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.

中文翻译：

---

维生素C治疗可挽救Prelamin A诱导的软骨下骨间充质干细胞的过早衰老。

衰老是许多慢性疾病的主要危险因素。干细胞功能障碍在衰老过程中起关键作用。据报道，Prelamin A是核纤层蛋白Lamin A的异常加工形式，可触发早衰。但是，驱动干细胞功能障碍的机制仍不清楚。在这项研究中，我们发现，尽管在传代软骨下骨间充质干细胞（SCB-MSCS）在体外，prelamin一个积累与增加衰老相关随之发生β半乳糖苷酶（SA- β-Gal）表达。与它们的对应物不同，具有prelamin A过表达（MSC / PLA）的SCB-MSC表现出增殖，成骨和脂肪形成减少，但炎症因子产生增加。在后肢缺血模型中，MSC / PLA也表现出受损的治疗效果。进一步的研究表明，外源性prelamin A引发异常的核形态，DNA和庇护蛋白复合物损伤，细胞周期阻滞，并最终导致细胞衰老。基因表达谱的变化也通过微阵列测定法得到证实。有趣的是，我们发现抗坏血酸或维生素C（VC）处理可以抑制MSC / PLA中prelamin A的表达，并部分逆转MSC / PLA中的过早衰老，从而减少炎症因子的分泌和细胞周期停滞以及对细胞凋亡的抵抗力。重要的是，经过VC治疗后，MSC / PLA在后肢缺血模型中显示出增强的治疗效果。总之，prelamin A可以通过诱导DNA损伤来加速SCB-MSC的过早衰老。VC可能是针对Prelamin A诱导的MSC衰老缺陷的潜在治疗剂。