TY - JOUR
T1 - Mesenchymal stromal cell aging impairs the self-organizing capacity of lung alveolar epithelial stem cells
AU - Chanda, Diptiman
AU - Rehan, Mohammad
AU - Smith, Samuel R.
AU - Dsouza, Kevin G.
AU - Wang, Yong
AU - Bernard, Karen
AU - Kurundkar, Deepali
AU - Memula, Vinayak
AU - Kojima, Kyoko
AU - Mobley, James A.
AU - Benavides, Gloria A.
AU - Darley-Usmar, Victor
AU - Kim, Young Il
AU - Zmijewski, Jaroslaw W.
AU - Deshane, Jessy S.
AU - De Langhe, Stijn
AU - Thannickal, Victor J.
N1 - Publisher Copyright:
© Chanda et al.
PY - 2021/9
Y1 - 2021/9
N2 - Multicellular organisms maintain structure and function of tissues/organs through emer-gent, 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 bioen-ergetics and redox homeostasis in an organoid model of self-organization and support the concept of thermodynamic entropy in aging biology.
AB - Multicellular organisms maintain structure and function of tissues/organs through emer-gent, 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 bioen-ergetics and redox homeostasis in an organoid model of self-organization and support the concept of thermodynamic entropy in aging biology.
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U2 - 10.7554/eLife.68049
DO - 10.7554/eLife.68049
M3 - Article
C2 - 34528872
AN - SCOPUS:85116374946
SN - 2050-084X
VL - 10
JO - eLife
JF - eLife
M1 - e68049
ER -