Abstract
Limited by the poor proliferation and restricted sources of adult hepatocytes, there is an urgent need to find substitutes for proliferation and cultivation of mature hepatocytes in vitro for use in disease treatment, drug approval, and toxicity testing. Hepatocyte-like cells (HLCs), which originate from undifferentiated stem cells or modified adult cells, are considered good candidates because of their advantages in terms of cell source and in vitro expansion ability. However, the majority of induced HLCs are in an immature state, and their degree of differentiation is heterogeneous, diminishing their usability in basic research and limiting their clinical application. Therefore, various methods have been developed to promote the maturation of HLCs, including chemical approaches, alteration of cell culture systems, and genetic manipulation, to meet the needs of in vivo transplantation and in vitro model establishment. This review proposes different cell types for the induction of HLCs, and provide a comprehensive overview of various techniques to promote the generation and maturation of HLCs in vitro.
Highlights
Liver transplantation is the only therapeutic modality for curing end-stage liver disease
Animal experiments have demonstrated that Hepatocyte-like cells (HLCs) transplantation in mice with liver injury significantly improves liver function and promotes liver regeneration (Park et al, 2019) and human induced pluripotent stem cells (iPSCs) combined with gene correction can induce normal hepatocytes to realize autologous cell therapy for patients with metabolic diseases (Yusa et al, 2011)
Li et al developed a new bioartificial liver (BAL) embedded with expandable liver progenitor-like cells from human primary hepatocytes for the treatment of an acute liver failure (ALF) porcine model, and the results showed that BAL attenuates liver damage, ameliorates inflammation, and enhances liver regeneration (Wei-Jian Li et al, 2020)
Summary
Liver transplantation is the only therapeutic modality for curing end-stage liver disease. Immature phenotypes and the inconsistent differentiation of HLCs in the same batch, especially those derived from stem cells, pose a risk of tumorigenesis after transplantation into humans (Xu et al, 2018) All of these obstacles block the transformation of HLCs as an alternative to HHs in clinical applications, and greatly discount the authenticity of drug prediction results in some basic experiments, because HLCs cannot fully express the function of mature hepatocytes. Researchers have developed several methods to promote hepatocyte maturation by attempting to simulate hepatocytes in vivo for liver progenitors to induce mature and stable HLCs in vitro (Berger et al, 2015; Touboul et al, 2016). We discuss various cell sources for HLCs formation and methods promoting the maturation of HLCs in vitro (Figure 1)
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