What have we accomplished so far?
Our work on liver stem and progenitor cells began in collaboration with Markus Grompe, Ph.D., of Oregon Health Science University. Dr. Grompe's work focuses on the discovery and development of methods for identifying and assessing the therapeutic potential of liver stem and progenitor cells. We obtained rights to a mouse model of liver failure developed by Dr.Grompe, the “FAH knockout mouse,” which lacks a key enzyme, FAH, or fumaryl-acetoacetate hydrolase. This mouse was developed to mimic a fatal human genetically-based liver disease called tyrosinemia type I. Toxic substances build up in these mice and cause liver damage. This model has allowed us to test methods for using cell transplantation to regenerate diseased livers.
We believe that a key accomplishment of the Liver Program was to develop proprietary monoclonal antibodies that enrich for distinct subsets of human liver cells. Using these antibodies we have identified a human liver stem-like cell which we call a human liver engrafting cell (hLEC). These cells produce human serum albumin in mouse serum following transplantation into immunodeficient mice, demonstrating that the hLEC, once transplanted, is a functional cell. We have filed a patent application on the hLEC and its uses in cell therapy for liver disease.
The program will focus on demonstrating the robust engraftment and function of these hLECs in animal models of liver degeneration (such as the FAH knockout mouse) as the next step in determining whether transplanted hLECs can be used to treat liver disease.
StemCells has also devised a culture assay that it uses to identify liver stem and progenitor cells. The culture supports the proliferation of hLECs and StemCells has shown that hLECs give rise to early bipotent progenitor cells that can produce two different types of liver cells, bile duct cells and hepatocytes.
It is also possible to infect this culture with human hepatitis virus to study the virus's effects on liver cells. The culture system could be used to test drugs that act on, or are metabolized by, human liver cells.
It is our belief that a source of well-defined human cells capable of engraftment and substantial liver regeneration will provide a cell-based therapeutic product available to many more patients than liver transplants. An in vitro culture system that can reproducibly grow human liver progenitor cells may also provide cells that can be modified genetically to correct inborn errors of metabolism.
What does the future hold?
StemCells' scientists have identified other monoclonal antibodies that divide the hLEC population into additional subsets of cells which can be tested for liver stem cell activity. We have also been developing additional models for examining the engraftment of the hLECs. Furthermore, in collaboration with scientists at Stanford University, we will test whether engrafted human liver cells can be infected by human hepatitis C virus. Engrafted humanized livers may provide a test system for the development of therapies or vaccines for hepatitis C infection.
Summary of Progress
We have identified a candidate human liver stem cell-like population referred to as a human liver engrafting cell (hLEC).
We have developed an in vitro culture assay for growing the hLECs and have demonstrated that hLECS give rise to progenitor cells that express markers for both bile duct cells and hepatocytes.
We have shown that the in vitro culture of hLECs also can permit infection of a human hepatitis virus, thereby having the potential to be an assay system to screen novel anti-viral compounds.
We have demonstrated the engraftment and survival (>6 months) of the candidate human LEC in an in vivo mouse model.
We have detected human albumin in mouse serum in animals transplanted with hLECs for 6 months.
We have established a culture system for expansion of sorted hLECs.
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