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

  • Stem Cell Res Ther. 2019 Sep 23;10(1):291. doi: 10.1186/s13287-019-1385-8.
Yoon Jeong Choi  1  2 ,  Jun Bon Koo  3 ,  Hee Yeon Kim  4 ,  Jin Won Seo  4 ,  Eun Jeong Lee  4 ,  Woo Ram Kim  5 ,  Joo Young Cho  1 ,  Ki Baik Hahm  1 ,  Sung Pyo Hong  1 ,  Duk Hwan Kim  6 ,  Jun-Hwan Yoo  7  8
Affiliations
  • 1. Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea.
  • 2. Institute of Basic Medical Sciences, School of Medicine, CHA University, Seongnam, South Korea.
  • 3. Clinical Research Center, CHA Bundang Medical Center, CHA University, Seongnam, South Korea.
  • 4. CHA Biotech, Co. Ltd., Seongnam, South Korea.
  • 5. Department of Surgery, CHA Bundang Medical Center, CHA University, Seongnam, South Korea.
  • 6. Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea. [email protected].
  • 7. Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea. [email protected].
  • 8. Institute of Basic Medical Sciences, School of Medicine, CHA University, Seongnam, South Korea. [email protected].
PMID: 31547873 DOI: 10.1186/s13287-019-1385-8
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.

Keywords
Intestinal fibrosis; Mesenchymal stem cells; Myofibroblasts; Placenta; Umbilical cord.
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