Liver repopulation by c-Met-positive stem/progenitor cells isolated from the developing rat liver.
OBJECTIVE
Self-renewing stem cells responsible for tissue or organ development and regeneration have been recently described. To isolate such cells using flow cytometry, it should be required to find molecules expressing on their cell surfaces. We have previously reported that, on cells fulfilling the criteria for hepatic stem cells, the hepatocyte growth factor receptor c-Met is expressed specifically in the developing mouse liver. In this study, to determine whether c-Met is an essential marker for hepatic stem cells in other animal strains, we examined the potential for in vivo liver-repopulation in sorted fetal rat-derived c-Met+ cells using the retrorsine model.


METHODS
Using flow cytometry and monoclonal antibodies for c-Met and leukocyte common antigen CD45, fetal rat liver cells were fractionated according to the expression of these molecules. Then, cells in each cell subpopulation were sorted and transplanted into the retrorsine-treated adult rats with two-third hepatectomy. At 9 months post transplant, frequency of liver-repopulation was examined by qualitative and quantitative analyses.


RESULTS
When we transplanted c-Met+ CD45- sorted cells, many donor-derived cells formed colonies that included mature hepatocytes expressing albumin and containing abundant glycogen in their cytoplasm. In contrast, c-Met- cells and CD45+ cells could not repopulate damaged recipient livers.


CONCLUSIONS
High enrichment of liver-repopulating cells was conducted by sorting of c-Met+ cells from the developing rat liver. This result suggests that c-Met/HGF interaction plays a crucial role for stem cell growth, differentiation, and self-renewal in rat liver organogenesis. Since the c-Met is also expressed in the fetal mouse-derived hepatic stem cells, this molecule could be expected to be an essential marker for such cell population in the various animal strains, including human.
Suzuki
Atsushi
A
Gene Expression Laboratories, The Salk Institute for Biological Studies, La Jolla, CA 92037-1099, USA.
Zheng
Yun-wen
YW
Fukao
Katashi
K
Nakauchi
Hiromitsu
H
Taniguchi
Hideki
H
D000818:Animals; D000911:Antibodies, Monoclonal; D002454:Cell Differentiation / Q000502:physiology; D002469:Cell Separation / Q000379:methods; D017690:Cell Transplantation; D005333:Fetus / Q000166:cytology*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000196:embryology / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D011763:Pyrrolizidine Alkaloids / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013234:Stem Cells / Q000502:physiology*; D019172:Transplantation Conditioning
D000911:Antibodies, Monoclonal; D011763:Pyrrolizidine Alkaloids; D019859:Proto-Oncogene Proteins c-met; D017493:Leukocyte Common Antigens; C003300:retrorsine