Jerusalem | Scientists have successfully grown human liver cells in the laboratory using a new technique that allows the cells to proliferate rapidly without losing their unique metabolic function. This groundbreaking development could help advance a variety of liver-related research and applications, from studying drug toxicity to creating bio-artificial liver support for patients awaiting transplantations.
Human hepatocytes cells that comprise 85 per cent of the liver are routinely used by the pharmaceutical industry for study of hepatotoxicity, drug clearance and drug-drug interactions. They also have clinical applications in cell therapy to correct genetic defects, reverse cirrhosis, or support patients with a liver assist device. However, while the human liver can rapidly regenerate in vivo, this capability to proliferate is rapidly lost when human cells are removed from the body.
Past attempts to expand human hepatocytes in the laboratory resulted in immortalised cancer cells with little metabolic function. To address this problem, Yaakov Nahmias, from the Hebrew University of Jerusalem, partnered with leading scientists at upcyte technologies GmbH in Germany to develop a new approach to rapidly expand the number of human liver cells in the laboratory without losing their unique metabolic function.
The researchers demonstrated that weak expression of Human Papilloma Virus (HPV) E6 and E7 proteins released hepatocytes from cell cycle arrest and allowed them to proliferate in response to Oncostatin M (OSM), a member of the interleukin 6 (IL-6) superfamily that is involved in liver regeneration. The researchers carefully selected colonies of human hepatocytes that only proliferate in response to OSM. Stimulation with OSM caused cell proliferation, with doubling time of 33 to 49 hours. Removal of OSM caused growth arrest and hepatic differentiation within 4 days, generating highly functional cells.
The method, called the upcyte process, allows expanding human hepatocytes for 35 population doubling. Its strength lies in our ability to generate liver cells from multiple donors, enabling the study of patient to patient variability and idiosyncratic toxicity, said Joris Braspenning, who led the German group.
The team generated hepatocyte lines from diverse ethnic backgrounds that could be serially passaged, while maintaining CYP450 activity, epithelial polarisation, and protein expression at the same level as primary human hepatocytes. Importantly, the proliferating hepatocytes showed identical toxicology response to primary human hepatocytes across 23 different drugs.
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