Abstract
Aging is a predominant risk factor for many chronic conditions. Stem cell dysfunction plays a pivotal role in the aging process. Prelamin A, an abnormal processed form of the nuclear lamina protein lamin A, has been reported to trigger premature senescence. However, the mechanism driving stem cell dysfunction is still unclear. In this study, we found that while passaging subchondral bone mesenchymal stem cells (SCB-MSCs) in vitro, prelamin A accumulation occurred concomitantly with an increase in senescence-associated β-galactosidase (SA-β-Gal) expression. Unlike their counterparts, SCB-MSCs with prelamin A overexpression (MSC/PLA) demonstrated decreased proliferation, osteogenesis, and adipogenesis but increased production of inflammatory factors. In a hind-limb ischemia model, MSC/PLA also exhibited compromised therapy effect. Further investigation showed that exogenous prelamin A triggered abnormal nuclear morphology, DNA and shelterin complex damage, cell cycle retardation, and eventually cell senescence. Changes in gene expression profile were also verified by microarray assay. Interestingly, we found that ascorbic acid or vitamin C (VC) treatment could inhibit prelamin A expression in MSC/PLA and partially reverse the premature aging in MSC/PLA, with reduced secretion of inflammatory factors and cell cycle arrest and resistance to apoptosis. Importantly, after VC treatment, MSC/PLA showed enhanced therapy effect in the hind-limb ischemia model. In conclusion, prelamin A can accelerate SCB-MSC premature senescence by inducing DNA damage. VC can be a potential therapeutic reagent for prelamin A-induced aging defects in MSCs.
Highlights
Aging is defined as a progressive deterioration of an organism’s physiological functions
We found that vitamin C (VC) treatment could rescue prelamin A-induced premature senescence of SCB-MSCs
Overexpression of prelamin A induced abnormal nuclear morphology, a decrease in expression of the shelterin complex, accelerated DNA damage, and cell cycle arrest leading to SCB-MSCs senescence
Summary
Aging is defined as a progressive deterioration of an organism’s physiological functions. Aging is a predominant risk factor for many chronic conditions, including atherosclerosis, cancer, and neurodegenerative and metabolic syndromes, which increases susceptibility to death [1]. Stem cells retain the capacity to differentiate into the cell types of their constituent tissues and contribute to regeneration and homeostasis [2]. Stem cell exhaustion is associated with the decline in the regenerative potential capacity linked to the accumulation of age-associated damage [3]. Recent studies have shown that targeting cellular senescence prevents age-related disease in animal models [4,5,6,7,8]. It is crucial to understand the mechanisms of stem cell senescence in order to prevent aging
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