Distinct Spatiotemporally Dynamic Wnt-Secreting Niches Regulate Proximal Airway Regeneration and Aging

Cody J Aros; Preethi Vijayaraj; Carla J Pantoja; Bharti Bisht; Luisa K Meneses; Jenna M Sandlin; Jonathan A Tse; Michelle W Chen; Arunima Purkayastha; David W Shia; Jennifer M S Sucre; Tammy M Rickabaugh; Eszter K Vladar; Manash K Paul; Brigitte N Gomperts

doi:10.1016/j.stem.2020.06.019

Distinct Spatiotemporally Dynamic Wnt-Secreting Niches Regulate Proximal Airway Regeneration and Aging

Cell Stem Cell. 2020 Sep 3;27(3):413-429.e4. doi: 10.1016/j.stem.2020.06.019. Epub 2020 Jul 27.

Authors

Affiliations

¹ UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; UCLA Department of Molecular Biology Interdepartmental Program, UCLA, Los Angeles, CA 90095, USA; UCLA Medical Scientist Training Program, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
² UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA.
³ UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
⁴ UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
⁵ Mildred Stahlman Division of Neonatology, Department of Pediatrics, Vanderbilt University, Nashville, TN 37232, USA.
⁶ Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine and Department of Cell and Developmental Biology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
⁷ UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA. Electronic address: [email protected].
⁸ UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; UCLA Department of Molecular Biology Interdepartmental Program, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA. Electronic address: [email protected].

Abstract

Our understanding of dynamic interactions between airway basal stem cells (ABSCs) and their signaling niches in homeostasis, injury, and aging remains elusive. Using transgenic mice and pharmacologic studies, we found that Wnt/β-catenin within ABSCs was essential for proliferation post-injury in vivo. ABSC-derived Wnt ligand production was dispensable for epithelial proliferation. Instead, the PDGFRα⁺ lineage in the intercartilaginous zone (ICZ) niche transiently secreted Wnt ligand necessary for ABSC proliferation. Strikingly, ABSC-derived Wnt ligand later drove early progenitor differentiation to ciliated cells. We discovered additional changes in aging, as glandular-like epithelial invaginations (GLEIs) derived from ABSCs emerged exclusively in the ICZ of aged mice and contributed to airway homeostasis and repair. Further, ABSC Wnt ligand secretion was necessary for GLEI formation, and constitutive activation of β-catenin in young mice induced their formation in vivo. Collectively, these data underscore multiple spatiotemporally dynamic Wnt-secreting niches that regulate functionally distinct phases of airway regeneration and aging.

Keywords: Wnt; aging; beta-catenin; homeostasis; intercartilaginous zone; lung repair; niche; signaling pathway.

Publication types

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

MeSH terms

Aging
Animals
Cell Differentiation
Cell Proliferation
Mice
Mice, Transgenic
Stem Cells* / metabolism
Wnt Signaling Pathway
beta Catenin* / metabolism

Substances

beta Catenin

Abstract

Publication types

MeSH terms

Substances

Grants and funding