Nicotinamide mononucleotide promotes osteogenesis and reduces adipogenesis by regulating mesenchymal stromal cells via the SIRT1 pathway in aged bone marrow

Jie Song,Qi Zhang,Gang Ning,Yongyuan Zheng,Chan Xie,Liang Peng,Jing Li,Fangji Yang,Limin Zhen,Lina Wu,Dongjun Lin

doi:10.1038/s41419-019-1569-2

Abstract

Mesenchymal stromal cells (MSCs) can differentiate to various cell types including osteoblasts, chondrocytes, and adipocytes. This cellular flexibility contributes to widespread clinical use of MSCs in tissue repair. However, challenges remain in efficient cellular expansion of MSCs for stem cell therapy. Current MSC culture methods have resulted in reduced self-renewal of MSCs and compromised therapeutic outcomes. This study identifies that nicotinamide mononucleotide (NMN), a key natural NAD+ intermediate, effectively encourages MSC expansion in vitro and in vivo. The in vitro expanded MSCs had heightened osteogenesis, but reduced adipogenesis. Furthermore, NMN supplementation stimulated osteogenesis of endogenous MSCs, and protected bone from aging and irradiation induced damage in mice. Mechanistically, we found that NMN treatment upregulated SIRT1. Genetically overexpressing SIRT1 in MSCs by using Prx1 cre; ColA1flox-stop-flox-SIRT1 mice promoted osteogenesis and reduced adipogenesis in aged mice. Overall, our data demonstrate that NMN promoted MSC self-renewal with strengthened osteogenesis and reduced adipogenesis via upregulating SIRT1 in aged mice.

Highlights

Aging is predicted to be an increasingly serious health and financial problem worldwide[1]
mesenchymal stromal cells (MSCs) in vitro, we performed the Colony-forming unit-fibroblast (CFU-F) assay using enzymatically digested mouse bone marrow (BM) cells administered with NMN (Fig. 1a)
The results showed that the CFU-F frequency increased in response to NMN administration in a dosage dependent manner (0.08–2.25 μM) (Fig. 1b, c) and reached the maximum at the concentrations between 0.75 and 2.25 μM

Summary

Introduction

Aging is predicted to be an increasingly serious health and financial problem worldwide[1]. Age-related disorders, such as tumor[2,3], metabolic disease[4], memory deterioration[5], and immunologic degeneration[6], are associated with declined regenerative capacity in rapidly dividing stem cells[7]. NMN administration alleviates age-related type 2 diabetes, ischemia-reperfusion injury, and Alzheimer’s disease[11,12]. We explored NMN’s role in combating age-related disorders via regulating mesenchymal stromal cells (MSCs). MSCs are nonhematopoietic multipotent stem cells with regeneration capacity[13]. Loss in number or functionality of MSCs with age profoundly limits tissue regeneration[14], most current MSC culture methods limits selfrenewal potential and functionality of MSCs, leading to compromised therapeutic outcomes[10,15]

Methods

Results

Conclusion