Liver-specific ablation of integrin-linked kinase in mice results in abnormal histology, enhanced cell proliferation, and hepatomegaly.
Hepatocyte differentiation and proliferation are greatly affected by extracellular matrix (ECM). Primary hepatocytes cultured without matrix dedifferentiate over time, but matrix overlay quickly restores differentiation. ECM also is critical in liver regeneration where ECM degradation and reconstitution are steps in the regenerative process. Integrin-linked kinase (ILK) is a cell-ECM-adhesion component implicated in cell-ECM signaling by means of integrins. We investigated the role of ILK in whole liver by using the LoxP/Cre model system. ILK was eliminated from the liver by mating homozygous ILK-floxed animals with mice expressing Cre-recombinase under control of the alpha fetoprotein enhancer and albumin promoter. After ablation of ILK, animals are born normal. Soon after birth, however, they develop histologic abnormalities characterized by disorderly hepatic plates, increased proliferation of hepatocytes and biliary cells, and increased deposition of extracellular matrix. Cell proliferation is accompanied by increased cytoplasmic and nuclear stabilization of beta-catenin. After this transient proliferation of all epithelial components, proliferation subsides and final liver to body weight ratio in livers with ILK deficient hepatocytes is two times that of wild type. Microarray analysis of gene expression during the stage of cell proliferation shows up-regulation of integrin and matrix-related genes and a concurrent down-regulation of differentiation-related genes. After the proliferative stage, however, the previous trends are reversed resulting in a super-differentiated phenotype in the ILK-deficient livers.


CONCLUSIONS
Our results show for the first time in vivo the significance of ILK and hepatic ECM-signaling for regulation of hepatocyte proliferation and differentiation.
Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Vasiliki
V
Gkretsi
Udayan
U
Apte
Wendy M
WM
Mars
William C
WC
Bowen
Jian-Hua
JH
Luo
Yu
Y
Yang
Yan P
YP
Yu
Ann
A
Orr
René
R
St-Arnaud
Shoukat
S
Dedhar
Klaus H
KH
Kaestner
Chuanyue
C
Wu
George K
GK
Michalopoulos
D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000502:physiology; D022781:Hepatocytes / Q000201:enzymology / Q000473:pathology; D006529:Hepatomegaly / Q000201:enzymology* / Q000473:pathology*; D019426:Integrases / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism; D000099200:Scaffold Protein ILK
D019426:Integrases; D017346:Protein Serine-Threonine Kinases; D051176:beta Catenin; D000099200:Scaffold Protein ILK; C045073:Cre recombinase