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The liver is a major organ responsible for maintaining the body's homeostasis and xenobiotic metabolism. Liver transplantation is essential for the alleviation of many severe liver diseases. However, there are many patients who cannot receive liver transplants because of donor shortage. Therefore development of effective therapeutic drugs that can replace the need for liver transplantation is desired. To this end, model cells that faithfully reproduce hepatic functions are essential. It is expected that human induced pluripotent stem cell (iPS)-derived hepatocyte-like cells, which faithfully reproduce hepatic functions, would be a valuable tool for drug discovery. Hepatic differentiation from human iPS cells has been performed using growth factors, but the hepatic differentiation efficiency was quite low and liver functions of human iPS cell-derived hepatocyte-like cells were lower than those of primary human hepatocytes. Therefore we tried to improve the hepatic differentiation technology using gene transfer, genome editing, three-dimensional culture, and extracellular matrix technologies. As a result, the purity of human iPS cell-derived hepatocyte-like cells was improved into 90% or more, and the liver functions of human iPS cell-derived hepatocyte-like cells were improved to a level comparable to primary human hepatocytes. In this article, we introduce the research results we have acquired over the last decade.

Pharmaceutical Research on Liver Diseases Using iPS Cell and Genome Editing Technologies