Bone marrow transplantation in mice leads to a minor population of hepatocytes that can be selectively amplified in vivo.
Cell-based therapy may some day be a therapeutic alternative to liver transplantation. Recent observations indicating that hematopoietic stem cells can differentiate into hepatocytes have opened new therapeutic prospects. However, the clinical relevance of this phenomenon is unknown. We have previously developed a strategy based on the protective effect of Bcl-2 against Fas-mediated apoptosis to selectively amplify a small number of hepatocytes in vivo. We now show that this approach can be used to amplify a minor population of bone marrow-derived hepatocytes. Normal mice were transplanted with unfractionated bone marrow cells from transgenic animals expressing Bcl-2 under the control of a liver-specific promoter. Recipients were then submitted to weekly injections of the anti-Fas antibody, Jo2. Upon sacrifice, the liver of the recipients showed bone marrow-derived clusters of mature hepatocytes expressing Bcl-2, which showed that the hepatocyte progeny of a genetically modified bone marrow can be selectively expanded in vivo. In contrast, no Bcl-2 expression could be detected without the selective pressure of Jo2, suggesting that differentiation of bone marrow cells into mature hepatocytes is very inefficient under physiologic conditions. We conclude that a selection strategy will be required to achieve a therapeutic level of liver repopulation with bone marrow-derived hepatocytes.
Mallet
Vincent O
VO
Department of Genetics, Development and Molecular Pathology, Cochin Institute, Paris, France.
Mitchell
Claudia
C
Mezey
Eva
E
Fabre
Monique
M
Guidotti
Jacques-Emmanuel
JE
Renia
Laurent
L
Coulombel
Laure
L
Kahn
Axel
A
Gilgenkrantz
Hélène
H
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002455:Cell Division; D016922:Cellular Senescence; D022781:Hepatocytes / Q000166:cytology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2