We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Postnatal Alveologenesis Depends on FOXF1 Signaling in c-KIT<sup>+</sup> Endothelial Progenitor Cells.
- Authors
Xiaomeng Ren; Ustiyan, Vladimir; Minzhe Guo; Guolun Wang; Bolte, Craig; Yufang Zhang; Yan Xu; Whitsett, Jeffrey A.; Kalin, Tanya V.; Kalinichenko, Vladimir V.; Ren, Xiaomeng; Guo, Minzhe; Wang, Guolun; Zhang, Yufang; Xu, Yan
- 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.
- Subjects
BRONCHOPULMONARY dysplasia; TRANSCRIPTION factors; PROGENITOR cells; LUNG diseases; RNA sequencing
- Publication
American Journal of Respiratory & Critical Care Medicine, 2019, Vol 200, Issue 9, p1164
- ISSN
1073-449X
- Publication type
journal article
- DOI
10.1164/rccm.201812-2312OC