Year 4

Because there is still considerable morbidity and mortality associated with the process of whole liver transplantation, and because more than a thousand people die each year while on the liver transplantation list, and tens of thousands more never get on the list because of the lack of available livers, it is evident that improved and safer liver transplantation would be valuable, as would approaches that provide for an increased number of transplantations in a timely manner. A technology that might address these issues is the development of a human liver cell line that can be employed in liver cell transplantation or in a bioartificial liver. Developing such a cell line from human embryonic stem cells (hESC) or from other human stem cell sources would provide a valuable tool for cell-based therapeutics.

In the past year, we have improved on our ability to differentiate the hESC towards liver cells in culture. They are producing normal human liver proteins. They also are capable of metabolizing drugs and other substances in the same manner of normal liver cells in culture. This means that they have the most important attributes of normal liver cells. Also, we have employed these cells in clinically-relevant models using techniques that can then be adapted to future human clinical trials. Moreover, they do not produce tumors.

We have also worked to differentiate human induced pluripotent cells (hiPSC) to become liver-like cells in culture. The hiPSC behave very much like hESC, in that they are pluripotent. However, they are derived from adult somatic cells and thus do not have the ethical concerns associated with hESC. Our differentiation protocol has been successful in deriving cells that again have most of the important attributes of normal liver cells. Thus, we are hopeful that they also may be helpful for cell-based therapeutics in the future.

Thus we are making some progress in establishing a clinically useful and viable liver cell line that could be used to repopulate an injured liver in a safer and less expensive manner than with liver transplantation.