Pdgfra marks a cellular lineage with distinct contributions to myofibroblasts in lung maturation and injury response

Elife. 2018 Sep 4;7:e36865. doi: 10.7554/eLife.36865.

Abstract

Pdgfra-expressing (Pdgfra+) cells have been implicated as progenitors in many mesenchymal tissues. To determine lineage potential, we generated PdgfrartTA knockin mice using CRISPR/Cas9. During lung maturation, counter to a prior study reporting that Pdgfra+ cells give rise equally to myofibroblasts and lipofibroblasts, lineage tracing using PdgfrartTA;tetO-cre mice indicated that ~95% of the lineaged cells are myofibroblasts. Genetic ablation of Pdgfra+ cells using PdgfrartTA-driven diphtheria toxin (DTA) led to alveolar simplification, demonstrating that these cells are essential for building the gas exchange surface area. In the adult bleomycin model of lung fibrosis, lineaged cells increased to contribute to pathological myofibroblasts. In contrast, in a neonatal hyperoxia model of bronchopulmonary dysplasia (BPD), lineaged cells decreased and do not substantially contribute to pathological myofibroblasts. Our findings revealed complexity in the behavior of the Pdgfra-lineaged cells as exemplified by their distinct contributions to myofibroblasts in normal maturation, BPD and adult fibrosis.

Keywords: development; developmental biology; lung; mouse; myofibroblasts; regenerative medicine; stem cells.

Publication types

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

MeSH terms

  • Animals
  • Bleomycin
  • CRISPR-Cas Systems / genetics
  • Cell Lineage*
  • Cell Proliferation
  • Disease Models, Animal
  • Gene Deletion
  • Gene Expression Profiling
  • Gene Knock-In Techniques
  • Green Fluorescent Proteins / metabolism
  • Homologous Recombination / genetics
  • Hyperoxia / pathology
  • Lung / growth & development*
  • Lung / metabolism
  • Lung / pathology*
  • Mice, Transgenic
  • Myofibroblasts / metabolism*
  • Myofibroblasts / pathology*
  • Pulmonary Fibrosis / pathology
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism*
  • Single-Cell Analysis

Substances

  • Bleomycin
  • Green Fluorescent Proteins
  • Receptor, Platelet-Derived Growth Factor alpha