Umbilical cord/placenta-derived mesenchymal stem cells inhibit fibrogenic activation in human intestinal myofibroblasts via inhibition of myocardin-related transcription factor A

Abstract

Background The lack of anti-fibrotic agents targeting intestinal fibrosis is a large unmet need in inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis. Previous studies have found that perinatal tissue (umbilical cord, UC; placenta, PL)-derived mesenchymal stem cells (MSCs) reduce fibrosis in several organs. However, their effects on human intestinal fibrosis are poorly understood. This study investigated the anti-fibrogenic properties and mechanisms of MSCs derived from UC and PL (UC/PL-MSCs) on human primary intestinal myofibroblasts (HIMFs). Methods The HIMFs were treated with TGF-β1 and co-cultured with UC/PL-MSCs. We used a small molecular inhibitor CCG-100602 to examine whether serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factor A (MRTF-A) are involved in TGF-β1-induced fibrogenic activation in HIMFs. The anti-fibrogenic mechanism of UC/PL-MSCs on HIMFs was analyzed by detecting the expression of RhoA, MRTF-A, and SRF in HIMFs. Results UC/PL-MSCs reduced TGF-β1-induced procollagen1A1, fibronectin, and α-smooth muscle actin expression in HIMFs. This anti-fibrogenic effect was more apparent in the UC-MSCs. TGF-β1 stimulation increased the expressions of RhoA, MRTF-A, and SRF in the HIMFs. TGF-β1 induced the synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin through a MRTF-A/SRF-dependent mechanism. Co-culture with the UC/PL-MSCs downregulated fibrogenesis by inhibition of RhoA, MRTF-A, and SRF expression. Conclusions UC/PL-MSCs suppress TGF-β1-induced fibrogenic activation in HIMFs by blocking the Rho/MRTF/SRF pathway and could be considered as a novel candidate for stem cell-based therapy of intestinal fibrosis.

Fibrostenotic strictures in Crohn’s disease

“…Finally, the MRTF/SRF complex induces fibrogenic genes including collagen, fibronectin, α-SMA, and myosin light-chain kinase. [51][52][53] The overview of Smad-dependent and Smad-independent TGF-β signaling in intestinal fibrosis is summarized in Fig. 2.…”

“…The role of Rho/ROCK/Actin/MRTF/SRF signaling, which is induced by TGF-β1 or matrix stiffness, has been revealed in intestinal fibrosis. 11,51,53,181 ROCK is activated in inflamed and fibrotic tissue in CD. The rectal delivery of a novel small molecule ROCK inhibitor (AMA0825) reversed the established intestinal fibrosis in 2 different murine models of fibrosis by diminishing the TGF-β1-induced MRTF and p38 MAPK activation and increasing autophagy in fibroblasts.…”

“…Meanwhile, actin polymerization releases the globular actin from MRTF, and subsequently the free MRTF translocates into the nucleus and binds to SRF. Finally, the MRTF/SRF complex induces fibrogenic genes including collagen, fibronectin, α-SMA, and myosin light-chain kinase [ 51 - 53 ]. The overview of Smad-dependent and Smad-independent TGF-β signaling in intestinal fibrosis is summarized in Fig.…”

“…The role of Rho/ROCK/Actin/MRTF/SRF signaling, which is induced by TGF-β1 or matrix stiffness, has been revealed in intestinal fibrosis [ 11 , 51 , 53 , 181 ]. ROCK is activated in inflamed and fibrotic tissue in CD.…”

Immune Dysregulation in HFpEF: A Target for Mesenchymal Stem/Stromal Cell Therapy

“…Mesenchymal stem/stromal cells (MSCs) are multipotent mesenchymal cells that can be found in tissues such as the bone-marrow, fat, the umbilical cord or placenta [79,80]. While initial enthusiasm regarding MSCs originated from their capacity to differentiate into various cell types, it is now widely believed that tissue incorporation of exogenously-administered MSCs is negligible and does not account for the therapeutic effect of MSC infusions [42][43][44][45].…”