Secondary crest myofibroblast PDGFRα controls the elastogenesis pathway via a secondary tier of signaling networks during alveologenesis

Abstract

Postnatal alveolar formation is the most important and the least understood phase of lung development. Alveolar pathologies are prominent in neonatal and adult lung diseases. The mechanisms of alveologenesis remain largely unknown. We inactivated Pdgfra postnatally in secondary crest myofibroblasts (SCMF), a subpopulation of lung mesenchymal cells. Lack of Pdgfra arrested alveologenesis akin to bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease. The transcriptome of mutant SCMF revealed 1808 altered genes encoding transcription factors, signaling and extracellular matrix molecules. Elastin mRNA was reduced, and its distribution was abnormal. Absence of Pdgfra disrupted expression of elastogenic genes, including members of the Lox, Fbn and Fbln families. Expression of EGF family members increased when Tgfb1 was repressed in mouse. Similar, but not identical, results were found in human BPD lung samples. In vitro, blocking PDGF signaling decreased elastogenic gene expression associated with increased Egf and decreased Tgfb family mRNAs. The effect was reversible by inhibiting EGF or activating TGFβ signaling. These observations demonstrate the previously unappreciated postnatal role of PDGFA/ PDGFRα in controlling elastogenic gene expression via a secondary tier of signaling networks composed of EGF and TGFβ.

Single cell transcriptomic analysis of murine lung development on hyperoxia-induced damage

“…5e , respectively). Saa3 was increased in a lamb preterm lung injury model 30 and regulated Pdgfra 31 , which is critical for normal alveolar development, and have been reported to be decreased by hyperoxia-exposure 32 , 33 . In addition, decreased PDGFRA expression was associated with increased risk for male patients to develop BPD 34 .…”

Targeting Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension (BPD-PH): Potential Role of the FGF Signaling Pathway in the Development of the Pulmonary Vascular System

“…PDGFA/PDGFRA is an important signaling pathway controlling the elastogenesis of secondary crest myofibroblast during alveologenesis [ 93 ]. Interestingly, reduced PDGFRA has been found both in BPD patients and in hyperoxia-induced BPD mouse model [ 5 , 94 ].…”

Identification of a FGF18-expressing alveolar myofibroblast that is developmentally cleared during alveologenesis

“…Disruptions to the lung during postnatal development result in an insufficiency of secondary septa, characteristic of the pediatric disorder bronchopulmonary dysplasia (BPD), a major cause of preterm infant morbidity and chronic lung disease (Martinez, 2016;Voynow, 2017). The lung mesenchyme has long been recognized as important in directing alveologenesis (Boström et al, 1996;Kugler et al, 2017;Li et al, 2019Li et al, , 2017Nicola et al, 2009;Tsujino et al, 2017) and many mesenchymal proteins are dysregulated in models of BPD (Ahlfeld and Conway, 2012). Further alterations to AMF and ALF numbers are seen in genetic and hyperoxia-induced mouse models of BPD (Branchfield et al, 2016;Choi et al, 2013;Li et al, 2018;Popova et al, 2014;Rehan et al, 2006).…”