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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-?1 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-?1-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-?1-induced procollagen1A1, fibronectin, and ?-smooth muscle actin expression in HIMFs. This anti-fibrogenic effect was more apparent in the UC-MSCs. TGF-?1 stimulation increased the expressions of RhoA, MRTF-A, and SRF in the HIMFs. TGF-?1 induced the synthesis of procollagen1A1, fibronectin, and ?-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-?1-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.

SUBMITTER: Choi YJ

PROVIDER: S-EPMC6757442 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Choi Yoon Jeong YJ Koo Jun Bon JB Kim Hee Yeon HY Seo Jin Won JW Lee Eun Jeong EJ Kim Woo Ram WR Cho Joo Young JY Hahm Ki Baik KB Hong Sung Pyo SP Kim Duk Hwan DH Yoo Jun-Hwan JH

Stem cell research & therapy 20190923 1

<h4>Background</h4>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 der ...[more]

PMID: 31547873

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Project description:BackgroundIntestinal fibrosis is a serious complication of inflammatory bowel disease, including Crohn's disease and ulcerative colitis. There is no specific treatment for intestinal fibrosis. Studies have indicated that peroxisome proliferator-activated receptor- ? (PPAR-?) agonists have anti-fibrogenic properties in organs besides the gut; however, their effects on human intestinal fibrosis are poorly understood. This study investigated the anti-fibrogenic properties and mechanisms of PPAR-? agonists on human primary intestinal myofibroblasts (HIFs).MethodsHIFs were isolated from normal colonic tissue of patients undergoing resection due to colorectal cancer. HIFs were treated with TGF-?1 and co-incubated with or without one of two synthetic PPAR-? agonists, troglitazone or rosiglitazone. mRNA and protein expression of procollagen1A1, fibronectin, and ?-smooth muscle actin were determined by semiquantitative reverse transcription-polymerase chain reaction and Western blot. LY294002 (Akt inhibitor) was used to examine whether Akt phosphorylation was a downstream mechanism of TGF-?1 induced expression of procollagen1A1, fibronectin, and ?-smooth muscle actin in HIFs. The irreversible PPAR-? antagonist GW9662 was used to investigate whether the effect of PPAR-? agonists was PPAR-? dependent.ResultsBoth PPAR-? agonists reduced the TGF-?1-induced expression of ?-smooth muscle actin which was integrated into stress fibers in HIFs, as determined by actin microfilaments fluorescent staining and ?-smooth muscle actin-specific immunocytochemistry. PPAR-? agonists also inhibited TGF-?1-induced mRNA and protein expressions of procollagen1A1, fibronectin, and ?-smooth muscle actin. TGF-?1 stimulation increased phosphorylation of downstream signaling molecules Smad2, Akt, and ERK. TGF-?1 induced synthesis of procollagen1A1, fibronectin, and ?-smooth muscle actin through a phosphatidylinositol 3-kinase/Akt-dependent mechanism. PPAR-? agonists down regulated fibrogenesis, as shown by inhibition of Akt and Smad2 phosphorylation. This anti-fibrogenic effect was PPAR-? independent.ConclusionsTroglitazone and rosiglitazone suppress TGF-?1-induced synthesis of procollagen1A1, fibronectin, and ?-smooth muscle actin in HIFs and may be useful in treating intestinal fibrosis.

Project description:Mesenchymal stem cells (MSCs) possess self-renewal and multipotential differentiation abilities, and they are thought to be one of the most reliable stem cell sources for a variety of cell therapies. Recently, cell therapy using MSCs has been studied as a novel therapeutic approach for cancers that show refractory progress and poor prognosis. MSCs from different tissues have different properties. However, the effect of different MSC properties on their application in anticancer therapies has not been thoroughly investigated. In this study, to characterize the anticancer therapeutic application of MSCs from different sources, we established two different kinds of human MSCs: umbilical cord blood-derived MSCs (UCB-MSCs) and adipose-tissue-derived MSCs (AT-MSCs). We used these MSCs in a coculture assay with primary glioblastoma multiforme (GBM) cells to analyze how MSCs from different sources can inhibit GBM growth. We found that UCB-MSCs inhibited GBM growth and caused apoptosis, but AT-MSCs promoted GBM growth. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling assay clearly demonstrated that UCB-MSCs promoted apoptosis of GBM via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL was expressed more highly by UCB-MSCs than by AT-MSCs. Higher mRNA expression levels of angiogenic factors (vascular endothelial growth factor, angiopoietin 1, platelet-derived growth factor, and insulin-like growth factor) and stromal-derived factor-1 (SDF-1/CXCL12) were observed in AT-MSCs, and highly vascularized tumors were developed when AT-MSCs and GBM were cotransplanted. Importantly, CXCL12 inhibited TRAIL activation of the apoptotic pathway in GBM, suggesting that AT-MSCs may support GBM development in vivo by at least two distinct mechanisms-promoting angiogenesis and inhibiting apoptosis. The opposite effects of AT-MSCs and UCB-MSCs on GBM clearly demonstrate that differences must be considered when choosing a stem cell source for safety in clinical application.

Dataset Information

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

Publications

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

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