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PDGF-A signaling is required for secondary alveolar septation and controls epithelial proliferation in the developing lung
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. (Christer Betsholtz)ORCID iD: 0000-0002-3825-8571
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.ORCID iD: 0000-0002-8494-971x
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.ORCID iD: 0000-0003-0700-4381
2018 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 7, article id dev161976Article in journal (Refereed) Published
Abstract [en]

Platelet-derived growth factor A (PDGF-A) signaling through PDGF receptor a is essential for alveogenesis. Previous studies have shown that Pdgfa(-/-) mouse lungs have enlarged alveolar airspace with absence of secondary septation, both distinctive features of bronchopulmonary dysplasia. To study how PDGF-A signaling is involved in alveogenesis, we generated lung-specific Pdgfa knockout mice (Pdgfa(fl/-); Spc-cre) and characterized their phenotype postnatally. Histological differences between mutant mice and littermate controls were visible after the onset of alveogenesis and maintained until adulthood. Additionally, we generated Pdgfa(fl/-); Spc-cre; Pdgfra(GFP/+) mice in which Pdgfra(+) cells exhibit nuclear GFP expression. In the absence of PDGF-A, the number of Pdgfra(GFP+) cells was significantly decreased. In addition, proliferation of Pdgfra(GFP+) cells was reduced. During alveogenesis, Pdgfra(GFP+) myofibroblasts failed to form the alpha-smooth muscle actin rings necessary for alveolar secondary septation. These results indicate that PDGF-A signaling is involved in myofibroblast proliferation and migration. In addition, we show an increase in both the number and proliferation of alveolar type II cells in Pdgfa(fl/-); Spc-cre lungs, suggesting that the increased alveolar airspace is not caused solely by deficient myofibroblast function.

Place, publisher, year, edition, pages
2018. Vol. 145, no 7, article id dev161976
National Category
Developmental Biology
Identifiers
URN: urn:nbn:se:uu:diva-347030DOI: 10.1242/dev.161976ISI: 000438944000005PubMedID: 29636361OAI: oai:DiVA.org:uu-347030DiVA, id: diva2:1192783
Funder
Swedish Research Council, 2015-00550EU, European Research Council, AdG294556Knut and Alice Wallenberg Foundation, 2015.0030Magnus Bergvall Foundation, 2014-00174Swedish Cancer Society, 150735Available from: 2018-03-23 Created: 2018-03-23 Last updated: 2018-09-27Bibliographically approved
In thesis
1. The role of PDGF-A in lung development, injury and repair
Open this publication in new window or tab >>The role of PDGF-A in lung development, injury and repair
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The developmental processes that take place during embryogenesis depend on a great number of proteins that are important for cell-to-cell communication. Platelet-derived growth factors are known to be important for epithelial-mesenchymal interactions during development and organogenesis. However, many details are still lacking regarding organ-specific PDGF expression patterns and detailed cellular functions. This thesis aims to better describe the contribution of PDGF-A signaling to lung developmental and injury processes.

To study the cell-specific expression patterns of PDGF-A we generated a reporter mouse that show LacZ expression in all PDGF-A positive cells. This mouse model was used to characterize PDGF-A expression in embryonic and adult mouse tissues (paper I).

With the use of three different reporter mice, we described the cell type specific expression patterns of PDGF-A, PDGF-C and PDGFRα in mouse lungs, from embryonic day 10.5 (E10.5) when development is initiated, until adulthood (Postnatal day 60) when the lung is fully mature (paper II).

A lung-specific Pdgfa knockout mouse was generated and the impact of the deletion was studied during lung development and adulthood. Mice lacking Pdgfa expression in the lung survived until adulthood but exhibited abnormal alveolar development. This phenotype was caused by the inability of myofibroblasts to assemble alpha smooth muscle actin ring around the forming alveoli (paper III).

To investigate if PDGF-A is involved in the injury response mechanisms of the adult lung, we generated inducible lung-specific Pdgfa knockout mice. In homeostasis, adult Pdgfa deletion did not result in any apparent phenotype, whereas after hyperoxia-induced lung injury, preliminary data show that mutant mice exhibit substantially more alveolar damage and immune cell infiltration (paper IV).

In conclusion, this thesis reports novel insights into the expression and role of PDGF-A and PDGFRα for the lung, both in development and adulthood.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 53
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1448
Keywords
Lung, organogenesis, PDGF, signalling pathway, development
National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-347032 (URN)978-91-513-0291-1 (ISBN)
Public defence
2018-05-18, Rudbecksalen, Dag Hammarskjöls väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-04-27 Created: 2018-03-23 Last updated: 2018-10-08

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Gouveia, LeonorBetsholtz, ChristerAndrae, Johanna

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