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April 10, 2020

Liver disease is monkey business

The Kenji Osafune laboratory manufactures liver fibrosis in monkeys to better predict the effect of stem cell therapies for the liver in humans

Most experimental liver cell therapies are tested in patients after passing pre-clinical tests in rodents. Rodents are not the best animal model, however, and successful therapies in them too often fail in humans. In a new study, a team of researchers led by CiRA Professor Kenji Osafune show how liver fibrosis can be stimulated in monkeys to more reliably test iPS cell-based therapies.

Liver fibrosis is a common feature of many chronic liver diseases including cirrhosis. The only curative treatment is liver transplantation, but donors are rare. The transplantation of hepatocytes, on the other hand, is not curative, but regular treatment does bide the patient time until a liver donor becomes available. However, these cells too are not readily available, which is why hepatocyte-like cells made from stem cells are under consideration. iPS cells are especially attractive because they can be expanded into large numbers, meaning a small number of iPS cells can provide a large number of hepatocyte-like cells for many patients.

"Liver transplant is more effective than hepatocyte transplant, so if we can procure a liver donor, we prefer to use the liver for a whole transplantation," explains Osafune.

Because they are cheaper, rodents are normally used for preclinical studies on many iPS cell-based experimental therapies including hepatocyte-like cells. However, tests on animals that more closely resemble humans, namely, monkeys, are more reliable and would reduce the failure rate when translating the experimental therapy to the clinic.

The researchers therefore manufactured liver fibrosis in macaques by the administration of thioacetamide, a method commonly done with rodents. They further showed that transplanted hepatocyte-like cells made from human iPS cells could engraft into the damaged livers, although observation was not long enough to evaluate their therapeutic effects.

"The important advancement is the primate model. This will provide more accurate testing for experimental therapies," says Osafune.

Paper Details
  • Journal: Biochemical and Biophysical Research Communications
  • Title: A Nonhuman Primate Model of Liver Fibrosis towards Cell Therapy for Liver Cirrhosis
  • Authors: Katsutaro Yasuda1,2, Maki Kotaka1, Takafumi Toyohara1, Shin-Ichi Sueta1, Yuko Katakai3, Naohide Ageyama4, Shinji Uemoto2, Kenji Osafune1
  • Author Affiliations:
    1. Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
    2. Department of Hepatobiliary Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
    3. The Corporation for Production and Research of Laboratory Primates, Sakura 1-16-2, Tsukuba, Ibaraki, 305-0003, Japan.
    4. Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Hachimandai 1-1, Tsukuba, Ibaraki, 305-0843, Japan.
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