Distal lung epithelial progenitor cell function declines with age

Julie K Watson,Tomas Mustelin,Richard May,Rebecca Dunmore,Emma L Rawlins,Philip Sanders,Donna K Finch,Guglielmo Rosignoli,Yvon Julé,Deborah Clarke

doi:10.1038/s41598-020-66966-y

Abstract

Tissue stem cell exhaustion is a key hallmark of aging, and in this study, we characterised its manifestation in the distal lung. We compared the lungs of 3- and 22-month old mice. We examined the gross morphological changes in these lungs, the density and function of epithelial progenitor populations and the epithelial gene expression profile. Bronchioles became smaller in their cross-sectional area and diameter. Using long-term EdU incorporation analysis and immunohistochemistry, we found that bronchiolar cell density remained stable with aging, but inferred rates of bronchiolar club progenitor cell self-renewal and differentiation were reduced, indicative of an overall slowdown in cellular turnover. Alveolar Type II progenitor cell density and self-renewal were maintained per unit tissue area with aging, but rates of inferred differentiation into Type I cells, and indeed overall density of Type I cells was reduced. Microarray analysis revealed age-related changes in multiple genes, including some with roles in proliferation and differentiation, and in IGF and TGFβ signalling pathways. By characterising how lung stem cell dynamics change with aging, this study will elucidate how they contribute to age-related loss of pulmonary function, and pathogenesis of common age-related pulmonary diseases.

Highlights

Tissue stem cell exhaustion is a key hallmark of aging, and in this study, we characterised its manifestation in the distal lung
Tissue stem cell exhaustion is a key hallmark of aging[1], but has not been fully investigated in the lung
It is important to characterise how lung stem cell dynamics change with aging, and how they contribute to age-related loss of pulmonary function

Summary

Introduction

Tissue stem cell exhaustion is a key hallmark of aging, and in this study, we characterised its manifestation in the distal lung. By characterising how lung stem cell dynamics change with aging, this study will elucidate how they contribute to age-related loss of pulmonary function, and pathogenesis of common age-related pulmonary diseases. It is important to characterise how lung stem cell dynamics change with aging, and how they contribute to age-related loss of pulmonary function. Specific changes in defined progenitor cell populations likely underlie the changes in structure and function of the lung. Disruption of telomerase activity in alveolar Type II epithelial progenitors drove development of pulmonary fibrosis[17]. This highlights the importance of epithelial senescence in driving pathogenesis, fibroblast senescence may play a role[18]. Telomere shortening is observed in COPD endothelial progenitor cells and leukocytes[20,21], as is increased DNA damage response at telomeres in COPD airway epithelial cells[22]

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