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.
Highlights
Substantial progress has been made in our understanding of the biology of aging, and these advances have the potential to improve both healthspan and lifespan, while alleviating the burden of age- related diseases
lung mesenchymal stromal cell (L-M SC) and AEC2s are mixed together in a ratio of 100,000–5000, respectively, and seeded in Matrigel (Figure 1A); alveolospheres with a single layer of epithelial cells composed of both AEC2s and AEC1s surrounding a hollow sphere typically form 9–12 days following co-c ulture (Figure 1B and C)
L-M SCs expressing platelet-d erived growth factor receptor-α (PDFGRα), with a fewer number expressing α-smooth muscle actin (α-SMA), were found primarily in cells lining the outer edges of alveolospheres (Figure 1D and E)
Summary
Substantial progress has been made in our understanding of the biology of aging, and these advances have the potential to improve both healthspan and lifespan, while alleviating the burden of age- related diseases. Stem Cells and Regenerative Medicine eLife digest Many tissues in the body are capable of regenerating by replacing defective or worn-out cells with new ones This process relies heavily on stem cells, which are precursor cells that lack a set role in the body and can develop into different types of cells under the right conditions. Chanda et al probed AEC2s and L-MSCs in the alveoli of young and old mice The researchers collected both cell types from young (2-3 months) and aged (22-24 months) mice. Reducing Nox levels in aged L-MSCs allowed these cells to form normal 3D structures with young AEC2 cells, but not aged AEC2 cells These findings highlight the varying effects specific stem cells have, and how their behaviour is affected by pro-aging factors. Account for age-related phenotypes; through these studies, we identify cellular bioenergetics and redox imbalance as critical drivers of these inter-dependent aging hallmarks
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