Figure 3.

Signalling pathways and transcription factors involved in MSC senescence. Three major pathways contribute to the senescence of MSCs: Sirtuins/NAD+, AKT/mTOR, and Wnt/β-catenin and some transcription factors. The Sirtuin family of NAD-dependent protein deacetylases affects the functioning and metabolism of MSCs. SIRT1, SIRT6, and SIRT7 are found in the nucleus, SIRT2 is found in the cytoplasm, and SIRT3, SIRT4, and SIRT5 are found in the mitochondria. The knockout of Sirtuin induces the senescence of MSCs and inhibits their proliferation. ROS and other pro-senescence factors activate the p53-p21 and p16INK4A cell cycle arrest pathways. Consequently, retinoblastoma protein (Rb) is maintained in a hypophosphorylated state, which suppresses the expression of S-phase genes. AKT/mTOR signaling activates the p53/p21 and Rb/p16 pathways to block cell cycle progression and maintain an arrest in cell growth. Wnt/β-catenin signaling can lead to MSC senescence by promoting the production of intracellular ROS. Oxidative stress-associated β-catenin downregulation is involved in MSC senescence during aging. SRIT, Sirtuin; ROS, reactive oxygen species; mTOR, mammalian target of rapamycin; NAD+, oxidized nicotinamide adenine dinucleotide; NMN, nicotinamide mononucleotide; NAM, nicotinamide; Nampt, nicotinamide phosphoribosyltransferase; NAMPT, nicotinamide phosphoribosyltransferase; NMNAT, Nicotinamide mononucleotide adenylyltransferase.