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

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

Author information

1
Department of Pediatrics, University of California, San Diego, La Jolla, United States.
2
Laboratory of Genetics, Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States.
3
Department of Medicine, University of Wisconsin-Madison, Madison, United States.
4
Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States.

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

PMID:
30178747
PMCID:
PMC6122952
DOI:
10.7554/eLife.36865
[Indexed for MEDLINE]
Free PMC Article

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