Abstract
Mesenchymal stem cells (MSCs) senescence is an age-related process that impairs the capacity for tissue repair and compromises the clinical use of autologous MSCs for tissue regeneration. Here, we describe the effects of SIRT1, a NAD+-dependent deacetylase, on age-related MSCs senescence. Knockdown of SIRT1 in young MSCs induced cellular senescence and inhibited cell proliferation whereas overexpression of SIRT1 in aged MSCs reversed the senescence phenotype and stimulated cell proliferation. These results suggest that SIRT1 plays a key role in modulating age-induced MSCs senescence. Aging-related proteins, P16 and P21 may be downstream effectors of the SIRT1-mediated anti-aging effects. SIRT1 protected MSCs from age-related DNA damage, induced telomerase reverse transcriptase (TERT) expression and enhanced telomerase activity but did not affect telomere length. SIRT1 positively regulated the expression of tripeptidyl peptidase 1 (TPP1), a component of the shelterin pathway that protects chromosome ends from DNA damage. Together, the results demonstrate that SIRT1 quenches age-related MSCs senescence by mechanisms that include enhanced TPP1 expression, increased telomerase activity and reduced DNA damage.
Highlights
Mesenchymal stem cells (MSCs) are thought to play important roles in tissue regeneration and repair
In the present study, we aimed to investigate: first, whether the aging process of MSCs is associated with a downregulated expression of SIRT1 and whether over-expression of SIRT1 would reverse the phenotype of the age-related MSCs senescence; second, whether cyclin-dependent kinase (CDK) regulators, including P16INK4A (P16) and P21WAF1 (P21) are involved in the aging process of MSCs and act as the key mediators of SIRT1 activity through which tripeptidyl peptidase 1 (TPP1) plays the key roles in mediating telomerase function and protects against DNA damage
These findings reveal the existence of age-related upregulated cellular senescence in MSCs, which is evidenced by a down-regulated cellular proliferation rate
Summary
Mesenchymal stem cells (MSCs) are thought to play important roles in tissue regeneration and repair This can be handicapped by age-dependent MSCs senescence and loss of function. Aging negatively affects MSCs proliferation and differentiation including osteogenesis and chondrogenesis (Stolzing et al, 2008; Zhou et al, 2008; Alt et al, 2012) These aging-induced loss of MSCs number and function may be related to the fact that the population of senescent cells shows an age-dependent increase in the stem cell pool (Stolzing et al, 2008; Zhou et al, 2008; Alt et al, 2012). Recent studies indicate that cellular senescence might inhibit cancer early in life but drive age-related phenotypes and associated pathologies later in life (Campisi, 2013; Sikora, 2013). It could potentially provide solutions to reverse or prevent MSCs aging processes
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