Liver Cell Transplantation

Liver Cell Transplantation

Funding Type: 
Early Translational II
Grant Number: 
TR2-01857
Award Value: 
$4,215,748
Disease Focus: 
Liver Disease
Stem Cell Use: 
Embryonic Stem Cell
Status: 
Closed
Public Abstract: 
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) would provide a valuable tool for pharmacology studies, as well as for use in cell-based therapeutics. The objective of this proposal is to focus a team effort to determine which differentiated hESC will be the most effective liver-like cells in cell culture and in animal studies, and to then use the best cells in clinical trials of cell transplantation in patients with advanced liver disease. In the proposed studies, the team will differentiate hESC so that they act like liver cells in culture. Once it has been established that the cells are acting like liver cells by producing normal human liver proteins, and that they do not result in tumors, the cells will be assessed in clinically-relevant models using techniques that can then be adapted to future human clinical trials. One of the ways cells can be evaluated is to label the cells which will provide a means to monitor them with various imaging systems. The intent in these studies is to determine which will be the most effective cells to use in human clinical trials. Once this is determined, the best cells can then be employed in human patients. If the studies are successfully undertaken, we will have established 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 whole liver transplantation. Moreover, all people who have liver failure or an inherited liver disease could be treated, because there would be an unlimited supply of liver cells.
Statement of Benefit to California: 
In California, as in all parts of the US, there are not enough livers available for transplantation for all the people who need them. The result is that many more people die of liver failure than is necessary. One way to improve this situation is the transplantation of liver cells rather than whole organ transplantation. We are attempting to develop liver cell lines from stem cells that will act like normal liver cells. If the cells that we develop function well and do not act like cancer cells in culture, the cells will be assessed in clinically-relevant models using techniques that can then be adapted to future human clinical trials. In our studies, we will compare human embryonic stem cells with other stem cells to determine which will be the most effective cells to transplant into people. In the future, we will employ the best cells in clinical trials in humans. If the studies are successfully undertaken, we will have established 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 whole liver transplantation. Moreover, all people who have liver failure or an inherited liver disease could be treated, because there would be an unlimited supply of liver cells.
Progress Report: 

Year 1

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) would provide a valuable tool for pharmacology studies, as well as for use in cell-based therapeutics. The objective of this proposal is to focus a team effort to determine which differentiated hESC will be the most effective liver-like cells in cell culture and in animal studies, and to then use the best cells in clinical trials of cell transplantation in patients with advanced liver disease. In the past year, we have been able to differentiate hESC so that they act like liver cells in culture. The cells are acting like liver cells by producing normal human liver proteins, and they metabolize drugs in a manner similar to liver cells, and they do not cause tumors when transplanted. Now we are ready to assess the cells in clinically-relevant models using techniques that can then be adapted to future human clinical trials. The intent in these studies is to determine which will be the most effective cells to use in human clinical trials. Once this is determined, the best cells can then be employed in human patients. If the studies are successfully undertaken, we will have established 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 whole liver transplantation. Moreover, all people who have liver failure or an inherited liver disease could be treated, because there would be an unlimited supply of liver cells.

Year 2

Some patients with life-threatening liver disease can be effectively treated with liver transplantation. However, this requires a major surgical procedure that is associated with considerable morbidity and mortality. More importantly, the long-standing shortage of donor livers has rendered this treatment unavailable to most patients. Consequently, thousands of patients with end-stage liver disease die each year while on a waiting list for liver transplantation, and tens of thousands are never put on this list. Since human embryonic stem cells replicate virtually indefinitely in culture, these cells, if differentiated into liver cells (hepatocytes), represent an infinite source of cells that can be made available to treat patients with liver failure. The objective of this award than is to develop a reproducible and efficient differentiation method to produce metabolically active human embryonic stem cell-derived hepatocytes. The initial requirement is that at least 90-95% of the cells must have liver-specific gene expression and possess metabolic function comparable to freshly isolated human hepatocytes. In addition, the yield from differentiation should be adequate to support preclinical studies. We believe that we made excellent progress during the grant award period towards meeting the success criteria for the quality of the cells in in vitro analysis. We firmly believe that our cells represent an exceedingly good level of hepatocyte function in culture, and that the remaining tasks are to scale-up their production and to determine a strategy to enhance their in vivo function.

Year 3

The objective of this Early Translational II Research Award is to develop a reproducible and efficient differentiation method to produce metabolically active human embryonic stem cell-derived hepatocytes (hEDH)(also called liver cells). We have determined that at least 90-95% of the cells have liver-specific gene expression and possess biotransformation ability comparable to freshly isolated human hepatocytes. This means that our cells that we have differentiated from embryonic stem cells are acting like human liver cells. In addition, the yield from differentiation should be adequate to support preclinical studies. We believe that we made excellent progress during the grant award period towards meeting the success criteria for the quality of the cells and that further work may well yield cells that can be transplanted into people.

© 2013 California Institute for Regenerative Medicine