Mesothelial cells give rise to hepatic stellate cells and myofibroblasts via mesothelial–mesenchymal transition in liver injury

Abstract

In many organs, myofibroblasts play a major role in the scarring process in response to injury. In liver fibrogenesis, hepatic stellate cells (HSCs) are thought to transdifferentiate into myofibroblasts, but the origins of both HSCs and myofibroblasts remain elusive. In the developing liver, lung, and intestine, mesothelial cells (MCs) differentiate into specific mesenchymal cell types; however, the contribution of this differentiation to organ injury is unknown. In the present study, using mouse models, conditional cell lineage analysis has demonstrated that MCs expressing Wilms tumor 1 give rise to HSCs and myofibroblasts during liver fibrogenesis. Primary MCs, isolated from adult mouse liver using antibodies against glycoprotein M6a, undergo myofibroblastic transdifferentiation. Antagonism of TGF-β signaling suppresses transition of MCs to mesenchymal cells both in vitro and in vivo. These results indicate that MCs undergo mesothelial–mesenchymal transition and participate in liver injury via differentiation to HSCs and myofibroblasts.

Myofibroblastic Conversion and Regeneration of Mesothelial Cells in Peritoneal and Liver Fibrosis

“…27,28 Tamoxifen (Sigma-Aldrich, St. Louis, MO) dissolved in ethanol was emulsified in sesame oil at 12.5 mg/mL and injected intraperitoneally into the mice (10 to 12 weeks old) at 100 mg/g body weight twice during a 3-day interval. 12 Two weeks after the last injection, the mice were injected with 0.1% chlorhexidine gluconate (CG) solution (Sigma-Aldrich) in 15% ethanol/phosphatebuffered saline at 1.5 mL/100 g body weight to the right part of the peritoneum every other day. 29 After 10 injections of CG, the mice developed peritoneal fibrosis.…”

“…Interestingly, a similar conversion of MCs was recently reported in fibrosis of the adult liver or lung. 12,13 In the mouse liver, MCs express WT1, cytokeratin 8 (KRT8), and vimentin (VIM) but not E-cadherin (CDH1) and a-smooth muscle actin (ACTA2). 12 On liver injury, Wt1 þ MCs give rise to hepatic stellate cells or ACTA2 þ myofibroblasts, depending on causes.…”

“…12,13 In the mouse liver, MCs express WT1, cytokeratin 8 (KRT8), and vimentin (VIM) but not E-cadherin (CDH1) and a-smooth muscle actin (ACTA2). 12 On liver injury, Wt1 þ MCs give rise to hepatic stellate cells or ACTA2 þ myofibroblasts, depending on causes. 12 Because MCs show an intermediate phenotype between epithelial cells and mesenchymal cells in normal tissues, we defined the change of MCs into myofibroblasts as a mesothelialemesenchymal transition (MMT) rather than an epithelialemesenchymal transition.…”

“…12 On liver injury, Wt1 þ MCs give rise to hepatic stellate cells or ACTA2 þ myofibroblasts, depending on causes. 12 Because MCs show an intermediate phenotype between epithelial cells and mesenchymal cells in normal tissues, we defined the change of MCs into myofibroblasts as a mesothelialemesenchymal transition (MMT) rather than an epithelialemesenchymal transition. Transforming growth factor (TGF)-b has an essential role in the generation of myofibroblasts in organ fibrosis.…”

“…14 We found that TGF-b induces the conversion of MCs into myofibroblasts in vitro. 12 Furthermore, antagonism of TGF-b signaling by treatment with a soluble TGF-b type II receptor (STR) led to the suppression of MMT in liver fibrosis. 12 However, whether direct TGF-b signaling is involved in MMT in both visceral and parietal MCs in organ fibrosis remained unclear.…”