In Vitro Generated Hepatocyte-Like Cells: A Novel Tool in Regenerative Medicine and Drug Discovery

Abstract Hepatocyte-like cells (HLCs) are generated from either various human pluripotent stem cells (hPSCs) including induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), or direct cell conversion, mesenchymal stem cells as well as other stem cells like gestational tissues. They provide potential cell sources for biomedical applications. Liver transplantation is the gold standard treatment for the patients with end stage liver disease, but there are many obstacles limiting this process, like insufficient number of donated healthy livers. Meanwhile, the number of patients receiving a liver organ transplant for a better life is increasing. In this regard, HLCs may provide an adequate cell source to overcome these shortages. New molecular engineering approaches such as CRISPR/ Cas system applying in iPSCs technology provide the basic principles of gene correction for monogenic inherited metabolic liver diseases, as another application of HLCs. It has been shown that HLCs could replace primary human hepatocytes in drug discovery and hepatotoxicity tests. However, generation of fully functional HLCs is still a big challenge; several research groups have been trying to improve current differentiation protocols to achieve better HLCs according to morphology and function of cells. Large-scale generation of functional HLCs in bioreactors could make a new opportunity in producing enough hepatocytes for treating end-stage liver patients as well as other biomedical applications such as drug studies. In this review, regarding the biomedical value of HLCs, we focus on the current and efficient approaches for generating hepatocyte-like cells in vitro and discuss about their applications in regenerative medicine and drug discovery. Keywords: Hepatocyte, Cell Therapy, Gene Therapy, Drug Discover

In vitro Generated Hepatocyte- like cells: a Novel Tool in Regenerative Medicine and Drug Discovery

Hepatocyte-like cells (HLCs) generated from various human pluripotent stem cells (hPSCs), mostly induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) or direct cell conversion and also other stem cells like gestational tissues stem cells and mesenchymal stromal cells; provide potential cell sources for biomedical applications. Liver transplantation is the gold standard treatment for patients with end stage liver disease, but there are many practical limits, mostly insufficient number of donated healthy livers. Meanwhile the number of patients to receive a liver organ transplant for a better life is increasing. In this regard, HLCs may provide an adequate cell source to overcome these shortages. New molecular engineering approaches such as CRISPR/Cas systen with iPSCs technology provid the basic principles of gene correction for monogenic inherited metabolic liver diseases as another application of HLCs. It has shown that HLCs could replace primary human hepatocytes in drug discovery and hepatotoxicity tests. However, generation of fully functional HLCs is still a big challenge; research groups have been trying to improve current differentiation protocols to achieve better HLCs according to morphology and function of cells. Large-scale generation of functional HLCs in bioreactors could make a new window in producing enough hepatocytes for treating end-stage liver patients as well as other biomedical applications such as drug studies. In this review, regarding the biomedical value of hepatocyte-like cells, we focus on the current and efficient approaches for generating hepatocyte- like cells in vitro and discuss about their applications in regenerative medicine and drug discovery