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

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.

Paracrine Regulation of Alveolar Epithelial Damage and Repair Responses by Human Lung-Resident Mesenchymal Stromal Cells

“…To the best of our knowledge, we are the first to demonstrate that human lung-derived MSCs reduce human epithelial cell damage and promote alveolar epithelial regenerative responses. In a murine setting, it was shown that LMSCs promote the self-organizing capacity of alveolar epithelial progenitors in organoids, in which LMSCs of aged mice were impaired [ 25 ]. Murine BM-MSCs and their conditioned media are able to support distal lung epithelium-derived organoid formation and increase alveolar differentiation [ 26 ].…”

The secretion profile of mesenchymal stem cells and potential applications in treating human diseases

“… 76 In the organoid model of alveolospheres, aged lung MSCs have higher levels of NADPH oxidase 4(NOX4) to produce oxidants and acquire senescence-associated secretory phenotype, so that they lose the normal 3D structure with type 2 alveolar epithelial cells. 77 The senescent MSCs appeared to be less potent in tissue protection than the young ones, due to insufficient production of growth factors and chemokines. 78 Therefore, senescent MSCs deploy a more blunted secreting response to the activated immune cells compared to young MSCs, but IFNγ could partly restore the immunosuppressive deficiency of senescent ones.…”

Pre‐clinical evidence of a dual NADPH oxidase 1/4 inhibitor (setanaxib) in liver, kidney and lung fibrosis

“…10,54 Cellular senescence is also thought to contribute to the pathology of lung fibrosis, in which senescent cells secrete senescence-associated secretory phenotype factors to promote inflammation, tissue remodelling and cell growth. 10,56,57 NOX1 is expressed in a range of pulmonary cell types, including pulmonary epithelial cells, pulmonary vascular smooth muscle cells and bronchial epithelial cells. 58 NOX4 is expressed in macrophages, smooth muscle cells, endothelial cells, mesenchymal cells and epithelial cells.…”

“…Immune cells in turn amplify inflammatory signalling and contribute to fibrosis development by exacerbating myofibroblast differentiation and ECM deposition 10,54 . Cellular senescence is also thought to contribute to the pathology of lung fibrosis, in which senescent cells secrete senescence‐associated secretory phenotype factors to promote inflammation, tissue remodelling and cell growth 10,56,57 …”