Department of Emergency Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, Guangdong, China.
Cell Death Dis. 2020 Dec 15;11(12):1075. doi: 10.1038/s41419-020-03289-w.
Mesenchymal stem cell (MSC)-based therapy has emerged as a novel strategy to treat many degenerative diseases. Accumulating evidence shows that the function of MSCs declines with age, thus limiting their regenerative capacity. Nonetheless, the underlying mechanisms that control MSC ageing are not well understood. We show that compared with bone marrow-MSCs (BM-MSCs) isolated from young and aged samples, NADH dehydrogenase (ubiquinone) iron-sulfur protein 6 (Ndufs6) is depressed in aged MSCs. Similar to that of Ndufs6 knockout (Ndufs6) mice, MSCs exhibited a reduced self-renewal and differentiation capacity with a tendency to senescence in the presence of an increased p53/p21 level. Downregulation of Ndufs6 by siRNA also accelerated progression of wild-type BM-MSCs to an aged state. In contrast, replenishment of Ndufs6 in Ndufs6-BM-MSCs significantly rejuvenated senescent cells and restored their proliferative ability. Compared with BM-MSCs, Ndufs6-BM-MSCs displayed increased intracellular and mitochondrial reactive oxygen species (ROS), and decreased mitochondrial membrane potential. Treatment of Ndufs6-BM-MSCs with mitochondrial ROS inhibitor Mito-TEMPO notably reversed the cellular senescence and reduced the increased p53/p21 level. We provide direct evidence that impairment of mitochondrial Ndufs6 is a putative accelerator of adult stem cell ageing that is associated with excessive ROS accumulation and upregulation of p53/p21. It also indicates that manipulation of mitochondrial function is critical and can effectively protect adult stem cells against senescence.
间充质干细胞（MSC）为基础的治疗已成为治疗许多退行性疾病的新策略。越来越多的证据表明，MSC 的功能随年龄的增长而下降，从而限制了其再生能力。然而，控制 MSC 衰老的潜在机制尚不清楚。我们发现，与从年轻和老年样本中分离的骨髓间充质干细胞（BM-MSCs）相比，NADH 脱氢酶（泛醌）铁硫蛋白 6（Ndufs6）在老年 MSC 中受到抑制。类似于 Ndufs6 敲除（Ndufs6）小鼠，在 p53/p21 水平升高的情况下，MSC 的自我更新和分化能力降低，并有衰老的趋势。siRNA 下调 Ndufs6 也加速了野生型 BM-MSCs 向衰老状态的进展。相比之下，Ndufs6 在 Ndufs6-BM-MSCs 中的补充显著使衰老细胞恢复活力并恢复其增殖能力。与 BM-MSCs 相比，Ndufs6-BM-MSCs 显示出增加的细胞内和线粒体活性氧（ROS），以及降低的线粒体膜电位。用线粒体 ROS 抑制剂 Mito-TEMPO 处理 Ndufs6-BM-MSCs 显著逆转了细胞衰老，并降低了增加的 p53/p21 水平。我们提供了直接证据，表明线粒体 Ndufs6 的损伤是与过量 ROS 积累和 p53/p21 上调相关的成体干细胞衰老的一个潜在加速器。这也表明操纵线粒体功能至关重要，可以有效地防止成体干细胞衰老。
