Using human induced pluripotent stem cell-derived liver cells to investigate the mechanisms of liver fibrosis in vitro

The liver is a highly organized organ that consists of hepatic parenchymal cells, hepatocytes, and non-parenchymal cells such as the liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), cholangiocytes, and Kupffer cells. Although previous studies have primarily focused on the hepatocyte dynamics in the injured liver, recent studies have shown that non-parenchymal cells play an essential role in both liver regeneration and liver fibrosis progression. Among the non-parenchymal cells, HSCs directly contribute to the progression of liver fibrosis because the activation of HSCs in response to liver injury or inflammation results in the excess production of extra cellular matrix. LSECs also contribute to modulate the function of hepatocytes, HSCs, and immune cells during liver fibrosis. Therefore, to investigate the mechanisms for liver fibrosis in vitro, it is necessary to develop an appropriate liver model that accurately recapitulates the pathology of human liver fibrosis including HSC activation. However, the supply of human cells is limited and freshly isolated liver cells easily lose their specific characteristics in culture. To overcome this shortage of human liver cells, human induced pluripotent stem cell (hiPSC)-derived liver cells were generated by mimicking the liver developmental process. In this review article, we outline the differentiation system of liver non-parenchymal cells from hiPSCs and development of in vitro liver disease models using hiPSC-derived liver cells. We describe the utility of these liver models as experimental systems to investigate the mechanism of liver fibrosis and development of drugs for the treatment thereof.