Mar Coll1,2,3, Silvia Ariño1, Celia Martínez-Sánchez1, Ester Garcia-Pras1,3, Javier Gallego1,3, Anna Moles4,5, Beatriz Aguilar-Bravo1, Delia Blaya1, Julia Vallverdú1, Teresa Rubio-Tomás1, Juan Jose Lozano3, Elisa Pose1,3,5, Isabel Graupera1,2,3,5, Andrea Fernández-Vidal6, Albert Pol6,7,8, Ramón Bataller9, Jian-Guo Geng10, Pere Ginès1,2,3,5, Mercedes Fernandez1, Pau Sancho-Bru1,2,3. 1. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 2. Medicine Department, Faculty of Medicine, University of Barcelona, Barcelona, Spain. 3. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. 4. Cell Death and Proliferation, Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain. 5. Liver Unit, Hospital Clínic, Barcelona, Spain. 6. Cell Compartments and Signaling Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 7. Department of Biomedical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain. 8. Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain. 9. Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. 10. Department of Biologic and Material Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
Abstract
BACKGROUND AND AIMS: 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 the 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. APPROACH AND RESULTS: In mouse models of liver injury, DR cells express genes involved in angiogenesis. Among angiogenesis-related genes, the expression of Slit2 and its receptor Roundabout 1 (Robo1) was 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 3,5-diethoxycarbonyl-1,4-dihydrocollidine, 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 alcohol-associated disease, angiogenesis was associated with DR, and up-regulation of SLIT2-ROBO1 correlated with DR and disease severity. In vitro, human liver-derived organoids produced SLIT2 and induced tube formation of endothelial cells. CONCLUSIONS: Overall, our data indicate that DR expansion promotes angiogenesis through the Slit2-Robo1 pathway and recognize DR cells as key players in the liver wound-healing response.
BACKGROUND AND AIMS: 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 the 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. APPROACH AND RESULTS: In mouse models of liver injury, DR cells express genes involved in angiogenesis. Among angiogenesis-related genes, the expression of Slit2 and its receptor Roundabout 1 (Robo1) was 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 3,5-diethoxycarbonyl-1,4-dihydrocollidine, 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 alcohol-associated disease, angiogenesis was associated with DR, and up-regulation of SLIT2-ROBO1 correlated with DR and disease severity. In vitro, human liver-derived organoids produced SLIT2 and induced tube formation of endothelial cells. CONCLUSIONS: Overall, our data indicate that DR expansion promotes angiogenesis through the Slit2-Robo1 pathway and recognize DR cells as key players in the liver wound-healing response.
Authors: Pau Sancho-Bru; José Altamirano; Daniel Rodrigo-Torres; Mar Coll; Cristina Millán; Juan José Lozano; Rosa Miquel; Vicente Arroyo; Juan Caballería; Pere Ginès; Ramon Bataller Journal: Hepatology Date: 2012-04-23 Impact factor: 17.425
Authors: Alexander Raven; Wei-Yu Lu; Tak Yung Man; Sofia Ferreira-Gonzalez; Eoghan O'Duibhir; Benjamin J Dwyer; John P Thomson; Richard R Meehan; Roman Bogorad; Victor Koteliansky; Yuri Kotelevtsev; Charles Ffrench-Constant; Luke Boulter; Stuart J Forbes Journal: Nature Date: 2017-07-12 Impact factor: 49.962
Authors: Christopher A Jones; Nyall R London; Haoyu Chen; Kye Won Park; Dominique Sauvaget; Rebecca A Stockton; Joshua D Wythe; Wonhee Suh; Frederic Larrieu-Lahargue; Yoh-Suke Mukouyama; Per Lindblom; Pankaj Seth; Antonio Frias; Naoyuki Nishiya; Mark H Ginsberg; Holger Gerhardt; Kang Zhang; Dean Y Li Journal: Nat Med Date: 2008-03-16 Impact factor: 53.440