Transplanted hepatocytes over-expressing FoxM1B efficiently repopulate chronically injured mouse liver independent of donor age.
Orthotopic liver transplantation is limited by the shortage of liver donors, leading to elderly patients being enrolled as donors with increasing frequency. Alternative strategies such as cell therapy are therefore needed. Because transplanted hepatocytes do not proliferate into a recipient liver, repopulation strategies have been developed. We have previously published a proof of concept that hepatocytes harboring a survival selective advantage can efficiently repopulate a mouse liver. We develop here an alternative approach by conferring a selective proliferative advantage on transplanted hepatocytes over resident ones. FoxM1B is a transcription factor that, when over-expressed into hepatocytes, accelerates the cell cycle and maintains the hepatocyte in vivo proliferative capacity of aged livers. We now demonstrate that transplanted hepatocytes over-expressing FoxM1B repopulate the liver of mice subjected to continuous injury far more efficiently than control hepatocytes. We show that old hepatocytes that over-express FoxM1B retain their cell division capacity and repopulate liver as well as young ones, in contrast with old non-modified hepatocytes, which lose their proliferative capacity. In conclusion, our results point to the potential use of FoxM1B expression in hepatocyte-based therapy protocols in diseases where host hepatocytes are chronically injured, especially if donor hepatocytes come from old livers.
Brezillon
Nicolas
N
Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
Lambert-Blot
Martine
M
Morosan
Serban
S
Couton
Dominique
D
Mitchell
Claudia
C
Kremsdorf
Dina
D
Costa
Robert H
RH
Gilgenkrantz
Helene
H
Guidotti
Jacques-Emmanuel
JE
D000367:Age Factors; D000818:Animals; D049109:Cell Proliferation; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000502:physiology; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation*; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000601:surgery*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D014184:Transplantation, Homologous / Q000379:methods
D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse