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TRAF3IP2 drives mesenchymal stem cell senescence via regulation of NAMPT-mediated NAD biosynthesis.

ABSTRACT: The cellular senescence of mesenchymal stem cells (MSCs) limits their application in regenerative medicine. This study aimed to clarify the role of TNF receptor-associated factor 3 interacting protein 2 (TRAF3IP2), a pro-inflammatory cytoplasmic adaptor protein, in regulating MSC senescence and to explore the potential mechanisms. Methods: MSC senescence was determined by senescence-associated β-galactosidase (SA-β-gal) staining. The expression of TRAF3IP2 and senescence-related proteins was detected by Western blotting. The nicotinamide adenine dinucleotide (NAD+) level and nicotinamide phosphoribosyl transferase (NAMPT) expression in MSCs was measured. Results: Compared with that in MSCs isolated from young donors (YMSCs), the expression of TRAF3IP2 was greatly increased in MSCs derived from aged donors (AMSCs). Overexpression of TRAF3IP2 accelerated YMSC senescence whereas downregulation significantly rescued cellular senescence. The protein level of NAMPT and the level of NAD+ were significantly decreased in AMSCs compared with YMSCs. Mechanistically, TRAF3IP2 induced MSC senescence via downregulation of NAMPT expression and NAD + level by inhibiting the AMPK signaling pathway. These effects were partially reversed by treatment with an AMPK or NAMPT activator. Conclusion: We revealed that TRAF3IP2 accelerated MSC senescence via downregulation of NAMPT-mediated NAD biosynthesis by mediation of the AMPK pathway, highlighting a novel means to rejuvenate senescent MSCs.

SUBMITTER: Huang X

PROVIDER: S-EPMC10558736 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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TRAF3IP2 drives mesenchymal stem cell senescence via regulation of NAMPT-mediated NAD biosynthesis.

Huang Xiaoran X Liu Baojuan B Liang Yaowen Y Mai Cong C Shen Ying Y Huang Xinran X Chen Jiaqi J Liang Xiaoting X Hu Bei B Li Weifeng W Li Xin X Zhang Yuelin Y

Heliyon 20230829 9

The cellular senescence of mesenchymal stem cells (MSCs) limits their application in regenerative medicine. This study aimed to clarify the role of TNF receptor-associated factor 3 interacting protein 2 (TRAF3IP2), a pro-inflammatory cytoplasmic adaptor protein, in regulating MSC senescence and to explore the potential mechanisms. <b>Methods</b>: MSC senescence was determined by senescence-associated β-galactosidase (SA-β-gal) staining. The expression of TRAF3IP2 and senescence-related proteins ...[more]

PMID: 37809895

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Project description:ObjectiveThe ability of adipose tissue to expand and contract in response to fluctuations in nutrient availability is essential for the maintenance of whole-body metabolic homeostasis. Given the nutrient scarcity that mammals faced for millions of years, programs involved in this adipose plasticity were likely evolved to be highly efficient in promoting lipid storage. Ironically, this previously advantageous feature may now represent a metabolic liability given the caloric excess of modern society. We speculate that nicotinamide adenine dinucleotide (NAD+) biosynthesis exemplifies this concept. Indeed NAD+/NADH metabolism in fat tissue has been previously linked with obesity, yet whether it plays a causal role in diet-induced adiposity is unknown. Here we investigated how the NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) supports adipose plasticity and the pathological progression to obesity.MethodsWe utilized a newly generated Nampt loss-of-function model to investigate the tissue-specific and systemic metabolic consequences of adipose NAD+ deficiency. Energy expenditure, glycemic control, tissue structure, and gene expression were assessed in the contexts of a high dietary fat burden as well as the transition back to normal chow diet.ResultsFat-specific Nampt knockout (FANKO) mice were completely resistant to high fat diet (HFD)-induced obesity. This was driven in part by reduced food intake. Furthermore, HFD-fed FANKO mice were unable to undergo healthy expansion of adipose tissue mass, and adipose depots were rendered fibrotic with markedly reduced mitochondrial respiratory capacity. Yet, surprisingly, HFD-fed FANKO mice exhibited improved glucose tolerance compared to control littermates. Removing the HFD burden largely reversed adipose fibrosis and dysfunction in FANKO animals whereas the improved glucose tolerance persisted.ConclusionsThese findings indicate that adipose NAMPT plays an essential role in handling dietary lipid to modulate fat tissue plasticity, food intake, and systemic glucose homeostasis.

Project description:As the proportion of the elderly population grows rapidly, the senescence-delaying effects of Traditional Chinese Medicine is being investigated. The aim of the present study was to investigate the senescence-delaying effects of saffron in naturally aging mice. The active ingredients in an aqueous saffron extract were determined using high-performance liquid chromatography (HPLC). Mice were divided into saffron (8- and 16-months-old) and control groups (3-, 8-, and 16-months-old), and saffron extract was administered to the former groups for 8 weeks. The open field test and Barnes maze test were used to evaluate the locomotor activity, learning and memory function of the mice. The levels of inflammatory factors in the brain were determined by ELISA. In addition, the activities of acetylcholinesterase (AChE) and superoxide dismutase, and the contents of malondialdehyde and nicotinamide adenine dinucleotide (NAD+) were detected by enzyme immunoassay, and the content of NAMPT was detected by ELISA, western blotting and reverse transcription-quantitative PCR. The cellular distribution of NAMPT and synaptic density were evaluated by immunofluorescence, and the pathological morphologies of the liver, skin, kidneys were observed by hematoxylin and eosin staining. HPLC revealed that the crocin and picrocrocin contents of the saffron extract were 19.56±0.14 and 12.00±0.13%, respectively. Saffron exhibited the potential to improve the learning and memory function in aging mice as it increased synaptic density and decreased AChE activity. Also, saffron ameliorated the pathological changes associated with organ aging, manifested by increasing the number of hepatocytes and the thickness of the skin, and preventing the aging-induced ballooning and bleeding in the kidneys. Furthermore, saffron increased the contents of NAMPT and NAD+ in the brain and decreased the content of NAMPT in the serum. In addition, it changed the cellular distribution of NAMPT in aging mice, manifested as reduced NAMPT expression in microglia and astrocytes, and increased NAMPT expression in neurons. Saffron also decreased the contents of proinflammatory cytokines and oxidative stress factors in aging mice. Altogether, these findings indicate that saffron exerts senescence-delaying effects in naturally aging mice, which may be associated with the NAMPT-NAD+ pathway.

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TRAF3IP2 drives mesenchymal stem cell senescence via regulation of NAMPT-mediated NAD biosynthesis.

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TRAF3IP2 drives mesenchymal stem cell senescence via regulation of NAMPT-mediated NAD biosynthesis.

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