Ductular reaction promotes intrahepatic angiogenesis through Slit2-Roundabout 1 signaling.
Ductular reaction promotes intrahepatic angiogenesis through Slit2-Roundabout 1 signaling.
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DOI：
10.1002/hep.32140
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Sancho-Bru P
中科院分区：
文献类型：
--
作者：
Coll M;Ariño S;Martínez-Sánchez C;Garcia-Pras E;Gallego J;Moles A;Aguilar-Bravo B;Blaya D;Vallverdú J;Rubio-Tomás T;Lozano JJ;Pose E;Graupera I;Fernández-Vidal A;Pol A;Bataller R;Geng JG;Ginès P;Fernandez M;Sancho-Bru P
胆管反应（DR）在慢性肝病中扩大，并与疾病严重程度相关。除了其在肝再生中的潜在作用外，DR在促进导管周围纤维化和炎性细胞募集的肝脏伤口愈合反应中起作用。然而，没有关于其在肝内血管生成中的作用的信息。在目前的研究中，我们调查了DR细胞在慢性肝病期间对肝血管重塑的潜在贡献。在小鼠肝损伤模型中，DR细胞表达参与血管生成的基因。在血管生成相关基因中，Slit 2及其受体Robo 1的表达分别定位于DR细胞和新生血管。Slit 2-Robo 1通路在慢性肝病中的血管生成作用在用DDC治疗的ROBO 1/2−/+小鼠中得到证实，与野生型小鼠相比，其肝内新生血管密度降低。然而，ROBO 1/2缺陷并不影响部分肝切除术中的血管生成。在晚期酒精性疾病患者中，血管生成与DR相关，SLIT 2-ROBO 1的上调与DR和疾病严重程度相关。在体外，人类肝脏来源的类器官产生SLIT 2并诱导内皮细胞的管形成。总的来说，我们的数据表明，DR扩增通过Slit 2-Robo 1途径促进血管生成，并将DR细胞视为肝脏伤口愈合反应的关键参与者。
Ductular reaction (DR) expands in chronic liver diseases and correlates with disease severity. Besides its potential role in liver regeneration, DR plays a role in wound-healing response of the liver promoting periductular fibrosis and inflammatory cell recruitment. However, there is no information regarding its role in intrahepatic angiogenesis. In the current study we investigated the potential contribution of DR cells to hepatic vascular remodeling during chronic liver disease. In mouse models of liver injury, DR cells express genes involved in angiogenesis. Among angiogenesis-related genes, the expression of Slit2 and its receptor Robo1 were localized in DR cells and neoangiogenic vessels, respectively. The angiogenic role of the Slit2-Robo1 pathway in chronic liver disease was confirmed in ROBO1/2−/+ mice treated with DDC, which displayed reduced intrahepatic neovascular density compared to wild-type mice. However, ROBO1/2 deficiency did not affect angiogenesis in partial hepatectomy. In patients with advanced alcoholic disease, angiogenesis was associated with DR, and upregulation of SLIT2-ROBO1 correlated with DR and disease severity. In vitro, human liver-derived organoids produced SLIT2 and induced tube formation of endothelial cells. Overall, our data indicate that DR expansion promotes angiogenesis through the Slit2-Robo1 pathway and recognize DR cells as key players in liver wound-healing response.
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