From iPS to hepatocytes

As noted in the study, while “cryopreserved primary human hepatocytes are useful in drug screening and liver cell transplantation, they rapidly lose their functions (such as drug metabolism capacity) and hardly proliferate in in-vitro culture systems.” However, “the human pluripotent stem cell (hPSC)-derived hepatoblast-like cells (HBCs), which have potential to differentiate into the hepatocyte-like cells, would be an attractive cell source to provide abundant hepatocyte-like cells for drug screening and liver cell transplantation.”

The team’s approach consisted of culturing progenitor cells of hepatocytes developed from induced pluripotent stem cells via endoderm, one of the primary germ cell layers in embryos. The cells were cultured in dishes coated with laminin-111, a glycoprotein found primarily in the embryonic epithelium that plays a role in both epithelial development and differentiation. The progenitor cells ended up multiplying more than 10 billion-fold without turning into hepatocytes, and were later found to also be capable of differentiating into hepatocytes.

This approach offers both easier generation of hepatocytes and larger amounts of the cells. As noted in the paper, “By culturing on the LN111-coated dish, human PSC-derived HBCs were maintained for more than three months and had the ability to differentiate into both hepatocyte-like cells and cholangiocyte-like cells. These expandable human PSC-derived HBCs would be manageable tools for drug screening, experimental platforms to elucidate mechanisms of hepatoblasts and cell sources for hepatic regenerative therapy.”

While the ability to derive tissue of any type from stem cells is helpful, hepatocytes are particularly useful and sought after in drug discovery. The ability to generate liver cells or model organs at will enables drug developers to test potential drug candidates for toxicity issues and determine the safety of a compound without having to risk patients. And given that most drug product candidates fail in the later stages of development due to issues with safety and toxicity, the ability to identify such problems in the early stages of development can aid drug developers in fine-tuning compounds to address toxicity problems, preventing the loss of millions of dollars’ worth of investments by catching such an issue before a compound reaches clinical trials.

“Hepatocytes are the most important cells for the drug screening and development,” the Laboratory of Stem Cell Regulation at the National Institute of Biomedical Innovation notes on its website. “Hepatoma cell lines are often used for this purpose; however, these cells contain low levels of drug-metabolizing enzymes and poorly reflect the human hepatocytes in vivo.”

Mizuguchi, who is also the chief project leader at the Laboratory of Stem Cell Regulation, noted that this new method is less labor intensive than current methods of hepatocyte production, in addition to being faster; while current approaches require at least three weeks, this method takes approximately 10 days.

More work must be done to fully realize the potential of this new approach, though, as the study notes that “to transplant these cells for purposes of regenerative medicine, a xeno-free culture condition for hPSC-derived HBCs must be developed in the future. It is hoped that the hPSC-derived HBCs and their derivatives will be helpful in various medical applications, such as drug screening and regenerative medicine.”