Human embryoid bodies to hepatocyte-like clusters: Preparing for translation

Abstract

End-stage liver disease and acute liver failure are some of the most common causes of death worldwide, affecting over 40,000 patients in the United States, for most of whom liver transplantation is the only treatment. Transplantable livers are obtained primarily from deceased donors in the west and living donors in the east, with demand outstripping supply, leading to thousands of deaths each year for those on the transplant waiting lists.As a bridge to liver transplantation, human primary hepatocytes have been transplanted with low success, owing to their inability to grow and expand in vitro, their high sensitivity to cold storage-induced damage, and their dedifferentiation following two-dimensional culture. In the past decade, human induced pluripotent stem cells (hiPSCs) have been studied as a potential alternative to liver and primary hepatocyte transplantation through their differentiation into hepatocyte-like cells (HLCs). Differentiation of hiPSCs into HLCs is limited by the low percentage of differentiated cells that reach a mature hepatic phenotype, poor reproducibility of existing differentiation protocols, and inadequate long-term viability and function in vitro and in vivo. In this review, we will discuss the mechanisms of the various techniques that aim to improve the hepatic differentiation of hiPSCs into mature and genotypically stable HLCs for use in drug studies, as a potential bridge for liver transplantation after liver failure or as therapy for liver regeneration and replacement. Keywords: Hepatocyte differentiation, Human induced pluripotent stem cells (hiPSCs), Cell transplantation, Embryoid bodies (EBs), Hepatocyte-like cells (HLCs)