Potential applications for cell regulatory factors in liver progenitor cell therapy

Abstract

Orthotopic liver transplant represent the state of the art treatment for terminal liver pathologies such as cirrhosis in adults and hemochromatosis in neonates. A limited supply of transplantable organs in relationship to the demand means that many patients will succumb to disease before an organ becomes available. One promising alternative to liver transplant is therapy based on the transplant of liver progenitor cells. These cells may be derived from the patient, expanded in vitro, and transplanted back to the diseased liver. Inborn metabolic disorders represent the most attractive target for liver progenitor cell therapy, as many of these disorders may be corrected by repopulation of only a portion of the liver by healthy cells. Another potential application for liver progenitor cell therapy is the seeding of bio-artificial liver matrix. These ex vivo bioreactors may someday be used to bridge critically ill patients to other treatments. Conferring a selective growth advantage to the progenitor cell population remains an obstacle to therapy development. Understanding the molecular signaling mechanisms and micro-environmental cues that govern liver progenitor cell phenotype may someday lead to strategies for providing this selective growth advantage. The discovery of a population of cells within the bone marrow possessing the ability to differentiate into hepatocytes may provide an easily accessible source of cells for liver therapies.

Figure 1. Potential applications of liver progenitor cell regulatory factors in cell therapy

1) Progenitor cells are isolated either from the patient’s own liver or bone marrow. G-CSF and SDF-1 may increase the number of cells within the bone marrow that possess the ability to differentiate into epithelial cells. 2) Following isolation, the liver progenitor cell population is expanded in culture. Several growth factors, particularly HGF, greatly enhance the survivability and maintenance of the undifferentiated state in culture. For the correction of inborn metabolic disorders, cells may be transfected with a normal copy of the miscoded gene(s). 3) The cultured cells may be used to seed bio-artificial liver matrix. The combination of a fibronectin rich matrix with CTGF supplemented media may promote more robust colonization of the matrix. It is also possible that material within the matrix impregnated with IGFBP3 or SST would promote migration of the progenitor cells throughout the matrix. 4) Cells may be transplanted back into the liver through the organ’s circulation. Pretreatment of the cells or systemic treatment of the patient with chemotactic factors such as SST and IGFBP3 may promote migration of the cells within the organ. Additionally, simultaneous transplant of fibroblasts conditioned to produce the fibronectin rich provisional matrix may provide an environment that promotes progenitor cell migration and proliferation. 5) It may also be possible to transplant curative progenitor cells into the bone marrow. 6) Mobilization of these cells from the bone marrow to the liver may be positively influenced by G-CSF and SDF-1.