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 - Funding Information:
We thank Dr. Tingting Yuan for assistance with preparing paraffin blocks and cutting histological sections. We thank Dr. Robert Grabski and Mr. Shawn Williams for their assistance with confocal imaging at the High Resolution Imaging Facility at the University of Alabama at Birmingham (UAB). We also thank Dr. Stephen Barnes, Dr. Landon Wilson, and Mr. Taylor Berryhill at the Targeted Proteomics & Metabolomics Lab, UAB, for their assistance with measuring TCA cycle metabolites. This work was supported by NIH grants P01 HL114470, R01 AG046210, and R01 HL152246; and by VA Merit Award I01BX003056 (to VJT). DC is supported by NIH/NHLBI grant R01 HL139617 (to JZ and VJT); JAM is supported by NIH/NCI grant P30 CA013148; JSD is supported by NIH grants R01 HL128502 and P42 ES027723.
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 -