Platelet-derived SDF-1 primes the pulmonary capillary vascular niche to drive lung alveolar regeneration

• Published in: Nature cell biology Vol. 17; no. 2; pp. 123 - 136
• Main Authors: Rafii, Shahin, Cao, Zhongwei, Lis, Raphael, Siempos, Ilias I., Chavez, Deebly, Shido, Koji, Rabbany, Sina Y., Ding, Bi-Sen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2015; Nature Publishing Group
• Subjects: 631/136/16; 631/136/532/489; Animals; Antigens, CD - metabolism; Blood Platelets - metabolism; Cadherins - metabolism; Cancer Research; Capillaries - metabolism; Cell Biology; Cellular proteins; Chemokine CXCL12 - metabolism; Developmental Biology; Diseases; Endothelial Cells - enzymology; Endothelium; Epidermal Growth Factor - metabolism; Gene Deletion; Genetic aspects; Life Sciences; Ligands; Lung diseases; Lungs; Matrix Metalloproteinase 14 - metabolism; Mice; Organ Specificity; Platelet Membrane Glycoprotein IIb - metabolism; Pneumonectomy; Properties; Pulmonary Alveoli - blood supply; Pulmonary Alveoli - physiology; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Receptors, CXCR - metabolism; Receptors, CXCR4; Regeneration; Regeneration (Biology); Regrowth; Respiratory tract diseases; Signal Transduction; Stem Cells; Thrombopoietin - deficiency; Thrombopoietin - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; New York
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb3096

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. Ding and colleagues report that blood platelets recruited to the lung by injury release the chemokine SDF-1, which interacts with its receptor CXCR4 on pulmonary capillary endothelial cells and thereby initiates alveolar regeneration.