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

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. To determine whether c-KIT EC progenitors stimulate alveologenesis in the neonatal lung. 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. 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 in mice increased apoptosis and decreased proliferation of c-KIT ECs. Inactivation of either or 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. Cell therapy involving c-KIT EC progenitors can be beneficial for the treatment of BPD.