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

Abstract

<i>Pdgfra</i>-expressing (<i>Pdgfra+</i>) cells have been implicated as progenitors in many mesenchymal tissues. To determine lineage potential, we generated <i>Pdgfra^rtTA</i> knockin mice using CRISPR/Cas9. During lung maturation, counter to a prior study reporting that <i>Pdgfra</i>+ cells give rise equally to myofibroblasts and lipofibroblasts, lineage tracing using <i>Pdgfra^rtTA;tetO-cre</i> mice indicated that ~95% of the lineaged cells are myofibroblasts. Genetic ablation of <i>Pdgfra⁺</i> cells using <i>Pdgfra^rtTA</i>-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 <i>Pdgfra</i>-lineaged cells as exemplified by their distinct contributions to myofibroblasts in normal maturation, BPD and adult fibrosis.