Emergence of a Wave of Wnt Signaling that Regulates Lung Alveologenesis by Controlling Epithelial Self-Renewal and Differentiation

David B Frank; Tien Peng; Jarod A Zepp; Melinda Snitow; Tiffaney L Vincent; Ian J Penkala; Zheng Cui; Michael J Herriges; Michael P Morley; Su Zhou; Min Min Lu; Edward E Morrisey

doi:10.1016/j.celrep.2016.11.001

Emergence of a Wave of Wnt Signaling that Regulates Lung Alveologenesis by Controlling Epithelial Self-Renewal and Differentiation

Cell Rep. 2016 Nov 22;17(9):2312-2325. doi: 10.1016/j.celrep.2016.11.001.

Authors

Affiliations

¹ Division of Pediatric Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
² Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA 94117, USA.
³ Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: emorrise@mail.med.upenn.edu.

Abstract

Alveologenesis is the culmination of lung development and involves the correct temporal and spatial signals to generate the delicate gas exchange interface required for respiration. Using a Wnt-signaling reporter system, we demonstrate the emergence of a Wnt-responsive alveolar epithelial cell sublineage, which arises during alveologenesis, called the axin2+ alveolar type 2 cell, or AT2^Axin2. The number of AT2^Axin2 cells increases substantially during late lung development, correlating with a wave of Wnt signaling during alveologenesis. Transcriptome analysis, in vivo clonal analysis, and ex vivo lung organoid assays reveal that AT2s^Axin2 promote enhanced AT2 cell growth during generation of the alveolus. Activating Wnt signaling results in the expansion of AT2s, whereas inhibition of Wnt signaling inhibits AT2 cell development and shunts alveolar epithelial development toward the alveolar type 1 cell lineage. These findings reveal a wave of Wnt-dependent AT2 expansion required for lung alveologenesis and maturation.

Keywords: Wnt; alveolus; cell fate; lung.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Axin Protein / metabolism
Cell Differentiation*
Cell Lineage
Cell Proliferation
Cell Self Renewal*
Clone Cells
Epithelial Cells / cytology*
Epithelial Cells / metabolism
Epithelium / embryology
Genes, Reporter
Integrases / metabolism
Lung / embryology*
Mice
Models, Biological
Organogenesis* / genetics
Organoids
Pulmonary Alveoli / cytology
Pulmonary Alveoli / embryology*
Wnt Signaling Pathway* / genetics

Substances

Axin Protein
Axin2 protein, mouse
Cre recombinase
Integrases

Abstract

Publication types

MeSH terms

Substances

Grants and funding