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

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

Posted 07 Mar 2021
bioRxiv DOI: 10.1101/2021.03.05.434121

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.

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