AICAR and nicotinamide treatment synergistically augment the proliferation and attenuate senescence-associated changes in mesenchymal stromal cells

Stem Cell Research & Therapy

Mohammadreza Dorvash¹  Armin Attar²  Ahmad Monabati³  Mohammad Ali Faghihi⁴  Malihe Mirzaei⁴  Mohammadhossein Khorraminejad-Shirazi⁵  Mahsa Sani⁶  Tahereh Talaei-Khozani⁷ 

[1] Cell and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences;Department of Cardiovascular Medicine, Shiraz University of Medical Sciences;Department of Pathology, School of Medicine, Shiraz University of Medical Sciences;Persian BayanGene Research and Training Center, Shiraz University of Medical Sciences;Student Research Committee, Shiraz University of Medical Sciences;Tissue Engineering Department, School of Advanced Medical Science and Technology, Shiraz University of Medical Science;Tissue Engineering Lab, Department of Anatomical Sciences, School of Medicine, Shiraz University of Medical Sciences;

关键词: mTOR;    AMPK;    SIRT1;    Autophagy;    Senescence;    AICAR;   

DOI  :  10.1186/s13287-020-1565-6

来源: DOAJ

【 摘 要 】

Abstract Background Mesenchymal stromal cell (MSC) stemness capacity diminishes over prolonged in vitro culture, which negatively affects their application in regenerative medicine. To slow down the senescence of MSCs, here, we have evaluated the in vitro effects of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator, and nicotinamide (NAM), an activator of sirtuin1 (SIRT1). Methods Human adipose-derived MSCs were cultured to passage (P) 5. Subsequently, the cells were grown in either normal medium alone (control group), the medium supplemented with AICAR (1 mM) and NAM (5 mM), or in the presence of both for 5 weeks to P10. Cell proliferation, differentiation capacity, level of apoptosis and autophagy, morphological changes, total cellular reactive oxygen species (ROS), and activity of mTORC1 and AMPK were compared among different treatment groups. Results MSCs treated with AICAR, NAM, or both displayed an increase in proliferation and osteogenic differentiation, which was augmented in the group receiving both. Treatment with AICAR or NAM led to decreased expression of β-galactosidase, reduced accumulation of dysfunctional lysosomes, and characteristic morphologic features of young MSCs. Furthermore, while NAM administration could significantly reduce the total cellular ROS in aged MSCs, AICAR treatment did not. Moreover, AICAR-treated cells possess a high proliferation capacity; however, they also show the highest level of cellular apoptosis. The observed effects of AICAR and NAM were in light of the attenuated mTORC1 activity and increased AMPK activity and autophagy. Conclusions Selective inhibition of mTORC1 by AICAR and NAM boosts autophagy, retains MSCs’ self-renewal and multi-lineage differentiation capacity, and postpones senescence-associated changes after prolonged in vitro culture. Additionally, co-administration of AICAR and NAM shows an additive or probably a synergistic effect on cellular senescence.

【 授权许可】

Unknown