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

Development. 2019 Aug 9;146(15):dev176354. doi: 10.1242/dev.176354.


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.

Keywords: Alveolar formation; Elastogenesis; Human; Lung development; Mouse; Pdgfra; Secondary crest myofibroblast.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bronchopulmonary Dysplasia / pathology
  • Calcium-Binding Proteins / biosynthesis
  • Cell Differentiation / physiology
  • Cells, Cultured
  • EGF Family of Proteins / metabolism*
  • Elastin / genetics
  • Extracellular Matrix Proteins / biosynthesis
  • Fibrillin-1 / biosynthesis
  • Humans
  • Mice
  • Mice, Knockout
  • Myofibroblasts / metabolism*
  • Protein-Lysine 6-Oxidase / biosynthesis
  • Pulmonary Alveoli / embryology*
  • RNA, Messenger / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism*
  • Transforming Growth Factor beta1 / biosynthesis
  • Transforming Growth Factor beta1 / metabolism*


  • Calcium-Binding Proteins
  • EGF Family of Proteins
  • Extracellular Matrix Proteins
  • Fbn1 protein, mouse
  • Fibrillin-1
  • RNA, Messenger
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta1
  • fibulin
  • Lox protein, mouse
  • Elastin
  • Protein-Lysine 6-Oxidase
  • Receptor, Platelet-Derived Growth Factor alpha