Large amounts of functional liver cells have now been produced from human embryonic and genetic engineered stem cells, scientists from the Hebrew University of Jerusalem’s Alexander Grass Center for Bioengineering report.
The liver plays a major role in our metabolism. This massive organ, the gatekeeper of the digestive track, is responsible for drug breakdown, and so is the first to be injured from overdose or misuse.
Assessing such drug-induced liver injury is a critical part of pharmaceutical drug development, and needs to be carried out on human liver cells. Human liver cells, called hepatocytes, are unfortunately in short supply as they can only be isolated from donated organs.
The Hepatocytes Bottleneck
Prof. Yaakov Nahmias, the study’s senior author, said:
“This is quite a revolution for pharmaceutical drug discovery. While other groups have been able to produce liver cells before us, their cells showed little functional activity, and could not be reliably used for drug discovery. In fact, up until now stem cell-derived hepatocytes showed little ability to predict clinical outcome."
Limited functional hepatocytes availability for drug testing is a major bottleneck, leading pharmaceutical companies to spend $1 billion/year on liver cells alone.
“Our ability to produce an unlimited supply of functional liver cells from human pluripotent stem cells can change all that,” said Nahmias.
The concept came about along with the birth of Nahmias’ baby girl earlier this year.
“I watched her feeding just moments after birth, and realized this is the first time her liver started working,” said Nahmias. “Nobody had thought of mimicking this part of human development before, so that’s exactly what we did."
The team went on to discover that the bacteria populating the infant gut moments after birth produce vitamin K2 and bile acids that activate the fetal liver’s dormant drug metabolism program.
The work further demonstrated that liver cells produced from either embryonic stem cells or genetically engineered skin cells, can detect the toxic effect of over a dozen drugs with greater than 97% accuracy.
Said Prof. Oren Shibolet, Head of the Liver Unit at the Tel-Aviv Sourasky Medical Center, who was not involved in this study:
“The implications for liver biology and drug discovery are quite staggering. The method provides access to unlimited amounts of functional liver cells and is likely to critically improve our ability to predict drug toxicity, which was previously limited by the unavailability of liver cells. Furthermore, as gut bacteria develop differently in infants delivered by caesarean section, the mode of delivery can possibly affect newborns’ liver maturation. Current practice is to routinely administer Vitamin K to newborns. The data presented suggest that parents abstaining from this practice may cause liver maturation and drug metabolism in their children to develop quiet differently."
Yishai Avior, Gahl Levy, Michal Zimerman, Daniel Kitsberg, Robert Schwartz, Ronen Sadeh, Arieh Moussaieff, Merav Cohen, Joseph Itskovitz-Eldor and Yaakov Nahmias Microbial-derived lithocholic acid and vitamin K2 drive the metabolic maturation of pluripotent stem cells–derived and fetal hepatocytes Hepatology Volume 62, Issue 1, July 2015, Pages: 265–278 DOI: 10.1002/hep.27803
Illustration credit: Yaakov Nahmias / Hebrew University