title: Platelet-derived SDF-1 primes the pulmonary capillary vascular niche to drive lung alveolar regeneration.
abstract: The lung alveoli regenerate after surgical removal of the left lobe by pneumonectomy (PNX). How this alveolar regrowth/regeneration is initiated remains unknown. We found that platelets trigger lung regeneration by supplying stromal-cell-derived factor-1 (SDF-1, also known as CXCL12). After PNX, activated platelets stimulate SDF-1 receptors CXCR4 and CXCR7 on pulmonary capillary endothelial cells (PCECs) to deploy the angiocrine membrane-type metalloproteinase MMP14, stimulating alveolar epithelial cell (AEC) expansion and neo-alveolarization. In mice lacking platelets or platelet Sdf1, PNX-induced alveologenesis was diminished. Reciprocally, infusion of Sdf1(+/+) but not Sdf1-deficient platelets rescued lung regeneration in platelet-depleted mice. Endothelial-specific ablation of Cxcr4 and Cxcr7 in adult mice similarly impeded lung regeneration. Notably, mice with endothelial-specific Mmp14 deletion exhibited impaired expansion of AECs but not PCECs after PNX, which was not rescued by platelet infusion. Therefore, platelets prime PCECs to initiate lung regeneration, extending beyond their haemostatic contribution. Therapeutic targeting of this haemo-vascular niche could enable regenerative therapy for lung diseases.
authors.affiliation: Ansary Stem Cell Institute, Weill Cornell Medical College, New York, NY 10065.|Department of Medicine, Weill Cornell Medical College, New York, NY 10065.|Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.affiliation: Ansary Stem Cell Institute, Weill Cornell Medical College, New York, NY 10065.|Department of Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Ansary Stem Cell Institute, Weill Cornell Medical College, New York, NY 10065.|Department of Medicine, Weill Cornell Medical College, New York, NY 10065.|Department of Reproductive Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Raphael
authors.initials: R
authors.lastname: Lis
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065.|First Department of Critical Care Medicine and Pulmonary Services, Evangelismos Hospital, University of Athens Medical School, Athens 10675, Greece.
authors.forename: Ilias I
authors.initials: II
authors.lastname: Siempos
authors.affiliation: Ansary Stem Cell Institute, Weill Cornell Medical College, New York, NY 10065.|Department of Medicine, Weill Cornell Medical College, New York, NY 10065.|Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Deebly
authors.initials: D
authors.lastname: Chavez
authors.affiliation: Ansary Stem Cell Institute, Weill Cornell Medical College, New York, NY 10065.|Department of Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Koji
authors.initials: K
authors.lastname: Shido
authors.affiliation: Ansary Stem Cell Institute, Weill Cornell Medical College, New York, NY 10065.|Department of Medicine, Weill Cornell Medical College, New York, NY 10065.|Bioengineering Program, Hofstra University, Hempstead, NY 11549.
authors.forename: Sina Y
authors.initials: SY
authors.lastname: Rabbany
authors.affiliation: Ansary Stem Cell Institute, Weill Cornell Medical College, New York, NY 10065.|Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Bi-Sen
authors.initials: BS
authors.lastname: Ding
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000378:metabolism*; D042783:Endothelial Cells / Q000201:enzymology; D004815:Epidermal Growth Factor / Q000378:metabolism; D017353:Gene Deletion; D008024:Ligands; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D051379:Mice; D009928:Organ Specificity; D040201:Platelet Membrane Glycoprotein IIb / Q000378:metabolism; D011013:Pneumonectomy; D011650:Pulmonary Alveoli / Q000098:blood supply* / Q000502:physiology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D054387:Receptors, CXCR / Q000378:metabolism; D019718:Receptors, CXCR4; D012038:Regeneration; D015398:Signal Transduction; D013926:Thrombopoietin / Q000172:deficiency / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D054377:Chemokine CXCL12; D004815:Epidermal Growth Factor; D008024:Ligands; D053511:Matrix Metalloproteinase 14; D040201:Platelet Membrane Glycoprotein IIb; D051496:Receptor, Fibroblast Growth Factor, Type 1; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D013926:Thrombopoietin; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5; C501897:Cmkor1 protein, mouse; C496349:Fgfr1 protein, mouse