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

Xiaoran Huang; Baojuan Liu; Yaowen Liang; Cong Mai; Ying Shen; Xinran Huang; Jiaqi Chen; Xiaoting Liang; Bei Hu; Weifeng Li; Xin Li; Yuelin Zhang

doi:10.1016/j.heliyon.2023.e19505

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

Heliyon. 2023 Aug 29;9(9):e19505. doi: 10.1016/j.heliyon.2023.e19505. eCollection 2023 Sep.

Authors

Xiaoran Huang¹, Baojuan Liu¹, Yaowen Liang^{1

2}, Cong Mai¹, Ying Shen¹, Xinran Huang¹, Jiaqi Chen¹, Xiaoting Liang³, Bei Hu¹, Weifeng Li¹, Xin Li¹, Yuelin Zhang¹

Affiliations

¹ Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.
² Medical College, Shantou University, Shantou, Guangdong, China.
³ Institute of Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

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.

Keywords: Mesenchymal stem cells; NAD+; NAMPT; Senescence; TRA3IP2.