Abstract
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.
Highlights
Bone morphogenetic proteins (BMPs), and Bone morphogenetic protein 9 (BMP9), have emerged as new regulators of liver physiology and pathology [1,2,3,4,5]
We found that BMP9-treated oval cells (B9T-OC) express higher levels of hepatocytic markers than parental oval cells, with a marked and sustained increase of albumin (Alb) and α-fetoprotein (Afp), two plasma proteins secreted by hepatocytes; as well as the hepatocyte nuclear factor 4α (HNF4α, Hnf4a); and fibronectin (Fn1), an extracellular matrix (ECM) protein that promotes the differentiation of liver progenitor cells towards the hepatocyte phenotype [28]
The amount of urea produced by parental oval cells was low, as expected for undifferentiated hepatic progenitor cells, but after BMP9 chronic treatment urea production was significantly increased, reaching levels similar to those found in HepG2 cells, a differentiated hepatic cell line (Figure 2D)
Summary
Bone morphogenetic proteins (BMPs), and BMP9, have emerged as new regulators of liver physiology and pathology [1,2,3,4,5]. Recent studies are uncovering the function of BMP9 in different liver pathologic settings. Additional in vitro and in vivo evidence reveal a role for BMP9 in the regulation of glucose and lipid metabolism as well as the hepatic inflammatory response, having been associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) development, somehow contradictory results have been described [9,10,11,12]. We and others have demonstrated that BMP9 is a key regulator of liver fibrosis. The controversy is heightened, as some studies have suggested a protective effect for BMP9 in liver fibrosis, and, to render an even more complicated picture, mouse strain-dependent responses have been found in terms of liver fibrosis upon genetic deletion of BMP9, which appear to be related to alterations in liver sinusoidal endothelial cell (LSEC) fenestrations and subsequent capillarization [1,2]
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