Alveologenesis: key cellular players and fibroblast growth factor 10 signaling

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Abstract

Background

Alveologenesis is the last stage in lung development and is essential for building the gas-exchanging units called alveoli. Despite intensive lung research, the intricate crosstalk between mesenchymal and epithelial cell lineages during alveologenesis is poorly understood. This crosstalk contributes to the formation of the secondary septae, which are key structures of healthy alveoli.

Conclusions

A better understanding of the cellular and molecular processes underlying the formation of the secondary septae is critical for the development of new therapies to protect or regenerate the alveoli. This review summarizes briefly the alveologenesis process in mouse and human. Further, it discusses the current knowledge on the epithelial and mesenchymal progenitor cells during early lung development giving rise to the key cellular players (e.g., alveolar epithelial cell type I, alveolar epithelial cell type II, alveolar myofibroblast, lipofibroblast) involved in alveologenesis. This review focusses mainly on the role of fibroblast growth factor 10 (FGF10), one of the most important signaling molecules during lung development, in epithelial and mesenchymal cell lineage formation.

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Most cited references 46

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Fgf10 is essential for limb and lung formation.

K Sekine, H Ohuchi, M. Fujiwara … (1999)

The interactions between fibroblast growth factors (FGF) and their receptors have important roles in mediating mesenchymal-epithelial cell interactions during embryogenesis. In particular, Fgf10 is predicted to function as a regulator of brain, lung and limb development on the basis of its spatiotemporal expression pattern in the developing embryo. To define the role of Fgf10, we generated Fgf10-deficient mice. Fgf10-/- mice died at birth due to the lack of lung development. Trachea was formed, but subsequent pulmonary branching morphogenesis was disrupted. In addition, mutant mice had complete truncation of the fore- and hindlimbs. In Fgf10-/- embryos, limb bud formation was initiated but outgrowth of the limb buds did not occur; however, formation of the clavicles was not affected. Analysis of the expression of marker genes in the mutant limb buds indicated that the apical ectodermal ridge (AER) and the zone of polarizing activity (ZPA) did not form. Thus, we show here that Fgf10 serves as an essential regulator of lung and limb formation.

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Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung.

S Bellusci, J Grindley, H Emoto … (1997)

During mouse lung morphogenesis, the distal mesenchyme regulates the growth and branching of adjacent endoderm. We report here that fibroblast growth factor 10 (Fgf10) is expressed dynamically in the mesenchyme adjacent to the distal buds from the earliest stages of lung development. The temporal and spatial pattern of gene expression suggests that Fgf10 plays a role in directional outgrowth and possibly induction of epithelial buds, and that positive and negative regulators of Fgf10 are produced by the endoderm. In transgenic lungs overexpressing Shh in the endoderm, Fgf10 transcription is reduced, suggesting that high levels of SHH downregulate Fgf10. Addition of FGF10 to embryonic day 11.5 lung tissue (endoderm plus mesenchyme) in Matrigel or collagen gel culture elicits a cyst-like expansion of the endoderm after 24 hours. In Matrigel, but not collagen, this is followed by extensive budding after 48-60 hours. This response involves an increase in the rate of endodermal cell proliferation. The activity of FGF1, FGF7 and FGF10 was also tested directly on isolated endoderm in Matrigel culture. Under these conditions, FGF1 elicits immediate endodermal budding, while FGF7 and FGF10 initially induce expansion of the endoderm. However, within 24 hours, samples treated with FGF10 give rise to multiple buds, while FGF7-treated endoderm never progresses to bud formation, at all concentrations of factor tested. Although exogenous FGF1, FGF7 and FGF10 have overlapping activities in vitro, their in vivo expression patterns are quite distinct in relation to early branching events. We conclude that, during early lung development, localized sources of FGF10 in the mesoderm regulate endoderm proliferation and bud outgrowth.

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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.

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Author and article information

Contributors

Cho-Ming Chao: Cho-Ming.Chao@paediat.med.uni-giessen.de

Alena Moiseenko: alena.v.moiseenko@gmail.com

Klaus-Peter Zimmer: Klaus-Peter.Zimmer@paediat.med.uni-giessen.de

Saverio Bellusci: Saverio.Bellusci@innere.med.uni-giessen.de

Journal

Journal ID (nlm-ta): Mol Cell Pediatr

Journal ID (iso-abbrev): Mol Cell Pediatr

Title: Molecular and Cellular Pediatrics

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Electronic): 2194-7791

Publication date (Electronic): 21 April 2016

Publication date PMC-release: 21 April 2016

Publication date Collection: December 2016

Volume: 3

Electronic Location Identifier: 17

Affiliations

[ ]Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Aulweg 130, 35392 Giessen, Germany

[ ]Division of General Pediatrics and Neonatology, University Children’s Hospital Gießen, Justus-Liebig-University, Gießen, Germany

[ ]Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russian Federation

Article

Publisher ID: 45

DOI: 10.1186/s40348-016-0045-7

PMC ID: 4840179

PubMed ID: 27098664

SO-VID: f23733d4-066a-4af9-aa02-f0c6df044a29

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 29 December 2015

Date accepted : 14 April 2016

Funding

Funded by: Universtätsklinikum Giessen Marburg

Funded by: FundRef http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;

Award ID: HL107307

Award Recipient : Saverio Bellusci

Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;

Award ID: BE4443/4-1

Award ID: BE4443/6-1

Award Recipient : Saverio Bellusci

Funded by: COST initiative

Award ID: BM1201

Award Recipient : Saverio Bellusci

Funded by: Program of competitive growth of Kazan Federal University

Funded by: Landes-Offensive zur Entwicklung Wissenschaftlich-ökonomischer Exzellenz

Funded by: University of Giessen Marburg Lung Center

Funded by: German Center for Lung Research

Funded by: Clinical Career Grant (ECCPS)

Custom metadata

Keywords: alveologenesis,fibroblast growth factor 10 (fgf10),alveolar epithelial cell type i (aec i),alveolar epithelial cell type ii (aec ii),alveolar myofibroblast,secondary septae

Data availability:

Keywords: alveologenesis, fibroblast growth factor 10 (fgf10), alveolar epithelial cell type i (aec i), alveolar epithelial cell type ii (aec ii), alveolar myofibroblast, secondary septae

Alveologenesis: key cellular players and fibroblast growth factor 10 signaling

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Abstract

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Neuronal Signaling

Most cited references 46

Fgf10 is essential for limb and lung formation.

Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung.

PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis.

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