Abstract
The lung changes functionally and structurally with aging. However, age-related effects on the extracellular matrix (ECM) and corresponding effects on lung cell behavior are not well understood. We hypothesized that ECM from aged animals would induce aging-related phenotypic changes in healthy inoculated cells. Decellularized whole organ scaffolds provide a powerful model for examining how ECM cues affect cell phenotype. The effects of age on ECM composition in both native and decellularized mouse lungs were assessed as was the effect of young vs old acellular ECM on human bronchial epithelial cells (hBECs) and lung fibroblasts (hLFs). Native aged (1 year) lungs demonstrated decreased expression of laminins α3 and α4, elastin and fibronectin, and elevated collagen, compared to young (3 week) lungs. Proteomic analyses of decellularized ECM demonstrated similar findings, and decellularized aged lung ECM contained less diversity in structural proteins compared to young ECM. When seeded in old ECM, hBECs and hLFs demonstrated lower gene expression of laminins α3 and α4, respectively, as compared to young ECM, paralleling the laminin deficiency of aged ECM. ECM changes appear to be important factors in potentiating aging-related phenotypes and may provide clues to mechanisms that allow for aging-related lung diseases.
Highlights
Aging is known to be associated with structural changes in extracellular matrix (ECM), and ECM dysregulation was recently proposed to be a hallmark of aging in the lung [1]
Elastin and GAGs, present, were the most affected by decellularization as seen by decreased staining intensity compared to native lungs
We found that young lung ECM expressed greater diversity in the type and variety of structural proteins detected compared to old lung ECM
Summary
Aging is known to be associated with structural changes in extracellular matrix (ECM), and ECM dysregulation was recently proposed to be a hallmark of aging in the lung [1]. The functional consequence is manifested primarily as decreased elasticity [2]. Much interest has focused on the roles of oxidative stress, stem cell senescence, autophagy, defective mitochondrial function, and inflammasome production by aging cells, the effects of age-related changes in lung ECM on normal cell behavior remains less well understood. National Institutes of Health R21HL108689 (DJW), and P20GM103449 (funding the Vermont Genomics Network). GalaxyP infrastructure is supported by National Science Foundation grant 1147079 (to UMN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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