Mesenchymal stromal cell aging impairs the self-organizing capacity of lung alveolar epithelial stem cells
Diptiman Chanda, Mohammad Rehan, S. Ray Smith, K.G. Dsouza, Yong Wang, Karen Bernard, Deepali Kurundkar, Vinayak Memula, Kyoko Kojima, James A. Mobley, Gloria A. Benavides, Victor Darley‐Usmar, Young-il Kim, Jaroslaw W. Zmijewski, Jessy S. Deshane, Stijn De Langhe, Victor J. Thannickal
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.