Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis

Agha, Elie El; Moiseenko, Alena; Kheirollahi, Vahid; Langhe, Stijn De; Crnković, Slaven; Kwapiszewska, Grażyna; Szibor, Marten; Kosanovic, Djuro; Schwind, Felix; Schermuly, Ralph Theo; Henneke, Ingrid; MacKenzie, BreAnne; Quantius, Jennifer; Herold, Susanne; Ntokou, Aglaia; Ahlbrecht, Katrin; Braun, Thomas; Morty, Rory E.; Günther, Andreas; Seeger, Werner; Bellusci, Savério

doi:10.1016/j.stem.2017.03.011

Cited by 92 publications

(112 citation statements)

References 23 publications

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“…These Pdgfra -lineaged cells are not the only source of pathological myofibroblasts in fibrosis. For example, a recent study showed that Plin2 -lineaged lipofibroblasts can also give rise to a-SMA+ cells in fibrosis (El Agha et al, 2017). …”

Section: Discussionmentioning

confidence: 99%

“…This possibility remains to be tested through lineage tracing of lipofibroblasts. Recently, a Plin2 ( Adrp ) creERT2 line was generated to label lipofibroblasts (El Agha et al, 2017; Ntokou et al, 2017). However, it also labels a number of other cell types in the lung (El Agha et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a Plin2 ( Adrp ) creERT2 line was generated to label lipofibroblasts (El Agha et al, 2017; Ntokou et al, 2017). However, it also labels a number of other cell types in the lung (El Agha et al, 2017). Thus, generation of a genetic tool that specifically labels lipofibroblasts will be critical to address the potential of these cells in development and injury.…”

Section: Discussionmentioning

confidence: 99%

“…This transient nature is not only a feature in development, but it also occurs in disease settings. For example, in fibrosis model, it has been shown that a-SMA+ cells can revert to lipofibroblasts, which contributes to resolution of the disease (El Agha et al, 2017). …”

Section: Discussionmentioning

confidence: 99%

“…In the adult lungs, using the BAC transgenic Pdgfra-creERT2 line, it was shown that lineaged cells do contribute to fibrotic myofibroblasts (Zepp et al, 2017). In addition, other cell lineages, for example, Adrp -expressing lipofibroblasts can also contribute to fibrotic myofibroblasts (El Agha et al, 2017). …”

Section: Introductionmentioning

confidence: 99%

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

Bernau

Sandbo

et al. 2018

eLife

158

173

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Bernau

Sandbo

et al. 2018

eLife

158

173

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A cell‐centric view of lung alveologenesis

Ellis

Chen

2020

Developmental Dynamics

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Lung alveologenesis, formation of the alveolar region, allows sufficient gas exchange surface to be packed inside the chest cavity yet with orderly connection to the trachea. The real-life alveolar region, however, bears little resemblance to idealized cartoons owing to its three-dimensional nature, nonuniform shape, and mostly air-filled void. This morphological complexity is matched by its cellular complexity-comprised of intermixed and often tangled cells of the epithelial, mesenchymal, endothelial, and immune lineages. Modern imaging, genetics, and genomics are shedding light on and updating traditional views of alveologenesis. Accordingly, this review describes a cellcentric 3-phase definition of alveologenesis and discusses its failure in diseases and possible reactivation during regeneration.

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A novel mouse Cre‐driver line targeting Perilipin 2‐expressing cells in the neonatal lung

Ntokou

Szibor

Rodríguez‐Castillo

et al. 2017

Genesis

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Pulmonary diseases such as chronic obstructive pulmonary disease, lung fibrosis, and bronchopulmonary dysplasia are characterized by the destruction or malformation of the alveolar regions of the lung. The underlying pathomechanisms at play are an area of intense interest since these mechanisms may reveal pathways suitable for interventions to drive reparative processes. Lipid-laden fibroblasts (lipofibroblasts) express the Perilipin 2 (Plin2) gene-product, PLIN2, commonly called adipose-differentiation related protein (ADRP). These cells are also thought to play a role in alveolarization and repair after injury to the alveolus. Progress in defining the functional contribution of lipofibroblasts to alveolar generation and repair is hampered by a lack of in vivo tools. The present study reports the generation of an inducible mouse Cre-driver line to target cells of the ADRP lineage. Robust Cre-mediated recombination in this mouse line was detected in mesenchymal cells of the postnatal lung, and in additional organs including the heart, liver, and spleen. The generation and validation of this valuable new tool to genetically target, manipulate, and trace cells of the ADRP lineage is critical for assessing the functional contribution of lipofibroblasts to lung development and repair.

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Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis

Cited by 92 publications

References 23 publications

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

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

A cell‐centric view of lung alveologenesis

A novel mouse Cre‐driver line targeting Perilipin 2‐expressing cells in the neonatal lung

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