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Oval cell proliferation in p16INK4a expressing mouse liver is triggered by chronic growth stimuli

: Ueberham, Elke; Lindner, Ricco; Kamprad, Manja; Hiemann, Rico; Hilger, Nadja; Woithe, Barbara; Mahn, Doris; Cross, Michael; Sack, Ulrich; Gebhardt, Rolf; Arendt, Thomas; Ueberham, Uwe


Journal of cellular and molecular medicine 12 (2008), Nr.2, S.622-638
ISSN: 1582-4934
ISSN: 1582-1838
Fraunhofer IZI ()
hepatic stem cell; Nodularin; starvation; Tet-system

Terminal differentiation requires molecules also involved in aging such as the cell cycle inhibitor p16INK4a.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 p16INK4a 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 p16INK4a leads to a faster differentiation of hepatocytes and an activation of oval cells already in postnatal mice without negative consequences on liver function.