Hepatic stellate cell-derived delta-like homolog 1 (DLK1) protein in liver regeneration.
Hepatic stellate cells (HSCs) undergo myofibroblastic activation in liver fibrosis and regeneration. This phenotypic switch is mechanistically similar to dedifferentiation of adipocytes as such the necdin-Wnt pathway causes epigenetic repression of the master adipogenic gene Pparγ, to activate HSCs. Now we report that delta-like 1 homolog (DLK1) is expressed selectively in HSCs in the adult rodent liver and induced in liver fibrosis and regeneration. Dlk1 knockdown in activated HSCs, causes suppression of necdin and Wnt, epigenetic derepression of Pparγ, and morphologic and functional reversal to quiescent cells. Hepatic Dlk1 expression is induced 40-fold at 24 h after partial hepatectomy (PH) in mice. HSCs and hepatocytes (HCs) isolated from the regenerating liver show Dlk1 induction in both cell types. In HC and HSC co-culture, increased proliferation and Dlk1 expression by HCs from PH are abrogated with anti-DLK1 antibody (Ab). Dlk1 and Wnt10b expression by Sham HCs are increased by co-culture with PH HSCs, and these effects are abolished with anti-DLK Ab. A tail vein injection of anti-DLK1 Ab at 6 h after PH reduces early HC proliferation and liver growth, accompanied by decreased Wnt10b, nonphosphorylated β-catenin, p-β-catenin (Ser-552), cyclins (cyclin D and cyclin A), cyclin-dependent kinases (CDK4, and CDK1/2), p-ERK1/2, and p-AKT. In the mouse developing liver, HSC precursors and HSCs express high levels of Dlk1, concomitant with Dlk1 expression by hepatoblasts. These results suggest novel roles of HSC-derived DLK1 in activating HSCs via epigenetic Pparγ repression and participating in liver regeneration and development in a manner involving the mesenchymal-epithelial interaction.
Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis and Department of Pathology, Keck School of Medicine, the University of Southern California, Los Angeles, California 90033.
Nian-Ling
NL
Zhu
Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis and Department of Pathology, Keck School of Medicine, the University of Southern California, Los Angeles, California 90033.
Kinji
K
Asahina
Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis and Department of Pathology, Keck School of Medicine, the University of Southern California, Los Angeles, California 90033.
Jiaohong
J
Wang
Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis and Department of Pathology, Keck School of Medicine, the University of Southern California, Los Angeles, California 90033.
Akiko
A
Ueno
Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis and Department of Pathology, Keck School of Medicine, the University of Southern California, Los Angeles, California 90033.
Raul
R
Lazaro
Institute of Molecular and Cellular Biosciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan, and.
Yuichiro
Y
Miyaoka
Institute of Molecular and Cellular Biosciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan, and.
Atsushi
A
Miyajima
Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis and Department of Pathology, Keck School of Medicine, the University of Southern California, Los Angeles, California 90033,; Department of Veterans Affairs, Greater Los Angeles Healthcare System, Los Angeles, California 90073. Electronic address: htsukamo@usc.edu.
Hidekazu
H
Tsukamoto
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002135:Calcium-Binding Proteins; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D002645:Chickens; D018920:Coculture Techniques; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D056741:Cyclin D / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000096:biosynthesis / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics
D000906:Antibodies; D002135:Calcium-Binding Proteins; D019925:Cyclin A; D056741:Cyclin D; C512925:Dlk1 protein, mouse; C512923:Dlk1 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D047495:PPAR gamma; D051153:Wnt Proteins; C102068:Wnt10b protein, mouse; C501228:Wnt10b protein, rat; C069766:necdin; D051057:Proto-Oncogene Proteins c-akt; C495902:Cdk4 protein, mouse; C495903:Cdk4 protein, rat; D051358:Cyclin-Dependent Kinase 4; D048052:Mitogen-Activated Protein Kinase 3