Adult mesenchymal stem cell ageing interplays with depressed mitochondrial Ndufs6

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.

CXCL2 Impairs Functions of Bone Marrow Mesenchymal Stem Cells and Can Serve as a Serum Marker in High-Fat Diet-Fed Rats

“…Functional and regenerative capacities of MSCs are known to decline with senescence, while the underlying mechanisms that control MSC senescence are not well understood. The work by Zhang et al showed that during the aging process in human and mice, mitochondrial Ndufs6 expression was significantly decreased in aged BMSCs and accelerated BMSC senescence ( Zhang et al, 2020 ). However, based on our microarray results, we did not detect significant depressed expression of mitochondrial Ndufs6 in BMSCs isolated from rats fed with HFD for up-to 12 months ( Supplementary Figure 4A ).…”

Conditioned medium from induced pluripotent stem cell-derived mesenchymal stem cells accelerates cutaneous wound healing through enhanced angiogenesis

“…Protein extracts were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to polyvinylidene fluoride membranes as previously described [23]. The membranes were incubated with the following antibodies: anti-VEGFA (Proteintech, 66828-1-1 g); anti-pERK1/2 (Cell Signaling, 4370), anti-ERK1/2 (Cell Signaling, 4695), anti-MFN1 (Proteintech, 13798-1-AP), anti-MFN2 (Proteintech, 12186-1-AP), anti-pDRP1 ser616 (Cell Signaling, 3455), anti-DRP1 (Proteintech, 12957-1-AP), and anti-β-actin (Cell Signaling, 3700), at 4°C overnight.…”

Mitigation of Sodium Iodate-Induced Cytotoxicity in Retinal Pigment Epithelial Cells in vitro by Transgenic Erythropoietin-Expressing Mesenchymal Stem Cells

“…In the present study, Wharton's jelly MSC was used because these cells boast enhanced proliferative markers and immunomodulatory capabilities (Kamal and Kassem, 2020). However, the use of Wharton's jelly MSC may also lead to inconsistent results as these postnatal cells are prone to donorspecific variations, such as increased senescence, that can limit its therapeutic efficacy (Zhang et al, 2020a). Using other cell types, such as iPSC-derived MSCs have been shown to have enhanced proliferation as well as safety in human trials (Zhang et al, 2012;Lian and Zhang, 2016;Bloor et al, 2020).…”