Mesenchymal stromal cell aging impairs the self-organizing capacity of lung alveolar epithelial stem cells

eLife

Kyoko Kojima¹  James A Mobley²  Gloria A Benavides³  Victor Darley-Usmar³  Diptiman Chanda⁴  Jaroslaw W Zmijewski⁴  Jessy S Deshane⁴  Stijn De Langhe⁴  Yong Wang⁴  Samuel R Smith⁴  Kevin G Dsouza⁴  Deepali Kurundkar⁴  Karen Bernard⁴  Vinayak Memula⁵  Young-iL Kim⁶  Victor J Thannickal⁷  Mohammad Rehan⁷ 

[1] Comprehensive Cancer Center Mass Spectrometry & Proteomics Shared Facility, Birmingham, United States;Department of Anesthesiology and Perioperative Medicine, Birmingham, United States;Department of Pathology, Birmingham, United States;Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Birmingham, United States;Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Birmingham, United States;Department of Surgery, Birmingham, United States;Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Birmingham, United States;Division of Preventive Medicine, Department of Medicine; University of Alabama at Birmingham, Birmingham, United States;John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, United States;

关键词: Aging;    senescence;    mesenchymal stromal cells;    epithelial stem cells;    oxidative stress;    regeneration;    Mouse;   

DOI  :  10.7554/eLife.68049

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY