title: Hepatic stellate cell-expressed endosialin balances fibrogenesis and hepatocyte proliferation during liver damage.
abstract: Liver fibrosis is a reversible wound-healing response to injury reflecting the critical balance between liver repair and scar formation. Chronic damage leads to progressive substitution of liver parenchyma by scar tissue and ultimately results in liver cirrhosis. Stromal cells (hepatic stellate cells [HSC] and endothelial cells) have been proposed to control the balance between liver fibrosis and regeneration. Here, we show that endosialin, a C-type lectin, expressed in the liver exclusively by HSC and portal fibroblasts, is upregulated in liver fibrosis in mouse and man. Chronic chemically induced liver damage resulted in reduced fibrosis and enhanced hepatocyte proliferation in endosialin-deficient (EN(KO)) mice. Correspondingly, acute-liver-damage-induced hepatocyte proliferation (partial hepatectomy) was increased in EN(KO) mice. A candidate-based screen of known regulators of hepatocyte proliferation identified insulin-like growth factor 2 (IGF2) as selectively endosialin-dependent hepatocyte mitogen. Collectively, the study establishes a critical role of HSC in the reciprocal regulation of fibrogenesis vs. hepatocyte proliferation and identifies endosialin as a therapeutic target in non-neoplastic settings.
authors: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany Institute of Pathology Heidelberg University, Heidelberg, Germany.
authors: Carolin
authors: C
authors: Mogler
authors: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors: Matthias
authors: M
authors: Wieland
authors: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors: Courtney
authors: C
authors: König
authors: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.
authors: Junhao
authors: J
authors: Hu
authors: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors: Anja
authors: A
authors: Runge
authors: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.
authors: Claudia
authors: C
authors: Korn
authors: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.
authors: Eva
authors: E
authors: Besemfelder
authors: Department of Medicine II, Section Molecular Hepatology - Alcohol Associated Diseases, Medical Faculty Mannheim Heidelberg University, Heidelberg, Germany.
authors: Katja
authors: K
authors: Breitkopf-Heinlein
authors: Division of Medical Physics in Radiology, German Cancer Research Center Heidelberg, Heidelberg, Germany.
authors: Dorde
authors: D
authors: Komljenovic
authors: Department of Medicine II, Section Molecular Hepatology - Alcohol Associated Diseases, Medical Faculty Mannheim Heidelberg University, Heidelberg, Germany.
authors: Steven
authors: S
authors: Dooley
authors: Institute of Pathology Heidelberg University, Heidelberg, Germany German Cancer Consortium, Heidelberg, Germany.
authors: Peter
authors: P
authors: Schirmacher
authors: Institute of Pathology Heidelberg University, Heidelberg, Germany.
authors: Thomas
authors: T
authors: Longerich
authors: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany German Cancer Consortium, Heidelberg, Germany augustin@angiogenese.de.
authors: Hellmut G
authors: HG
authors: Augustin
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000378:metabolism*; D049109:Cell Proliferation; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology*; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology*; D008115:Liver Regeneration; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000172:deficiency / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; C078203:CD248 protein, human; D009363:Neoplasm Proteins; C509258:tumor endothelial marker 1, mouse
keywords: angiocrine signaling; endosialin; liver fibrosis; liver regeneration