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Cellular crosstalk in the development and regeneration of the respiratory system

Nature Reviews Molecular Cell Biology volume 20, pages 551–566 (2019)Cite this article

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Abstract

The respiratory system, including the peripheral lungs, large airways and trachea, is one of the most recently evolved adaptations to terrestrial life. To support the exchange of respiratory gases, the respiratory system is interconnected with the cardiovascular system, and this interconnective nature requires a complex interplay between a myriad of cell types. Until recently, this complexity has hampered our understanding of how the respiratory system develops and responds to postnatal injury to maintain homeostasis. The advent of new single-cell sequencing technologies, developments in cellular and tissue imaging and advances in cell lineage tracing have begun to fill this gap. The view that emerges from these studies is that cellular and functional heterogeneity of the respiratory system is even greater than expected and also highly adaptive. In this Review, we explore the cellular crosstalk that coordinates the development and regeneration of the respiratory system. We discuss both the classic cell and developmental biology studies and recent single-cell analysis to provide an integrated understanding of the cellular niches that control how the respiratory system develops, interacts with the external environment and responds to injury.

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Fig. 1: Cellular composition of airways.
Fig. 2: Cellular composition of alveoli.
Fig. 3: Respiratory tract development and endoderm–mesoderm interactions.
Fig. 4: The airway niche turnover at homeostasis and in response to injury.
Fig. 5: Response of the alveolar niche to tissue injury.

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Acknowledgements

The authors apologize for the omission of any references due to the space constraints of this review. The authors acknowledge important support from the National Institutes of Health.

Reviewer information

Nature Reviews Molecular Cell Biology thanks J. Rajagopal, and other, anonymous, reviewer(s), for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Jarod A. Zepp & Edward E. Morrisey

  2. Penn Center for Pulmonary Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Jarod A. Zepp & Edward E. Morrisey

  3. Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Jarod A. Zepp & Edward E. Morrisey

  4. Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Edward E. Morrisey

  5. Penn Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Edward E. Morrisey

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The authors contributed equally to all aspects of the article.

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Correspondence to Edward E. Morrisey.

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Related links

LungMAP project: https://lungmap.net

Tabula Muris: https://tabula-muris.ds.czbiohub.org

Supplementary information

Glossary

Foregut

The portion of the gut tube that gives rise to several organs, including the oesophagus, stomach and the entire respiratory tract.

Mesenchyme

Mesoderm-derived cells and tissue.

Branching morphogenesis

The developmental process that generates the branched ductal tree-like structures observed in multiple organ systems, including lung, pancreas, kidney, liver, prostate gland, mammary gland and circulatory system. The process is characteristically marked by tube outgrowth and tip branching.

Pseudostratified epithelium

A single layer of epithelial cells all with contacts to the basal laminal surface but with different positions of nuclei, giving the appearance of stratified layers.

Surfactant

A mixture of lipids and proteins that is secreted into the alveolar space to reduce surface tension and prevent lung collapse.

Lateral plate mesoderm

A portion of the primary germ layers of the embryo that resides on the periphery of the embryo and gives rise to the primordial mesoderm surrounding early lung endoderm.

ß-Catenin

A critical protein in the WNT signalling cascade that is retained in the cytoplasm in unstimulated cells. On WNT-ligand stimulation, ß-catenin translocates to the cell nucleus, where it cooperates with TCF/LEF proteins to promote WNT-target gene transcription.

Turing model

A mathematical model of diffusion-driven instability that has been applied to biologically relevant simulations of ligand-driven morphogenetic events.

Chromatin remodelling complex

A complex of proteins that control accessibility of chromatin through modification of histones or DNA.

Lamellar body

A secretory lysosomal-related organelle in the alveolar type 2 cells that stores lung surfactant phospholipids and proteins.

Naphthalene

An aromatic hydrocarbon that is metabolized to a toxic form by the airway epithelial club cell lineage in cells that express the enzyme CYP2F2. It is used to model club cell ablation.

Hippo signalling

A signalling pathway that controls nuclear translocation of the transcription co-activators YAP and TAZ and activation of their target genes that function as a key mechanoresponsive pathway.

Basement membrane

A thin layer of extracellular matrix that provides support and separates epithelia from the surrounding tissue.

Bleomycin

A chemotherapeutic drug that elicits extensive DNA damage. It is used to model lung injury that is associated with severe damage to the epithelium accompanied by stimulation of a fibrotic response from the mesenchyme.

Diphtheria toxin

An exotoxin derived from bacteria that when expressed in a cell-specific manner leads to the selective ablation of that cell type.

Matrigel

A gelatinous mixture of extracellular protein matrix, including laminin, that is used for three-dimensional organoid cell cultures.

Damage- and pathogen-associated molecular patterns

Cellular and microbial by-products that stimulate an inflammatory response.

Innate lymphoid cells

A group of innate immune cells that do not express B or T cell receptors but that exhibit functions analogous to those of helper T cells. These cells are mainly found at mucosal surfaces, such as in the lungs, where they act as critical sentinel cells responding to pathogens and allergens.

M2-polarized macrophages

Macrophage subpopulation that is considered to be more anti-inflammatory in activity and that is typically associated with wound healing responses.

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Zepp, J.A., Morrisey, E.E. Cellular crosstalk in the development and regeneration of the respiratory system. Nat Rev Mol Cell Biol 20, 551–566 (2019). https://doi.org/10.1038/s41580-019-0141-3

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