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

Chanda, D.; Rehan, M.; Smith, S. R.; Dsouza, K. G.; Wang, Y.; Bernard, K.; Kurundkar, D.; Memula, V.; Kojima, K.; Mobley, J. A.; Benavides, G.; Darley-Usmar, V.; Kim, Y.-i.; Zmijewski, J. W.; Deshane, J.; Thannickal, V. J.

doi:10.1101/2021.03.05.434121

bioRxiv · 10.1101/2021.03.05.434121

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

Chanda, D.·Rehan, M.·Smith, S. R.·Dsouza, K. G.·Wang, Y.·Bernard, K.·Kurundkar, D.·Memula, V.·Kojima, K.·Mobley, J. A.·Benavides, G.·Darley-Usmar, V.·Kim, Y.-i.·Zmijewski, J. W.·Deshane, J.·Thannickal, V. J.

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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.

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Chanda, D., Rehan, M., Smith, S. R., Dsouza, K. G., Wang, Y., Bernard, K., Kurundkar, D., Memula, V., Kojima, K., Mobley, J. A., Benavides, G., Darley-Usmar, V., Kim, Y.-i., Zmijewski, J. W., Deshane, J., Thannickal, V. J.. 2021-03-07. Mesenchymal Stromal Cell Aging Impairs the Self-Organizing Capacity of Lung Alveolar Epithelial Stem Cells. https://doi.org/10.1101/2021.03.05.434121

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