Dr. Grompe began by noting that the hepatocyte has a high regenerative ability, and the bile duct epithelial cell also has the capacity to regenerate. In instances of chronic injury, other cells can also give rise to oval cells, which in turn can generate hepatocytes and bile duct epithelial cells. Hepatocytes are currently used in preclinical drug development, infectious disease research, cell transplantation, and as components of liver-assist devices and bioartificial livers. He noted, however, that there is an incredible need for liver support in the United States. Currently, more than 17,000 patients are on wait lists for liver transplants (an estimated 1300 of whom die per year). However, a shortage of donor organs limits the number of transplants that can be performed in a given year. Other options that provide functional tissue include transplantation of split liver tissue or tissue from living related donors and auxiliary transplantation (e.g., the replacement of only one lobe).
Can hepatocyte transplantation be used as another option? Hepatocyte transplantation involves injecting a single cell suspension of hepatocytes into the portal circulation. This technique was first demonstrated in a rat model in 1977 (Groth CG, et.al. Transplantation Proc 9:313-316), and the first clinical report of autotransplantation of cells from a cirrhotic individual appeared in the literature in 1993 (Mito and Kusano. Cell Transplantation 2:65-74). A number of clinical trials have since demonstrated proof-of-concept. However, data supporting hepatocyte transplantation to treat cirrhosis of the liver are less compelling. Scar formation and inefficient metabolic exchange render the technique of questionable utility in established cases of cirrhosis, although the approach could prove useful as a preventive measure in patients at high risk for cirrhosis. Thus, hepatocyte transplants are useful for bridging patients to whole-organ transplantation and can sometimes obviate the need for the transplant. Therefore, the strategy provides a long-term, partial correction of metabolic diseases, although source material (e.g., abundance and immunological matching) and low donor cell replacement levels remain obstacles to the clinical application of hepatocyte transplantation.
Possible new cell sources for hepatic therapy include caudate and/or left lateral segments of transplanted livers, fetal livers, living-related cell donors, xenotransplants, reversibly immortalized cells, expanded cultures of human hepatocytes, and stem-cell derived hepatocytes. Stem/progenitor sources of hepatocytes include the hepatocytes themselves (which are unipotent cells), intrahepatic liver stem cells, bone-marrow derived stem cells, placental stem cells, and ES cells. The ideal donor cell should be fully mature and functional, immune-matched to the patient, and available in large quantity. However, hepatocytes rapidly dedifferentiate in culture, and culture conditions to maintain the fully mature, differentiated phenotype long-term have not been developed. Mouse hepatocytes lose the ability to differentiate within five days in culture. One avenue to improve this approach is to expand existing hepatocytes, either through fetal and postnatal donors (Schmelzer E, et.al. J Exp Med 2007;204:1973-1987), use of mesenchymal cells (Banas A, et.al. Hepatology 2007;46:219-228; Miki T, et.al. Stem Cells 2005;23:1549-1559), and through differentiation of ES cells (Gouon-Evans V, et.al. Nat Biotechnol 2006;24:1402-1411; Hay DC, et.al. Stem Cells 2008;26:894-902).
It should be noted, however, that clinical hepatocyte transplantation may still fail even if the ideal donor cell is determined. Hepatocyte transplantation results in limited cell replacement levels (< 1% using multiple doses), and the cells can cause portal vein embolisms. Therapeutic liver repopulation is a process similar to bone marrow transplantation in which the liver parenchyma is replaced by transplanted donor cells of sufficient hepatocyte mass to repair or ameliorate hepatic function. If successfully applied, the procedure could be an alternative to whole-liver transplantation. In the clinic, this strategy would require conditioning regimens (e.g., gene therapy, genetic selection), and no hepatocyte-specific regimen has currently been developed. As such, the entire liver is at risk for damage, and hepatic failure is a potential outcome of the procedure.
In conclusion, Dr. Grompe stated that cell culture conditions that maintain the differentiation and transplantability of human hepatocytes have not been developed. Current progenitor sources produce only immature, poorly transplantable hepatocyte-like cells. Moreover, the maturation of immature, partially-differentiated progenitors in vivo is limited, and a safe conditioning regimen that permits the engraftment and expansion of donor hepatocytes does not exist.
One attendee asked about the transplantation of fetal liver cells. Dr. Grompe noted that fetal precursors will mature in the adult environment, making these cells more robust candidates for therapy than stem-cell derived populations. Large-scale culture strategies will be necessary to identify the conditions to maintain differentiation of hepatocytes.
Another participant asked about the partial hepatotectomy as a viable treatment procedure. Dr. Grompe noted that this strategy can result in reduced fibrosis, but the surgery is risky in advanced patients and may have little effect in this population.