Abstract
Current induction methods of hepatocytes from human induced pluripotent stem cells (hiPSCs) are neither low cost nor stable. By screening a chemical library of 1,120 bioactive compounds and known drugs, we identified the α1-adrenergic receptor agonist methoxamine hydrochloride as a small molecule that promotes the differentiation of hiPSC-derived hepatoblasts into ALBUMIN+ hepatocyte-like cells. Other α1-adrenergic receptor agonists also induced the differentiation of hepatocyte-like cells, and an α1-receptor antagonist blocked the hepatic-inducing activity of methoxamine hydrochloride and that of the combination of hepatocyte growth factor (HGF) and Oncostatin M (OsM), two growth factors often used for the induction of hepatoblasts into hepatocyte-like cells. We also confirmed that treatment with methoxamine hydrochloride activates the signal transducer and activator of transcription 3 (STAT3) pathway downstream of IL-6 family cytokines including OsM. These findings allowed us to establish hepatic differentiation protocols for both mouse embryonic stem cells (mESCs) and hiPSCs using small molecules at the step from hepatoblasts into hepatocyte-like cells. The results of the present study suggest that α1-adrenergic agonists induce hepatocyte-like cells by working downstream of HGF and OsM to activate STAT3.
Highlights
Orthotopic liver transplantation is the only radical treatment for chronic liver diseases, but the majority of patients die due to the shortage of donor livers[1]
We found that other α1-adrenergic receptor agonists can induce human induced pluripotent stem cells (hiPSCs)-derived hepatoblasts into hepatocyte-like cells without hepatocyte growth factor (HGF) and Oncostatin M (OsM), and that the addition of an α1-adrenergic receptor antagonist to hepatic differentiation cultures using HGF and OsM abolished the hepatic inducing activity
We initiated the screening with hiPSC-derived hepatoblasts on culture day 14 and screened the Prestwick Chemical library, which consists of 1,120 bioactive compounds and known drugs, in 384-well plates
Summary
Orthotopic liver transplantation is the only radical treatment for chronic liver diseases, but the majority of patients die due to the shortage of donor livers[1]. Stepwise differentiation methods to generate hepatic lineage cells from hESCs/hiPSCs have been developed that mimic the developmental process of liver[6,7,8,9,10,11,12] In these protocols, definitive endoderm cells are initially induced by treatment with a high concentration of activin A, followed by hepatoblast and hepatocyte differentiation using growth factors, such as hepatocyte growth factor (HGF) and Oncostatin M (OsM). This report is the first to show that adrenergic receptor agonists act as inducers for hepatic lineage differentiation from pluripotent stem cells and to suggest adrenergic receptor signals may be downstream of HGF and OsM in hepatic differentiation
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