• Xiaomeng Ren, Vladimir Ustiyan, Minzhe Guo, Guolun Wang, Craig Bolte, Yufang Zhang, Yan Xu, Jeffrey A Whitsett, Tanya V Kalin, and Vladimir V Kalinichenko.
• Center for Lung Regenerative Medicine.
• Am. J. Respir. Crit. Care Med. 2019 Nov 1; 200 (9): 116411761164-1176.

AbstractRationale: 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.

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