In Vivo Liver Regeneration Potential of Human Induced Pluripotent Stem Cells from Diverse Origins

Treating Liver Disease, A Promethean Task

As the ancient Greek legend of the disgraced Prometheus showed, the only human organ that can regenerate itself is the liver. Despite the liver’s remarkable capacity for repair and regeneration, diseases such as liver cirrhosis or hepatocellular carcinoma eventually destroy this ability and the only option is for patients to receive a liver transplant. But there is a severe shortage of donor livers for transplantation, which has prompted interest in stem cell therapy for treating patients with end-stage liver disease. However, liver stem cells are difficult to isolate and expand in culture so alternatives are being sought. Enter Liu et al. with a stem cell strategy that involves deriving mature human liver cells (hepatocytes) from human induced pluripotent stem cells (iPSCs).

First, these investigators generated human iPSCs from a variety of adult human cells including hepatocytes, fibroblasts, and keratinocytes and showed that although these iPSCs were derived from very different cell types, they retained similar (although not identical) epigenetic signatures. The authors then used an established stepwise differentiation protocol to induce these human iPSCs to differentiate along the hepatic lineage first into definitive endoderm, then hepatic progenitor cells, and finally into mature hepatocyte-like cells. They found that, regardless of their origin, the different human iPSC lines all showed the same ability to differentiate into hepatic cells. To be useful for cell therapy, these human iPSC-derived hepatic cells must be able to engraft in liver tissue and function in the same way as normal human hepatocytes. So, the authors tested their human iPSC-derived hepatic cells (at different stages of differentiation) for their ability to engraft liver tissue in a xenograft model comprising immunodeficient mice treated with a chemical to induce liver injury. They intravenously infused the mice with 2 million human iPSC-derived hepatic cells or with normal human hepatocytes as a control. They found that human iPSC-derived hepatic cells engrafted mouse liver with an efficiency ranging from 8 to 15%, comparable to that for adult human hepatocytes (~11%). But were the engrafted human hepatic cells functional? The authors report that proteins normally secreted by adult human hepatocytes, such as albumin, transferrin, α-1-antitrypsin, and fibrinogen, could be detected in the serum of mice transplanted with human iPSC-derived hepatic cells at concentrations of 46, 101, 8.1, and 1100 ng/ml, respectively. Although preliminary, these encouraging findings suggest that it may be possible in the future to use infusions of human iPSC-derived hepatic cells to rescue injured liver tissue in patients with end-stage liver disease.