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Exogenous NAD⁺ Postpones the D-Gal-Induced Senescence of Bone Marrow-Derived Mesenchymal Stem Cells via Sirt1 Signaling.

ABSTRACT: Cell senescence is accompanied by decreased nicotinamide adenine dinucleotide (NAD⁺) levels; however, whether exogenous NAD⁺ affects bone marrow-derived mesenchymal stem cells (BMSCs) senescence and the involved mechanisms is still unclear. Here, we find that exogenous NAD⁺ replenishment significantly postpones BMSC senescence induced by D-galactose (D-gal). It is also shown that exogenous NAD⁺ leads to increased intracellular NAD⁺ levels and reduced intracellular reactive oxygen species in senescent BMSCs here. Further investigation showed that exogenous NAD⁺ weakened BMSC senescence by increasing Sirtuin 1 (Sirt1) expression. Moreover, exogenous NAD⁺ reduced senescence-associated-?-galactosidase activity, and downregulated poly (ADP-ribose) polymerase 1 expression. In addition, the reduced expression of Sirt1 by small interfering RNA abolished the beneficial effects of exogenous NAD⁺ in terms of postponing BMSCs senescence induced by D-gal. Taken together, our results indicate that exogenous NAD⁺ could postpone D-gal-induced BMSC senescence through Sirt1 signaling, providing a potential method for obtaining high quality BMSCs to support their research and clinical application.

SUBMITTER: Wang J

PROVIDER: S-EPMC7915830 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Exogenous NAD+ Postpones the D-Gal-Induced Senescence of Bone Marrow-Derived Mesenchymal Stem Cells via Sirt1 Signaling.

Wang Jie J Liu Lin L Ding Zhongjie Z Luo Qing Q Ju Yang Y Song Guanbin G

Antioxidants (Basel, Switzerland) 20210207 2

Cell senescence is accompanied by decreased nicotinamide adenine dinucleotide (NAD+) levels; however, whether exogenous NAD+ affects bone marrow-derived mesenchymal stem cells (BMSCs) senescence and the involved mechanisms is still unclear. Here, we find that exogenous NAD+ replenishment significantly postpones BMSC senescence induced by D-galactose (D-gal). It is also shown that exogenous NAD+ leads to increased intracellular NAD+ levels an ...[more]

PMID: 33562281

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Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic lung disease for which age is the most important risk factor. Different mechanisms associated with aging, including stem cell dysfunction, have been described to participate in the pathophysiology of IPF. We observed an extrapulmonary effect associated with IPF: increase in cell senescence of bone marrow-derived mesenchymal stem cells (B-MSCs).MethodsB-MSCs were obtained from vertebral bodies procured from IPF patients and age-matched normal controls. Cell senescence was determined by cell proliferation and expression of markers of cell senescence p16INK4A, p21, and β-galactosidase activity. Mitochondrial function and DNA damage were measured. Paracrine induction of senescence and profibrotic responses were analyzed in vitro using human lung fibroblasts. The reparative capacity of B-MSCs was examined in vivo using the bleomycin-induced lung fibrosis model.ResultsIn our study, we demonstrate for the first time that B-MSCs from IPF patients are senescent with significant differences in mitochondrial function, with accumulation of DNA damage resulting in defects in critical cell functions when compared with age-matched controls. Senescent IPF B-MSCs have the capability of paracrine senescence by inducing senescence in normal-aged fibroblasts, suggesting a possible link between senescent B-MSCs and the late onset of the disease. IPF B-MSCs also showed a diminished capacity to migrate and were less effective in preventing fibrotic changes observed in mice after bleomycin-induced injury, increasing illness severity and proinflammatory responses.ConclusionsWe describe extrapulmonary alterations in B-MSCs from IPF patients. The consequences of having senescent B-MSCs are not completely understood, but the decrease in their ability to respond to normal activation and the risk of having a negative impact on the local niche by inducing inflammation and senescence in the neighboring cells suggests a new link between B-MSC and the onset of the disease.

Dataset Information

Exogenous NAD⁺ Postpones the D-Gal-Induced Senescence of Bone Marrow-Derived Mesenchymal Stem Cells via Sirt1 Signaling.

Publications

Exogenous NAD<sup>+</sup> Postpones the D-Gal-Induced Senescence of Bone Marrow-Derived Mesenchymal Stem Cells via Sirt1 Signaling.

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