Induced pluripotent stem cell-derived stellate cells promote proliferation of induced pluripotent stem cell-derived hepatocytes through the mitogen-activated protein kinase pathway via hepatocyte growth factor

Purpose: Human-induced pluripotent stem cells (iPSCs) have the potential to differentiate into cells of various organs. Hepatocytes derived from iPSCs (i-Heps) have attracted much attention as an alternative treatment for liver transplantation in patients with liver failure. However, it is challenging to create sufficient i-Heps for clinical treatment, highlighting the need to develop an easier and more efficient culture method. In this study, we examined the effect of quiescent iPSC-derived stellate cells (i-Stes) on i-Hep proliferation. Methods: i-Stes and i-Heps were differentiated from iPSCs. Results: i-Stes expressed higher levels of hepatocyte growth factor (HGF) than the human hepatic stellate cell line LX-2. In addition, quiescent i-Sted promoted i-Hep proliferation via activation of the mitogen-activated protein kinase (MAPK) pathway in i-Heps, which was impaired by the activation of i-Sted with transforming growth factor beta. Conclusion: This study provides evidence that i-Sted can effectively induce i-Hep proliferation through HGF activation of the MAPK signaling pathway. Quiescent—but not activated—i-Stes may contribute to the creation of large numbers of i-Heps.