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Am J Respir Crit Care Med. 2019 Jun 24. doi: 10.1164/rccm.201812-2312OC. [Epub ahead of print]

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

Author information

1
Cincinnati Children's Hospital Medical Center, 2518, Cincinnati, Ohio, United States.
2
CCHMC, Pulmonary Biology, Cincinnati, Ohio, United States.
3
University of Cincinnati, Department of Electrical Engineering and Computing Systems, Cincinnati, Ohio, United States.
4
The Perinatal Institute and Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States.
5
Cincinnati Children's Hospital Medical Center, Pediatrics, Division of Pulmonary Biology, Cincinnati, Ohio, United States ; vladimir.kalinichenko@cchmc.org.

Abstract

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.

KEYWORDS:

Bronchopulmonary dysplasia,; C-KIT; Endothelial progenitor cells; FOXF1

PMID:
31233341
DOI:
10.1164/rccm.201812-2312OC

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