Fluorescently labeled polarized hepatocytes generated using a new process that allows for their continuous culture without losing metabolic function. [Prof. Yaakov Nahmias]
Fluorescently labeled polarized hepatocytes generated using a new process that allows for their continuous culture without losing metabolic function. [Prof. Yaakov Nahmias]

The Greek Titan Prometheus was punished for his altruism toward mortals after giving them fire. He was chained to a rock for eternity and forced to endure watching an eagle consume his liver during the day—regenerating overnight night to repeat the tortuous cycle at dawn. For their part, scientists have been trying to recreate parts of the mythology in the laboratory for decades, through attempts at continuous culturing of liver cells, in particular, primary hepatocytes.

Now, and international research team with scientists from The Hebrew University of Jerusalem and Upcyte® technologies in Germany have described a new technique for growing human hepatocytes in the laboratory. This 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.      

“The approach is revolutionary,” remarked co-senior author Joris Braspenning, Ph.D., chief scientific officer and managing director at Medicyte GmbH. “Its strength lies in our ability to generate liver cells from multiple donors, enabling the study of patient-to-patient variability and idiosyncratic toxicity.”

The findings from this study were published recently in Nature Biotechnology though an article entitled “Long-term culture and expansion of primary human hepatocytes.”

In vivo, the human liver can rapidly regenerate, however, all attempts to recapitulate this phenotype of primary hepatocytes have thus far resulted in generating immortalized cancer cells with little metabolic function. The inability to expand these cells without losing their function is a detrimental bottleneck for research as well as drug discovery, which often uses the cells for the study of hepatotoxicity, drug clearance, and drug-drug interactions.

To address this problem, the collaborative team developed a new approach to rapidly expand the number of human liver cells in the laboratory without the loss of metabolic function. The investigators demonstrated that low expression of human papilloma virus (HPV) proteins E6 and E7 freed hepatocytes from their normal 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 selected only the specific colonies that responded to the OSM treatment and allowed them to expand.

Stimulation with OSM caused cell proliferation, with doubling time of 33 to 49 hours. Removal of OSM caused growth arrest and hepatic differentiation within four days, generating highly functional cells. The new method induced hepatocytes to expand for up to 40 population doublings, producing 1013 to 1016 cells from a single human hepatocyte isolate. By comparison, only 109 cells can typically be isolated from a healthy organ.   

“This is the holy grail of liver research,” stated co-senior author Yaakov Nahmias, Ph.D., director of the Alexander Grass Center for Bioengineering at The Hebrew University of Jerusalem. “Our technology will enable thousands of laboratories to study fatty liver disease, viral hepatitis, drug toxicity and liver cancer at a fraction of the current cost.”

While the researchers noted that genetic modifications preclude using the cells for transplantation, Dr. Nahmias went on to state, “but we may have found the perfect cell source for the bio-artificial liver project.”

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