Enhanced liver regeneration following changes induced by hepatocyte-specific genetic ablation of integrin-linked kinase.
Following liver regeneration after partial hepatectomy, liver grows back precisely to its original mass and does not exceed it. The mechanism regulating this "hepatostat" is not clear and no exceptions have been found to date. Although pathways initiating liver regeneration have been well studied, mechanisms involved in the termination of liver regeneration are unclear. Here, we report that integrin-linked kinase (ILK) (involved in transmission of the extracellular matrix [ECM] signaling by way of integrin receptors) and/or hepatic adaptations that ensue following ILK hepatocyte-targeted removal are critical for proper termination of liver regeneration. Following partial hepatectomy (PHx), mice with a liver-specific ILK ablation (ILK-KO-Liver) demonstrate a termination defect resulting in 58% larger liver than their original pre-PHx mass. This increase in post-PHx liver mass is due to sustained cell proliferation driven in part by increased signaling through hepatocyte growth factor (HGF), and the beta-catenin pathway and Hippo kinase pathways.


CONCLUSIONS
The data indicate that ECM-mediated signaling by way of ILK is essential in proper termination of liver regeneration. This is the first evidence of a defect leading to impaired termination of regeneration and excessive accumulation of liver weight following partial hepatectomy.
Apte
Udayan
U
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Gkretsi
Vasiliki
V
Bowen
William C
WC
Mars
Wendy M
WM
Luo
Jian-Hua
JH
Donthamsetty
Shashikiran
S
Orr
Ann
A
Monga
Satdarshan P S
SP
Wu
Chuanyue
C
Michalopoulos
George K
GK
D000818:Animals; D049109:Cell Proliferation; D005109:Extracellular Matrix / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D008099:Liver / Q000033:anatomy & histology; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051176:beta Catenin / Q000502:physiology; D000099200:Scaffold Protein ILK
D017228:Hepatocyte Growth Factor; D017346:Protein Serine-Threonine Kinases; D016271:Proto-Oncogene Proteins c-myc; D051176:beta Catenin; D000099200:Scaffold Protein ILK