New approaches are needed to generate and maintain stable and mature adult liver cells ex vivo. In the April issue of Gastroenterology, Bart Spee and colleagues review factors that promote hepatocyte differentiation and maturation, and consider criteria for establishing whether cells derived from stem cells are fully mature hepatocytes. They discuss challenges to cell transplantation and future technologies for use in hepatic stem cell maturation, including 3-dimensional biofabrication and genome modification.
The only effective treatment for patients with end-stage liver disease is organ transplantation, but there are not enough donors. Primary hepatocytes are a resource for liver cell transplantation and bioartificial liver devices, but the complexity of the maturation process, instability of cultured hepatocytes, and inconsistent protocols limit their application.
The review by Spee and colleagues discusses hepatocyte functions, development, and cell types and in vitro techniques for generating a potential alternative to hepatocytes, called hepatocyte-like cells (HLCs). They review cell sources for hepatocyte generation, including induced PSCs (iPSCs), mesenchymal stromal or stem cells (MSCs), hepatic progenitor/stem cells (HPCs).
However, liver maturation is a complex process. The authors review the mechanisms by which the developing liver is affected by changes in the circulation, microbiome, and nutrition. Increasing our understanding of these changes might provide information needed to develop more efficient in vitro liver maturation methods.
Mature hepatocytes do not proliferate rapidly, posing challenges to their in vitro generation. Spee and colleagues review factors that regulate hepatocyte differentiation and maturation, such as growth factors, transcription factors, microRNAs, small molecules, and the extracellular matrix microenvironment (see figure).
The review lists the structural, metabolic, and functional features that define mature human hepatocytes. The authors state that these should all be considered during generation and maturation of human HLCs; freshly isolated primary human hepatocytes should always be used as the standard for comparison.
Spee and colleagues discuss the potential for cell therapies for patients with acute liver failure and inborn errors of hepatic metabolism, reviewing challenges and findings from studies in mice, and different mouse models of liver disease and repopulation. The also explain future possibilities, such as 3D bioprinting of whole livers and CRISPR/Cas9 systems for controlling human PSC differentiation into endodermal lineages.