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

Ueberham E, Lindner R, Kamprad M, Hiemann R, Hilger N, Woithe B, Mahn D, Cross M, Sack U, Gebhardt R, Arendt T, Ueberham U - J. Cell. Mol. Med. (2007)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry, University of Leipzig, Medical Faculty, Leipzig, Germany.

ABSTRACT
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.

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Enzyme histochemical detection of senescence-associated β-galactosidase. Eight weeks old p16INK4a expressing mice (A) and control mice (B) were treated with nodularin for a period of 12 weeks and killed 5 days after treatment. SA-β-Gal (light blue colour) was expressed mainly in hepatocytes. Bar represents 50μm.
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fig08: Enzyme histochemical detection of senescence-associated β-galactosidase. Eight weeks old p16INK4a expressing mice (A) and control mice (B) were treated with nodularin for a period of 12 weeks and killed 5 days after treatment. SA-β-Gal (light blue colour) was expressed mainly in hepatocytes. Bar represents 50μm.

Mentions: Physiological p16INK4a overexpression is associated with senescence [46] and is frequently accompanied by expression of senescence-associated β-galactosidase (SA-β-Gal) both in cultured cells [47, 48] and in liver in situ[49]. The age-related effects of p16INK4a expression revealed by interval feeding raise the question of whether p16INK4a is merely a marker of senescence or may actively promote senescence processes. To test this, we determined the expression level of SA-β-Gal in situ. We found equal levels of SA-β-Gal in the livers of p16INK4a expressing and control mice, either in the quiescent state (without any treatment) or following PH. In contrast, strong up-regulation of SA-β-Gal was detected in p16INK4a expressing livers both in nodularin-treated and interval-starved mice, both treatments being associated with recruitment of oval cells. Indeed, the most intensive staining for SA-β-Gal was detected in hepatocytes of livers with the highest numbers of oval cells (Fig.8A).


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

Ueberham E, Lindner R, Kamprad M, Hiemann R, Hilger N, Woithe B, Mahn D, Cross M, Sack U, Gebhardt R, Arendt T, Ueberham U - J. Cell. Mol. Med. (2007)

Enzyme histochemical detection of senescence-associated β-galactosidase. Eight weeks old p16INK4a expressing mice (A) and control mice (B) were treated with nodularin for a period of 12 weeks and killed 5 days after treatment. SA-β-Gal (light blue colour) was expressed mainly in hepatocytes. Bar represents 50μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3822548&req=5

fig08: Enzyme histochemical detection of senescence-associated β-galactosidase. Eight weeks old p16INK4a expressing mice (A) and control mice (B) were treated with nodularin for a period of 12 weeks and killed 5 days after treatment. SA-β-Gal (light blue colour) was expressed mainly in hepatocytes. Bar represents 50μm.
Mentions: Physiological p16INK4a overexpression is associated with senescence [46] and is frequently accompanied by expression of senescence-associated β-galactosidase (SA-β-Gal) both in cultured cells [47, 48] and in liver in situ[49]. The age-related effects of p16INK4a expression revealed by interval feeding raise the question of whether p16INK4a is merely a marker of senescence or may actively promote senescence processes. To test this, we determined the expression level of SA-β-Gal in situ. We found equal levels of SA-β-Gal in the livers of p16INK4a expressing and control mice, either in the quiescent state (without any treatment) or following PH. In contrast, strong up-regulation of SA-β-Gal was detected in p16INK4a expressing livers both in nodularin-treated and interval-starved mice, both treatments being associated with recruitment of oval cells. Indeed, the most intensive staining for SA-β-Gal was detected in hepatocytes of livers with the highest numbers of oval cells (Fig.8A).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry, University of Leipzig, Medical Faculty, Leipzig, Germany.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus