RESUMO
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.
Assuntos
Células-Tronco Adultas/citologia , Células-Tronco Adultas/metabolismo , Senescência Celular , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , NADH Desidrogenase/metabolismo , Células-Tronco Adultas/ultraestrutura , Animais , Células da Medula Óssea/metabolismo , Diferenciação Celular , Regulação para Baixo/genética , Técnicas de Silenciamento de Genes , Humanos , Células-Tronco Mesenquimais/ultraestrutura , Camundongos Endogâmicos C57BL , Mitocôndrias/ultraestrutura , Proteínas Mitocondriais/genética , NADH Desidrogenase/genética , Subunidades Proteicas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de SinaisRESUMO
Mitochondrial dysfunction has been linked to many diseases including organ degeneration and cancer. Mesenchymal stem cells/stromal cells (MSCs) provide a valuable source for stem cell-based therapy and represent an emerging therapeutic approach for tissue regeneration. Increasing evidence suggests that MSCs can directly donate mitochondria to recover from cell injury and rescue mitochondrial damage-provoked tissue degeneration. Meanwhile, cancer cells and cancer stromal cells also cross-talk through mitochondrial exchange to regulate cancer metastasis. This review summarizes the research on MSCs and their mitochondrial transfer. It provides an overview of the biology, function, niches and signaling that play a role in tissue repair. It also highlights the pathologies of cancer growth and metastasis linked to mitochondrial exchange between cancer cells and surrounding stromal cells. It becomes evident that the function of MSC mitochondrial transfer is a double-edged sword. MSC mitochondrial transfer may be a pharmaceutical target for tissue repair and cancer therapy.