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Research Paper|Volume 11, Issue 11|pp 3505—3522

Nicotinamide phosphoribosyltransferase postpones rat bone marrow mesenchymal stem cell senescence by mediating NAD+–Sirt1 signaling

Chenchen Pi1,2, Yue Yang1,3, Yanan Sun1, Huan Wang1, Hui Sun1, Mao Ma1,4, Lin Lin1, Yingai Shi1, Yan Li5, Yulin Li1, Xu He1
  • 1The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
  • 2The First Hospital, Jilin University, Changchun, Jilin 130021, China
  • 3Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China
  • 4Department of Pathology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
  • 5Division of Orthopedics and Biotechnology, Department for Clinical Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
* Equal contribution
Received: September 25, 2018Accepted: May 22, 2019Published: June 7, 2019
https://doi.org/10.18632/aging.101993

Copyright: Pi et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

In vitro replicative senescence affects MSC characteristics and functionality, thus severely restricting their application in regenerative medicine and MSC-based therapies. Previously, we found that MSC natural senescence is accompanied by altered intracellular nicotinamide adenine dinucleotide (NAD+) metabolism, in which Nampt plays a key role. However, whether Nampt influences MSC replicative senescence is still unclear. Our study showed that Nampt expression is down-regulated during MSC replicative senescence. Nampt depletion via a specific Nampt inhibitor FK866 or Nampt knockdown in early passage MSCs led to enhanced senescence as indicated by senescence-like morphology, reduced proliferation, and adipogenic and osteogenic differentiation, and increased senescence-associated-β-galactosidase activity and the expression of the senescence-associated factor p16INK4a. Conversely, Nampt overexpression ameliorated senescence-associated phenotypic features in late passage MSCs. Further, Nampt inhibition resulted in reduced intracellular NAD+ content, NAD+/NADH ratio, and Sirt1 activity, whereas overexpression had the opposite effects. Exogenous intermediates involved in NAD+ biosynthesis not only rescued replicative senescent MSCs but also alleviated FK866-induced MSC senescence. Thus, Nampt suppresses MSC senescence via mediating NAD+-Sirt1 signaling. This study provides novel mechanistic insights into MSC replicative senescence and a promising strategy for the severe shortage of cells for MSC-based therapies.