Oval cell proliferation in p16INK4a expressing mouse liver is triggered by chronic growth stimuli.
Terminal differentiation requires molecules also involved in aging such as the cell cycle inhibitor p16(INK4a). Like other organs, the adult liver represents a quiescent organ with terminal differentiated cells, hepatocytes and cholangiocytes. These cells retain the ability to proliferate in response to liver injury or reduction of liver mass. However, under conditions which prevent mitotic activation of hepatocytes, regeneration can occur instead from facultative hepatic stem cells.For therapeutic application a non-toxic activation of this stem cell compartment is required. We have established transgenic mice with conditional overexpression of the cell cycle inhibitor p16(INK4a) in hepatocytes and have provoked and examined oval cell activation in adult liver in response to a range of proliferative stimuli. We could show that the liver specific expression of p16(INK4a) leads to a faster differentiation of hepatocytes and an activation of oval cells already in postnatal mice without negative consequences on liver function.
Institute of Biochemistry, University of Leipzig, Medical Faculty, Leipzig, Germany.
Elke
E
Ueberham
Ricco
R
Lindner
Manja
M
Kamprad
Rico
R
Hiemann
Nadja
N
Hilger
Barbara
B
Woithe
Doris
D
Mahn
Michael
M
Cross
Ulrich
U
Sack
Rolf
R
Gebhardt
Thomas
T
Arendt
Uwe
U
Ueberham
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003433:Crosses, Genetic; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006133:Growth Substances / Q000494:pharmacology*; D007150:Immunohistochemistry; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008156:Luciferases / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D010456:Peptides, Cyclic / Q000494:pharmacology*; D013234:Stem Cells / Q000187:drug effects* / Q000502:physiology*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D006133:Growth Substances; D010456:Peptides, Cyclic; C063998:nodularin; D049452:Green Fluorescent Proteins; D008156:Luciferases