Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization. Academic Article uri icon

Overview

MeSH

  • Animals
  • Endothelial Cells
  • Epithelial Cells
  • Matrix Metalloproteinase 14
  • Mice
  • Mice, Knockout
  • Neovascularization, Physiologic
  • Pneumonectomy
  • Receptor, Fibroblast Growth Factor, Type 1
  • Regeneration
  • Stem Cells
  • Tissue Culture Techniques
  • Vascular Endothelial Growth Factor Receptor-2

MeSH Major

  • Endothelial Growth Factors
  • Lung
  • Pulmonary Alveoli

abstract

  • To identify pathways involved in adult lung regeneration, we employ a unilateral pneumonectomy (PNX) model that promotes regenerative alveolarization in the remaining intact lung. We show that PNX stimulates pulmonary capillary endothelial cells (PCECs) to produce angiocrine growth factors that induce proliferation of epithelial progenitor cells supporting alveologenesis. Endothelial cells trigger expansion of cocultured epithelial cells, forming three-dimensional angiospheres reminiscent of alveolar-capillary sacs. After PNX, endothelial-specific inducible genetic ablation of Vegfr2 and Fgfr1 in mice inhibits production of MMP14, impairing alveolarization. MMP14 promotes expansion of epithelial progenitor cells by unmasking cryptic EGF-like ectodomains that activate the EGF receptor (EGFR). Consistent with this, neutralization of MMP14 impairs EGFR-mediated alveolar regeneration, whereas administration of EGF or intravascular transplantation of MMP14(+) PCECs into pneumonectomized Vegfr2/Fgfr1-deficient mice restores alveologenesis and lung inspiratory volume and compliance function. VEGFR2 and FGFR1 activation in PCECs therefore increases MMP14-dependent bioavailability of EGFR ligands to initiate and sustain alveologenesis. Copyright © 2011 Elsevier Inc. All rights reserved.

publication date

  • October 28, 2011

has subject area

  • Animals
  • Endothelial Cells
  • Endothelial Growth Factors
  • Epithelial Cells
  • Lung
  • Matrix Metalloproteinase 14
  • Mice
  • Mice, Knockout
  • Neovascularization, Physiologic
  • Pneumonectomy
  • Pulmonary Alveoli
  • Receptor, Fibroblast Growth Factor, Type 1
  • Regeneration
  • Stem Cells
  • Tissue Culture Techniques
  • Vascular Endothelial Growth Factor Receptor-2

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3228268

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2011.10.003

PubMed ID

  • 22036563

Additional Document Info

start page

  • 539

end page

  • 553

volume

  • 147

number

  • 3