title: Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis.
abstract: Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin-dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladapted hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis.
authors.affiliation: Ansary Stem Cell Institute, Weill Cornell Medicine, New York, New York, USA.|Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.|Laboratory of Birth Defects and Related Diseases of Women and Children, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Ansary Stem Cell Institute, Weill Cornell Medicine, New York, New York, USA.|Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Lis
authors.affiliation: Angiocrine Bioscience, New York, New York, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ginsberg
authors.affiliation: Ansary Stem Cell Institute, Weill Cornell Medicine, New York, New York, USA.|Department of Genetic Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Deebly
authors.initials: D
authors.lastname: Chavez
authors.affiliation: Ansary Stem Cell Institute, Weill Cornell Medicine, New York, New York, USA.|Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Shido
authors.affiliation: Ansary Stem Cell Institute, Weill Cornell Medicine, New York, New York, USA.|Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.|Bioengineering Program, Hofstra University, Hempstead, New York, USA.
authors.forename: Sina Y
authors.initials: SY
authors.lastname: Rabbany
authors.affiliation: Department of Cell Biology, University of Connecticut, Farmington, Connecticut, USA.
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Fong
authors.affiliation: Laboratory of Chemical Biology &Signal Transduction, Rockefeller University, New York, New York, USA.|Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Sakmar
authors.affiliation: Ansary Stem Cell Institute, Weill Cornell Medicine, New York, New York, USA.|Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.affiliation: Ansary Stem Cell Institute, Weill Cornell Medicine, New York, New York, USA.|Laboratory of Birth Defects and Related Diseases of Women and Children, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.|Department of Genetic Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Bi-Sen
authors.initials: BS
authors.lastname: Ding
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis; D005455:Fluorescent Antibody Technique; D006801:Humans; D006851:Hydrochloric Acid / Q000633:toxicity; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D055370:Lung Injury / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology; D011658:Pulmonary Fibrosis / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D054387:Receptors, CXCR / Q000819:agonists / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D000072099:Serrate-Jagged Proteins; D051900:Smad3 Protein / Q000187:drug effects / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D000903:Antibiotics, Antineoplastic; D002135:Calcium-Binding Proteins; C501897:Cmkor1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D009842:Oligopeptides; D034741:RNA, Small Interfering; D054387:Receptors, CXCR; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C504129:TC14012; D001761:Bleomycin; D040281:Vascular Endothelial Growth Factor Receptor-1; D006851:Hydrochloric Acid