Open AccessThe secondary crest myofibroblast PDGFRα controls elastogenesis pathway via a secondary tier of signaling networks during alveologenesis
Author(s) -
Changgong Li,
Matt K. Lee,
Feng Gao,
Sha Webster,
Helen Di,
Duan Jiang,
ChihChao Yang,
Navin Bhopal,
Neil Peinado,
Gloria Pryhuber,
Susan Smith,
Zea Borok,
Saverio Bellusci,
Parviz Minoo
Publication year - 2019
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.176354
Subject(s) - biology , pdgfra , myofibroblast , microbiology and biotechnology , signal transduction , cancer research , transcriptome , gene expression , pathology , gene , genetics , fibrosis , stromal cell , medicine , gist
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. 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 Lox, Fbn, and Fbln families. Expression of EGF family members increased while Tgfb1 was repressed. 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 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 TGFb.