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

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          Abstract

          Pdgfra-expressing ( Pdgfra+) cells have been implicated as progenitors in many mesenchymal tissues. To determine lineage potential, we generated Pdgfra rtTA 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 Pdgfra rtTA;tetO-cre mice indicated that ~95% of the lineaged cells are myofibroblasts. Genetic ablation of Pdgfra + cells using Pdgfra rtTA -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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          Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition.

          Jason R. Rock, Christina E Barkauskas, Michael J Cronce … (2011)
          There are currently few treatment options for pulmonary fibrosis. Innovations may come from a better understanding of the cellular origin of the characteristic fibrotic lesions. We have analyzed normal and fibrotic mouse and human lungs by confocal microscopy to define stromal cell populations with respect to several commonly used markers. In both species, we observed unexpected heterogeneity of stromal cells. These include numerous cells with molecular and morphological characteristics of pericytes, implicated as a source of myofibroblasts in other fibrotic tissues. We used mouse genetic tools to follow the fates of specific cell types in the bleomcyin-induced model of pulmonary fibrosis. Using inducible transgenic alleles to lineage trace pericyte-like cells in the alveolar interstitium, we show that this population proliferates in fibrotic regions. However, neither these cells nor their descendants express high levels of the myofibroblast marker alpha smooth muscle actin (Acta2, aSMA). We then used a Surfactant protein C-CreER(T2) knock-in allele to follow the fate of Type II alveolar cells (AEC2) in vivo. We find no evidence at the cellular or molecular level for epithelial to mesenchymal transition of labeled cells into myofibroblasts. Rather, bleomycin accelerates the previously reported conversion of AEC2 into AEC1 cells. Similarly, epithelial cells labeled with our Scgb1a1-CreER allele do not give rise to fibroblasts but generate both AEC2 and AEC1 cells in response to bleomycin-induced lung injury. Taken together, our results show a previously unappreciated heterogeneity of cell types proliferating in fibrotic lesions and exclude pericytes and two epithelial cell populations as the origin of myofibroblasts.
          Article 0 comments Cited 372 times – based on 0 reviews     Review now
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            Anatomically and Functionally Distinct Lung Mesenchymal Populations Marked by Lgr5 and Lgr6

            Joo-Hyeon Lee, Tuomas Tammela, Matan Hofree … (2017)
            Summary The diversity of mesenchymal cell types in the lung that influence epithelial homeostasis and regeneration is poorly defined. We used genetic lineage tracing, single-cell RNA sequencing, and organoid culture approaches to show that Lgr5 and Lgr6, well-known markers of stem cells in epithelial tissues, are markers of mesenchymal cells in the adult lung. Lgr6+ cells comprise a subpopulation of smooth muscle cells surrounding airway epithelia and promote airway differentiation of epithelial progenitors via Wnt-Fgf10 cooperation. Genetic ablation of Lgr6+ cells impairs airway injury repair in vivo. Distinct Lgr5+ cells are located in alveolar compartments and are sufficient to promote alveolar differentiation of epithelial progenitors through Wnt activation. Modulating Wnt activity altered differentiation outcomes specified by mesenchymal cells. This identification of region- and lineage-specific crosstalk between epithelium and their neighboring mesenchymal partners provides new understanding of how different cell types are maintained in the adult lung.
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              PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis.

              Hans Boström, Karen Willetts, Milos Pekny … (1996)
              A mouse platelet-derived growth factor A chain (PDGF-A) null allele is shown to be homozygous lethal, with two distinct restriction points, one prenatally before E10 and one postnatally. Postnatally surviving PDGF-A-deficient mice develop lung emphysema secondary to the failure of alveolar septation. This is apparently caused by the loss of alveolar myofibroblasts and associated elastin fiber deposits. PDGF alpha receptor-positive cells in the lung having the location of putative alveolar myofibroblast progenitors were specifically absent in PDGF-A null mutants. We conclude that PDGF-A is crucial for alveolar myofibroblast ontogeny. We have previously shown that PDGF-B is required in the ontogeny of kidney mesangial cells. The PDGFs therefore appear to regulate the generation of specific populations of myofibroblasts during mammalian development. The two PDGF null phenotypes also reveal analogous morphogenetic functions for myofibroblast-type cells in lung and kidney organogenesis.
              Article 0 comments Cited 155 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Xin Sun:
                ORCID: https://orcid.org/0000-0001-8387-4966
                Edward Morrisey: Role: Reviewing Editor
                Harry C Dietz: Role: Senior Editor
                Journal
                Journal ID (nlm-ta): eLife
                Journal ID (iso-abbrev): Elife
                Journal ID (publisher-id): eLife
                Title: eLife
                Publisher: eLife Sciences Publications, Ltd
                ISSN (Electronic): 2050-084X
                Publication date (Electronic, pub): 04 September 2018
                Publication date Collection: 2018
                Volume: 7
                Electronic Location Identifier: e36865
                Affiliations
                [1 ]deptDepartment of Pediatrics University of California, San Diego La JollaUnited States
                [2 ]deptLaboratory of Genetics, Department of Medical Genetics University of Wisconsin-Madison MadisonUnited States
                [3 ]deptDepartment of Medicine University of Wisconsin-Madison MadisonUnited States
                [4 ]deptCenter for Epigenomics, Department of Cellular and Molecular Medicine University of California, San Diego La JollaUnited States
                University of Pennsylvania United States
                Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine United States
                University of Pennsylvania United States
                Author information
                http://orcid.org/0000-0001-9112-9712
                https://orcid.org/0000-0001-8387-4966
                Article
                Publisher ID: 36865
                DOI: 10.7554/eLife.36865
                PMC ID: 6122952
                PubMed ID: 30178747
                SO-VID: 407b25a0-4317-4517-b8c9-55ab64275041
                Copyright © © 2018, Li et al
                License:

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                Date received : 21 March 2018
                Date accepted : 27 August 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;
                Award ID: RO1 HL142215,RO1 HL097134,RO1 HL122406
                Award Recipient :
                Funded by: UCSD Pediatrics pilot funding;
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Subject: Research Article
                Subject: Developmental Biology
                Subject: Stem Cells and Regenerative Medicine
                Custom metadata
                Author impact statement Lineage tracing using a knockin Pdgfra-rtTA tool indicates distinct contributions of this cell lineage to myofibroblasts in normal development, fibrosis and bronchopulmonary dysplasia models.

                ScienceOpen disciplines: Life sciences
                Keywords: lung,development,myofibroblasts,mouse
                Data availability:
                ScienceOpen disciplines: Life sciences
                Keywords: lung, development, myofibroblasts, mouse

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