Determination of the source of myofibroblasts and therapeutic strategy against fibrosis

2018-07-22Organ fibrosis is a worldwide health care problem as it leads to end-stage organ failure in patients. Currently, there is no medical treatment for organ fibrosis, such as in the liver and peritoneum. Myofibroblasts have been suggested to participate in fibrogenesis through synthesizing extracellular matrices and proinflammatory cytokines. Accumulating evidence suggest that there are multiple cellular sources of myofibroblasts. However, it remains elusive how different cell types contribute to myofibroblasts in organ fibrosis. Thus, identification of cell types responsible for fibrogenesis and understanding molecular mechanisms underlying generation of myofibroblasts are essential to determine therapeutic targets for suppression of fibrogenesis. Prolonged injury to the liver often results in liver fibrosis. Similarly, patients who undergo peritoneal dialysis for kidney failure also cause peritoneal fibrosis. In the present study, we focused on the liver and peritoneum as visceral and parietal organs in the peritoneal cavity and identified the cellular sources of myofibroblasts in liver and peritoneal fibrosis. Moreover, we examined molecular mechanisms underlying fibrogenesis in these organs. Mesothelial cells (MCs) form a single epithelial cell layer, called mesothelium, on the surface of the both organs in the peritoneal cavity. We found that MCs give rise to myofibroblasts in both organs. Although MCs partly contributed to myofibroblasts in peritoneal fibrosis, protection of the mesothelium ameliorated fibrosis. In liver fibrosis, hepatic stellate cells (HSCs) reside in the space of Disse and are known to differentiate into myofibroblasts. In addition, portal fibroblasts (PFs) around the bile duct are believed to be the major source of myofibroblasts in biliary fibrosis. However, contribution of PFs to myofibroblasts remains elusive due to insufficient availability of markers and isolation methods. We established a unique protocol to isolate MCs, HSCs, and PFs from normal or injured mouse livers and demonstrated that all three cell types convert into myofibroblasts and transforming growth factor-beta (TGF-beta) stimulates their differentiation. Our data indicate that HSCs are the dominant source of myofibroblasts in liver fibrosis caused by different etiology. Although PFs and MCs partly contributed to myofibroblasts in liver fibrosis, they uniquely participated in biliary fibrosis and capsular fibrosis, respectively. Lastly, we identified lysophosphatidic acid (LPA) as a profibrogenic factor in liver fibrosis. We found that LPA signaling stimulates nuclear localization of TAZ coactivator and induces differentiation of HSCs and MCs toward myofibroblasts. Treatment with an LPA inhibitor reduced liver fibrosis in mice. In conclusion, we demonstrated that MCs act as a source of myofibroblasts in liver and peritoneal fibrosis. In liver fibrosis, HSCs are the major source of myofibroblasts and both MCs and PFs uniquely contribute to fibrosis beneath the liver surface and around the bile duct, respectively. Our data indicate that LPA acts as a profibrogenic factor and its signaling pathway will be a new therapeutic target for suppression of liver fibrosis