Assessing the therapeutic potential of lab-made hepatocytes

Abstract

Hepatocyte transplantation has potential as a bridge or even alternative to whole-organ liver transplantation. Because donor livers are scarce, realizing this potential requires the development of alternative cell sources. To be therapeutically effective, surrogate hepatocytes must replicate the complex function and ability to proliferate of primary human hepatocytes. Ideally, they are also autologous to eliminate the need for immune suppression, which can have severe side effects and may not be sufficient to prevent rejection long term. In the past decade, several methods have been developed to generate hepatocytes from other readily and safely accessible somatic cells. These lab-made hepatocytes show promise in animal models of liver diseases, supporting the feasibility of autologous liver cell therapies. Here, we review recent preclinical studies exemplifying different types of lab-made hepatocytes that can potentially be used in autologous liver cell therapies. To define the therapeutic efficacy of current lab-made hepatocytes, we compare them to primary human hepatocytes, focusing on engraftment efficiency and posttransplant proliferation and function. In addition to summarizing published results, we discuss animal models and assays effective in assessing therapeutic efficacy. This analysis underscores the therapeutic potential of current lab-made hepatocytes, but also highlights deficiencies and uncertainties that need to be addressed in future studies aimed at developing liver cell therapies with lab-made hepatocytes. (Hepatology 2016;64:287-294).

Fig. 1

Assays used to assess the therapeutic efficacy of lab-made hepatocytes.

Fig. 2

Comparison of HSA and liver repopulation levels between recent studies using lab-made hepatocytes and studies using pHeps that reported near-complete liver repopulation. For each study ALB levels were correlated with % liver repopulation. Studies are labeled with the number of transplanted cells (M = million), cell type, animal model, first author and year of publication. The left panel shows results from all studies. The right panel is a double-log plot showing only results from studies using lab-made hepatocytes (highlighted area in left panel). ^Anti-asialo-GM1 antibody. °Tacrolimus. *Equivalent % liver repopulation of liver buds transplanted under the kidney capsule was calculated as the ratio of 2.9 million iPSC-Heps to an estimated 50 million hepatocytes in the mouse liver. **Transplantation by intrahepatic injection. ***% liver repopulation was normalized by estimating that the engrafted median lobe contains 30% of the total liver mass.