Abstract
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.
Highlights
Preclinical and clinical trials have revealed mesenchymal stem cell (MSC)-based therapy to be a promising therapeutic strategy for many diseases[1,2,3,4,5]
One theory is that dysfunctional mitochondria accumulate with age[10], while another proposes that mitochondrial dysfunction can Official journal of the Cell Death Differentiation Association
We reveal that Ndufs[6] plays a critical role in the regulation of bone marrow-MSCs (BM-MSCs) senescence, and downregulation of Ndufs[6] accelerates BM-MSC senescence via complex I deficiency with consequent increased reactive oxygen species (ROS) generation and activation of the p53/p21 signaling pathway
Summary
Preclinical and clinical trials have revealed mesenchymal stem cell (MSC)-based therapy to be a promising therapeutic strategy for many diseases[1,2,3,4,5]. Several potential mechanisms, including telomere shortening[8], impaired autophagy[9], and increased reactive oxygen species (ROS) have been reported to mediate the senescence of MSCs. Importantly, in addition to these factors stem cell senescence is strongly associated with mitochondrial dysfunction. One theory is that dysfunctional mitochondria accumulate with age[10], while another proposes that mitochondrial dysfunction can Official journal of the Cell Death Differentiation Association. Compared with young MSCs, senescent MSCs exhibit increased ROS, largely as a result of mitochondrial structural remodeling[14]. Inflammation-induced ROS leads to MSC senescence by upregulating the expression of miR-155 that in turn suppresses the expression of redox genes including Nfe2l2, Sod[1], and Hmox[115]. To the best of our knowledge, mitochondria are the major source of ROS and structural alterations to mitochondria result in their excessive level[17]
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