Hepatocyte transplantation and advancements in alternative cell sources for liver-based regenerative medicine

Abstract

Human hepatocyte transplantation has been actively perused as an alternative to liver replacement for acute liver failure and liver-based metabolic defects. Current challenges in this field include a limited cell source, reduced cell viability following cryopreservation and poor engraftment of cells into the recipient liver with consequent limited life span. As a result, alternative stem cell sources such as pluripotent stem cells, fibroblasts, hepatic progenitor cells, amniotic epithelial cells and mesenchymal stem/stromal cells (MSCs) can be used to generate induced hepatocyte like cells (HLC) with each technique exhibiting advantages and disadvantages. HLCs may have comparable function to primary human hepatocytes and could offer patient-specific treatment. However, long-term functionality of transplanted HLCs and the potential oncogenic risks of using stem cells have yet to be established. The immunomodulatory effects of MSCs are promising, and multiple clinical trials are investigating their effect in cirrhosis and acute liver failure. Here, we review the current status of hepatocyte transplantation, alternative cell sources to primary human hepatocytes and their potential in liver regeneration. We also describe recent clinical trials using hepatocytes derived from stem cells and their role in improving the phenotype of several liver diseases.

Keywords: Fibroblast; Hepatic progenitor cells; Hepatocyte transplantation; Induced pluripotent stem cells; Liver regeneration; Mesenchymal stem/stromal cell.

Fig. 1

Potential alternative cell sources (induced pluripotent stem cells, fibroblasts, mesenchymal stem/stromal cells and hepatic progenitor cells) which can be used to generate hepatocytes. Gene transfer is used to convert somatic cells to iPSCs and fibroblasts to HLCs. All other transformations occur under culture conditions. HLC induced hepatocyte, iPSC induced pluripotent stem cells, MSC mesenchymal stem cells, HPC hepatic progenitor cells, hAEC human amniotic epithelial cells, BMP bone morphogenetic protein, OSM oncostatin M, HGF hepatic growth factor, HNF1A hepatocyte nuclear factor 1 homeobox alpha, HNF4A hepatocyte nuclear factor 4 alpha, FGF fibroblast growth factor, EGF epidermal growth factor, Dex dexamethasone, FBS foetal bovine serum