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 re...
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Published in | American journal of respiratory and critical care medicine Vol. 200; no. 9; pp. 1164 - 1176 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Thoracic Society
01.11.2019
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1073-449X 1535-4970 |
DOI: | 10.1164/rccm.201812-2312OC |