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

RATIONALE
Disruption of alveologenesis is associated with severe pediatric lung disorders, including Bronchopulmonary Dysplasia (BPD). While c-KIT+ endothelial (EC) progenitor cells are abundant in embryonic and neonatal lungs, their role in alveolar septation and the therapeutic potential of these cells remain unknown.


OBJECTIVE
To determine whether c-KIT+ EC progenitor cells 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 employed to identify molecular mechanisms critical for 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 is conserved in mouse and human lungs and is enriched in FOXF1-regulated transcriptional targets. Expression of FOXF1 and c-KIT are decreased in lungs of infants with BPD. In the mouse, neonatal hyperoxia decreases the number of c-KIT+ EC progenitors. Haploinsufficiency or endothelial-specific deletion of Foxf1 in mice increases apoptosis and decreases proliferation of c-KIT+ ECs. Inactivation of either Foxf1 or c-Kit causes alveolar simplification. Adoptive transfer of c-KIT+ ECs into the neonatal circulation increases lung angiogenesis and prevents alveolar simplification in neonatal mice exposed to hyperoxia.


CONCLUSIONS
Cell therapy involving c-KIT+ EC progenitors can be beneficial for treatment of BPD.