of MSCs. In fact, is has been shown that MSCs injected into the peritoneal space spread mostly to abdominal organs, including liver, spleen, and intestine, in contrast to intravenously injected cells, which have a preference for liver and lung tissue within the first 24 h after injection.…”

Therapeutic potential of mesenchymal stem/stromal cells (MSCs)-based cell therapy for inflammatory bowel diseases (IBD) therapy

“…Treatment improved OS rate, attenuated symptoms and ameliorated macroscopic and histologic scores in experimental mice [116]. Further analysis demonstrated that MSCs-secreted thrombospondin-1 (THBS1) may boost IL-10 + Bregs and control the development and recurrence of colitis [118]. These results confer the pivotal role of Tregs, rDC, and also Bregs in adjusting IBD progress and clarify its importance for further investigations to provide a new therapeutic avenue.…”

CD73 mediated host purinergic metabolism in intestine contributes to the therapeutic efficacy of a novel mesenchymal-like endometrial regenerative cells against experimental colitis

“…All experimental groups for colitis were induced with 3% DSS (36-50 kDa; 60316ES60, YEASEN) supplemented in the drinking water for 7 days and then received normal water for the following 3 days. For treatment, ERCs or CD73 -/- ERCs (5 th -7 th generation) were suspended in phosphate buffered saline (PBS) and injected intraperitoneally experimental mice (1×10 6 cells per mice) on days 2, 5, and 8 according to the protocols ( 31 , 32 ). All other treatments were also administered with the volume of PBS (200μL) as the vehicle group simultaneously.…”