Affiliation:
1. Qingdao University
2. Weifang People’s Hospital
3. The Affiliated Hospital of Qingdao University
4. Institute of Basic Medical Sciences Chinese Academy of Medical Sciences
Abstract
AbstractBackgroundThe senescence of mesenchymal stem cells (MSCs) greatly compromises their therapeutic effect in regenerative medicine. Numerous studies are focusing on possible rejuvenation strategies to enhance the efficacy of autologous MSC-based therapy. S-adenosyl-L-methionine (SAM) is a metabolite present in all living cells. However, there is little research about the effects and mechanisms of SAM on the senescence of MSCs.MethodsIn this study, the effects of SAM on adipose-derived MSC (ADSC) senescence were assessed in vitro by β-galactosidase staining, reactive oxygen species assay, cell cycle tests, and Western blot. The osteogenic and adipogenic differentiation ability changes were also detected. Mouse models of premature aging were established by subcutaneous injection of D-Galactose (D-gal). The in vivo antiaging roles of SAM were tested through behavioral tests, organ coefficient, pathological morphology, and the expression of aging-related proteins in the major organs, such as the heart, liver, and kidney. The bone density of the distal femur, as well as the volume, number, and thickness of bone trabecula were evaluated by micro-CT. The molecular mechanisms were searched and validated by transcriptome sequencing, Western blot, and immunofluorescence. Small RNA interfering was used to knock down FOXO3a.ResultsIn oxidative stress–induced senescent ADSCs, SAM ameliorated the cell cycle arrest, reduced β-galactosidase activity, inhibited the expression of P53 and P21, and restored the expression of SIRT1, which significantly improved biological function. In addition, SAM also reduced the level of ROS and promoted the adipogenic and osteogenic differentiation of senescent ADSCs. Moreover, in a D-gal-induced mouse model of aging, SAM improved exercise ability and heart, liver, and kidney aging in mice. Additionally, the number and thickness of the bone trabeculae in the distal femur of the mice were increased. Transcriptome sequencing results revealed that PI3K/AKT was involved in SAM-mediated anti-senescence effects on MSCs. Mechanistically, SAM activated PI3K/AKT signaling and increased the phosphorylation of FOXO3a, resulting in a decrease in the translocation of FOXO3a to the nucleus and the inhibition of the FOXO3a activity on P21. Ultimately, this attenuated the senescence of ADSCs and improved their differentiation potential.ConclusionsIn summary, our results suggested that SAM could ameliorate the senescence of MSCs in vitro through PI3K/AKT/FOXO3a signaling. Meanwhile, SAM could also exert antiaging roles in vivo.
Publisher
Research Square Platform LLC