Human umbilical cord/placenta-derived mesenchymal stem cell secretome attenuates intestinal fibrosis

Abstract Background: A significant unmet need in inflammatory bowel disease is the lack of anti-fibrotic agents targeting intestinal fibrosis. This study aimed to investigate the anti-fibrogenic properties and mechanisms of the secretome of human umbilical cord/placenta-derived mesenchymal stem cells (UC/PL-scrtm) in a murine intestinal fibrosis model and human primary intestinal myofibroblasts (HIMFs). Methods:UC/PL-scrtm was concentrated by 15 times using a 3 kDa cut-off filter. C57BL/6 mice aged 7 weeks old were randomly assigned to one of four groups: 1) control, 2) dextran sulfate sodium (DSS), 3) DSS + secretome (late-phase treatment), and 4) DSS + secretome (early-phase treatment). Chronic DSS colitis and intestinal fibrosis was induced by three cycles of DSS administration. One DSS cycle consisted of 7 d oral DSS administration (1.75%, 2%, and 2.5% DSS), followed by 14 d of water drinking. UC/PL-scrtm was intraperitoneally administered in the late phase (from day 50, 10 times) or early phase (from day 29, 10 times) of DSS cycles. HIMFs were treated with TGF-β1 and co-treated with UC/PL-scrtm (10% of culture media) in the cellular model. Results: In the animal study, UC/PL-scrtm reduced submucosa/muscularis propria thickness and collagen deposition, which improved intestinal fibrosis in chronic DSS colitis. The UC/PL-scrtm significantly reduced the expressions of procollagen1A1 and α-smooth muscle actin, which DSS significantly elevated. The anti-fibrogenic effect was more apparent in the UC-scrtm or early-phase treatment model. The UC/PL-scrtm reduced procollagen1A1, fibronectin, and α-smooth muscle actin expression in HIMFs in cellular model. The UC/PL-scrtm downregulated fibrogenesis by suppressing RhoA, MRTF-A, and SRF expression. Conclusions: Human UC/PL-scrtm inhibits TGF-β1-induced fibrogenic activation in HIMFs by blocking the Rho/MRTF/SRF pathway and chronic DSS colitis-induced intestinal fibrosis. Thus, it may be regarded as a novel candidate for stem cell-based therapy of intestinal fibrosis.