Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Complutense University of Madrid (UCM), 28040 Madrid, Spain.
Cells. 2022 Jan 21;11(3):365. doi: 10.3390/cells11030365.
Bone morphogenetic protein 9 (BMP9), a member of the TGF-β superfamily, has emerged as a new player in chronic liver diseases (CLDs). Its levels increase in the fibrotic liver where it promotes fibrogenesis. It also regulates hepatic progenitor cells (oval cells in rodents), a cell population that contributes to repopulate the liver and recover functionality upon severe damage, but it can also be pro-fibrogenic, depending upon the hepatic microenvironment. Here we analyze the effect of chronic exposure to BMP9 in oval cells. We show that cells chronically treated with BMP9 (B9T-OC) display a more epithelial and hepatocyte-like phenotype while acquiring proliferative and survival advantages. Since our previous studies had revealed a functional crosstalk between BMP9 and the HGF/c-Met signaling pathways in oval cells, we analyzed a possible role for HGF/c-Met in BMP9-induced long-term effects. Data evidence that active c-Met signaling is necessary to obtain maximum effects in terms of BMP9-triggered hepatocytic differentiation potential, further supporting functionally relevant cooperation between these pathways. In conclusion, our work reveals a novel action of BMP9 in liver cells and helps elucidate the mechanisms that serve to increase oval cell regenerative potential, which could be therapeutically modulated in CLD.
骨形态发生蛋白 9（BMP9），TGF-β 超家族的一员，在慢性肝病（CLDs）中崭露头角。它在纤维化的肝脏中含量增加，促进纤维化的形成。它还调节肝祖细胞（啮齿动物中的卵圆细胞），这是一种有助于在严重损伤时重新填充肝脏并恢复功能的细胞群体，但它也可以是促纤维化的，这取决于肝微环境。在这里，我们分析了慢性暴露于 BMP9 对卵圆细胞的影响。我们发现，长期用 BMP9 处理的细胞（B9T-OC）表现出更上皮和肝细胞样的表型，同时获得增殖和生存优势。由于我们之前的研究揭示了 BMP9 在卵圆细胞中与 HGF/c-Met 信号通路之间存在功能串扰，我们分析了 HGF/c-Met 在 BMP9 诱导的长期效应中的可能作用。数据表明，活性 c-Met 信号对于获得 BMP9 触发的肝细胞分化潜能的最大效果是必要的，进一步支持了这些途径之间功能上相关的合作。总之，我们的工作揭示了 BMP9 在肝细胞中的新作用，并有助于阐明增加卵圆细胞再生潜力的机制，这在 CLD 中可以进行治疗调节。
