Postnatal Alveologenesis Depends on FOXF1 Signaling in c-KIT + Endothelial Progenitor Cells

Am J Respir Crit Care Med. 2019 Nov 1;200(9):1164-1176. doi: 10.1164/rccm.201812-2312OC.

Abstract

Rationale: Disruption of alveologenesis is associated with severe pediatric lung disorders, including bronchopulmonary dysplasia (BPD). Although c-KIT+ endothelial cell (EC) progenitors are abundant in embryonic and neonatal lungs, their role in alveolar septation and the therapeutic potential of these cells remain unknown.Objectives: To determine whether c-KIT+ EC progenitors stimulate alveologenesis in the neonatal lung.Methods: We used single-cell RNA sequencing of neonatal human and mouse lung tissues, immunostaining, and FACS analysis to identify transcriptional and signaling networks shared by human and mouse pulmonary c-KIT+ EC progenitors. A mouse model of perinatal hyperoxia-induced lung injury was used to identify molecular mechanisms that are critical for the survival, proliferation, and engraftment of c-KIT+ EC progenitors in the neonatal lung.Measurements and Main Results: Pulmonary c-KIT+ EC progenitors expressing PECAM-1, CD34, VE-Cadherin, FLK1, and TIE2 lacked mature arterial, venal, and lymphatic cell-surface markers. The transcriptomic signature of c-KIT+ ECs was conserved in mouse and human lungs and enriched in FOXF1-regulated transcriptional targets. Expression of FOXF1 and c-KIT was decreased in the lungs of infants with BPD. In the mouse, neonatal hyperoxia decreased the number of c-KIT+ EC progenitors. Haploinsufficiency or endothelial-specific deletion of Foxf1 in mice increased apoptosis and decreased proliferation of c-KIT+ ECs. Inactivation of either Foxf1 or c-Kit caused alveolar simplification. Adoptive transfer of c-KIT+ ECs into the neonatal circulation increased lung angiogenesis and prevented alveolar simplification in neonatal mice exposed to hyperoxia.Conclusions: Cell therapy involving c-KIT+ EC progenitors can be beneficial for the treatment of BPD.

Keywords: C-KIT; FOXF1; bronchopulmonary dysplasia; endothelial progenitor cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Endothelial Progenitor Cells / physiology*
  • Forkhead Transcription Factors / physiology*
  • Humans
  • Infant, Newborn
  • Lung / growth & development*
  • Mice
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Proto-Oncogene Proteins c-kit / metabolism*
  • Signal Transduction / physiology*
  • Tissue Culture Techniques

Substances

  • FOXF1 protein, human
  • Forkhead Transcription Factors
  • Platelet Endothelial Cell Adhesion Molecule-1
  • KIT protein, human
  • Proto-Oncogene Proteins c-kit