Mogler Carolin, Wieland Matthias, König Courtney, Hu Junhao, Runge Anja, Korn Claudia, Besemfelder Eva, Breitkopf-Heinlein Katja, Komljenovic Dorde, Dooley Steven, Schirmacher Peter, Longerich Thomas, Augustin Hellmut G
Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany Institute of Pathology Heidelberg University, Heidelberg, Germany.
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.
EMBO Mol Med. 2015 Mar;7(3):332-8. doi: 10.15252/emmm.201404246.
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.
肝纤维化是一种对损伤的可逆性伤口愈合反应，反映了肝脏修复与瘢痕形成之间的关键平衡。慢性损伤导致肝实质逐渐被瘢痕组织替代，最终导致肝硬化。基质细胞（肝星状细胞[HSC]和内皮细胞）被认为可控制肝纤维化与再生之间的平衡。在此，我们发现，一种C型凝集素——内涎蛋白，仅由HSC和门静脉成纤维细胞在肝脏中表达，在小鼠和人类肝纤维化过程中上调。慢性化学诱导的肝损伤导致内涎蛋白缺陷（EN(KO)）小鼠的纤维化减轻且肝细胞增殖增强。相应地，EN(KO)小鼠中急性肝损伤诱导的肝细胞增殖（部分肝切除术）增加。一项基于候选物的肝细胞增殖已知调节因子筛选确定胰岛素样生长因子2（IGF2）为选择性依赖内涎蛋白的肝细胞有丝分裂原。总体而言，该研究确立了HSC在纤维生成与肝细胞增殖相互调节中的关键作用，并确定内涎蛋白为非肿瘤性疾病中的治疗靶点。
