Title: Mesenchymal stromal cell aging impairs the self-organizing capacity of lung alveolar epithelial stem cells.

Authors: Chanda, Diptiman; Rehan, Mohammad; Smith, Samuel R; Dsouza, Kevin G; Wang, Yong; Bernard, Karen; Kurundkar, Deepali; Memula, Vinayak; Kojima, Kyoko; Mobley, James A; Benavides, Gloria A; Darley-Usmar, Victor; Kim, Young-iL; Zmijewski, Jaroslaw W; Deshane, Jessy S; De Langhe, Stijn; Thannickal, Victor J

Published In Elife, (2021 09 16)

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 three-dimensional 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 support the concept of thermodynamic entropy in aging biology.

PubMed ID: 34528872

MeSH Terms: Alveolar Epithelial Cells*/metabolism; Alveolar Epithelial Cells*/physiology; Animals; Cells, Cultured; Cellular Senescence/physiology*; Male; Mesenchymal Stem Cells*/metabolism; Mesenchymal Stem Cells*/physiology; Mice; NADPH Oxidase 4/genetics; NADPH Oxidase 4/metabolism; Organoids/cytology; Organoids/metabolism; Oxidative Stress