Mesenchymal Stromal Cell Aging Impairs the Self-Organizing Capacity of Lung Alveolar Epithelial Stem Cells

Abstract

Multicellular organisms maintain structure and function of tissues/organs through emergent, self-organizing behavior. In this report, we demonstrate a critical role for lung mesenchymal stromal cell (L-MSC) aging in determining the capacity to form 3-dimentional organoids or alveolospheres with type 2 alveolar epithelial cells (AEC2s). In contrast to L-MSCs from aged mice, young L-MSCs support the efficient formation of alveolospheres when co-cultured with young or aged AEC2s. Aged L-MSCs demonstrated features of cellular senescence, altered bioenergetics, and a senescence-associated secretory profile (SASP). The reactive oxygen species generating enzyme, NADPH oxidase 4 (Nox4), was highly activated in aged L-MSCs and Nox4 downregulation was sufficient to, at least partially, reverse this age-related energy deficit, while restoring the self-organizing capacity of alveolospheres. Together, these data indicate a critical role for cellular bioenergetics and redox homeostasis in an organoid model of self-organization, and supports the concept of thermodynamic entropy in aging biology.

WNT Signalling in Lung Physiology and Pathology

“…In addition to the shift of WNT proteins in lung ageing, there is also evidence showing ageing-associated dysregulation of WNT target genes. Several WNT target genes including Tle1, Lef1, Nkd1 (Hofmann et al 2014), Ccnd2 (Cyclin D2), Ccna1 (Cyclin A1) (Watson et al 2020) were found to be reduced in the ageing mouse lung, while c-Myc (Zhang et al 2012a) and Wisp-1 (Chanda et al 2021) show increased expression. Another study exploring differential expression of WNT target genes in the ageing mouse lung (Hofmann et al 2014) also observed a decrease in WNT/β-catenin signalling with age on a whole lung level.…”