Abstract
BackgroundThe 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).MethodsThe 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.ResultsUC/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.ConclusionsUC/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.
Highlights
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
UC/PL-mesenchymal stem cells (MSCs) inhibit TGF-β1-induced extracellular matrix (ECM) and α-smooth muscle actin (α-SMA) expression in human intestinal myofibroblasts To determine whether UC/PL-MSCs inhibit fibrogenic activation of myofibroblasts, human primary intestinal myofibroblasts (HIMFs) were co-cultured with UC/PL-MSCs and simultaneously stimulated with TGF-β1
UC-MSCs decrease the TGF-β1-induced phosphorylation of Smad2 and Smad3 In addition, we examined whether the classical Smaddependent TGF-β pathways [13] are implicated in the anti-fibrotic mechanism of the UC/PL-MSCs in HIMFs
Summary
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. Their effects on human intestinal fibrosis are poorly understood. The Smad-independent TGF-β signaling is transduced by phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and AKT [8, 11, 12, 14]. Another Smad-independent TGF-β signaling includes Ras homolog family member A/Rho-associated coiled-coil forming protein kinase (RhoA/ROCK) pathway. RhoA-mediated ROCK activation results in polymerization of globular-actin (G-actin) into filamentous actin (F-actin) and releases transcriptional cofactor myocardin-related transcription factor A (MRTF-A) from the G-actin, enabling it to translocate into the nucleus and bind to the pro-fibrotic transcription factor, serum response factor (SRF) [10, 15]
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