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From the Department of Gastroenterology, Hepatology, and Endocrinology,*Hanover Medical School, Hanover; the Heinrich-Pette-Institute for Experimental Virology and Immunologyand the Clinic and Policlinic of Internal Medicine,University Hospital Hamburg, Eppendorf; and the Institute of Crystallography and Mineralogy,Ludwig-Maximilians University, Munich, Germany
Therapies for liver diseases with stem and progenitor cells will require a detailed knowledge of the molecular mechanisms driving the in vivo differentiation process toward adult hepatic tissue. We applied quantitative gene expression methods to analyze the differentiation process of fetal liver progenitor cells after transplantation into an animal model of liver regeneration. Enhanced green fluorescent protein (EGFP)-transgenic liver progenitor cells were isolated from fetal mouse liver at stage embryonic day 13.5 and transplanted into uPA/RAG-2 mice. Two, 4, and 6 weeks after cell transplantation cryosections of liver tissue were analyzed for EGFP-positive regeneration nodules. RNA from laser-microdissected EGFP-positive tissue was isolated and used as template for quantitative real-time reverse transcriptase-polymerase chain reaction. Phenotypic differentiation was analyzed by staining of the canalicular marker enzyme dipeptidyl-peptidase IV. Proliferation in regenerative nodules and surrounding tissue was monitored with the BrdU incorporation assay. Alpha fetoprotein gene expression had already decreased 2 weeks after transplantation in EGFP-positive regeneration nodules compared to pretransplantation values and was not detectable after 4 and 6 weeks, whereas albumin slightly increased in transplanted cells indicating differentiation into a mature phenotype. The dipeptidyl-peptidase IV antigen was associated with some liver progenitor cells 2 weeks after transplantation and in virtually all cells after 4 and 6 weeks. Cell proliferation index in transplanted cells was maximally increased (4.8% BrdU-positive cells) after 2 weeks and decreased (0.4%) after 6 weeks to normal levels. Our results demonstrate that gene expression in liver progenitor cells changes from fetal to adult phenotype within 4 to 6 weeks after transplantation despite ongoing proliferation of the transplanted cells in a mouse model of liver regeneration. Quantitative gene expression profiles as shown here will have important implications in our understanding of the in vivo differentiation process of stem cells.
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