Abstract
FOXF1, a member of the forkhead box family of transcription factors, has been previously shown to be critical for lung development, homeostasis, and injury responses. However, the role of FOXF1 in lung regeneration is unknown. Herein, we performed partial pneumonectomy, a model of lung regeneration, in mice lacking one Foxf1 allele in endothelial cells (PDGFb-iCre/Foxf1fl/+ mice). Endothelial cell proliferation was significantly reduced in regenerating lungs from mice deficient for endothelial Foxf1. Decreased endothelial proliferation was associated with delayed lung regeneration as shown by reduced respiratory volume in Foxf1-deficient lungs. FACS-sorted endothelial cells isolated from regenerating PDGFb-iCre/Foxf1fl/+ and control lungs were used for RNAseq analysis to identify FOXF1 target genes. Foxf1 deficiency altered expression of numerous genes including those regulating extracellular matrix remodeling (Timp3, Adamts9) and cell cycle progression (Cdkn1a, Cdkn2b, Cenpj, Tubb4a), which are critical for lung regeneration. Deletion of Foxf1 increased Timp3 mRNA and protein, decreasing MMP14 activity in regenerating lungs. ChIPseq analysis for FOXF1 and histone methylation marks identified DNA regulatory regions within the Cd44, Cdkn1a, and Cdkn2b genes, indicating they are direct FOXF1 targets. Thus FOXF1 stimulates lung regeneration following partial pneumonectomy via direct transcriptional regulation of genes critical for extracellular matrix remodeling and cell cycle progression.
Highlights
Lung regeneration plays an important role in lung repair after injury
Our study shows that FOXF1 transcriptionally regulates Timp[3], Cdkn1a, Cdkn2b, and Cd44, all of which are critical for extracellular matrix remodeling and endothelial proliferation
Evaluation of FOXF1 distribution in sham-operated and regenerating lungs showed that FOXF1 is widely distributed in the alveolar region but can only be detected in a subset of endothelial cells within pulmonary arteries and veins (Supplemental Fig. 1)
Summary
Lung regeneration plays an important role in lung repair after injury. It is reliant upon proliferation of multiple cell types in the lung, including endothelium, epithelium, and fibroblasts, as well as remodeling of the extracellular matrix. The alternative process is to increase the number of alveoli, which maintains a consistent pulmonary morphology while expanding lung volume and surface area for gas exchange[4] Both processes of post-PNX lung growth involve a period of rapid cell proliferation including endothelial and epithelial cells as both are essential for formation of alveoli to restore respiratory capacity after resection. A PNX model was used to investigate the role of FOXF1 in lung regeneration Since deletion of both Foxf[1] alleles in endothelial cells is lethal[11], a tamoxifen-inducible Cre (PDGFb-iCre) was used to cause Foxf[1] haploinsufficiency in endothelial cells prior to PNX surgery. This study demonstrates that FOXF1 induces lung regeneration and reestablishment of normal alveolar structure after PNX
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