miR‐155‐5p inhibition rejuvenates aged mesenchymal stem cells and enhances cardioprotection following infarction

Abstract

Aging impairs the functions of human mesenchymal stem cells (MSCs), thereby severely reducing their beneficial effects on myocardial infarction (MI). MicroRNAs (miRNAs) play crucial roles in regulating the senescence of MSCs; however, the underlying mechanisms remain unclear. Here, we investigated the significance of miR-155-5p in regulating MSC senescence and whether inhibition of miR-155-5p could rejuvenate aged MSCs (AMSCs) to enhance their therapeutic efficacy for MI. Young MSCs (YMSCs) and AMSCs were isolated from young and aged donors, respectively. The cellular senescence of MSCs was evaluated by senescence-associated β-galactosidase (SA-β-gal) staining. Compared with YMSCs, AMSCs exhibited increased cellular senescence as evidenced by increased SA-β-gal activity and decreased proliferative capacity and paracrine effects. The expression of miR-155-5p was much higher in both serum and MSCs from aged donors than young donors. Upregulation of miR-155-5p in YMSCs led to increased cellular senescence, whereas downregulation of miR-155-5p decreased AMSC senescence. Mechanistically, miR-155-5p inhibited mitochondrial fission and increased mitochondrial fusion in MSCs via the AMPK signaling pathway, thereby resulting in cellular senescence by repressing the expression of Cab39. These effects were partially reversed by treatment with AMPK activator or mitofusin2-specific siRNA (Mfn2-siRNA). By enhancing angiogenesis and promoting cell survival, transplantation of anti-miR-155-5p-AMSCs led to improved cardiac function in an aged mouse model of MI compared with transplantation

Mitochondrial Dynamics: Fission and Fusion in Fate Determination of Mesenchymal Stem Cells

“…Mfn1 silencing abrogates the protective effect of miR-181c on BMSCs under oxidative stress conditions (Fan et al, 2019). Inhibiting miR-155-5p or Mfn2-siRNA reverses mitochondrial hyperfusion-mediated senescence in MSCs, and transplantation of aged MSCs pretreated with anti-miR-155-5p significantly ameliorates cardiac dysfunction in an infarction mouse model (Hong et al, 2020). miR-214 improves fibroblast differentiation of ASCs by directly binding to the Mfn2 3 -UTR, enhancing ASC-mediated repair in pelvic floor dysfunction in rats with birth trauma.…”

Senescent mesenchymal stem/stromal cells and restoring their cellular functions

“…These studies include both preclinical and clinical trials of either autologous or allogeneic MSCs. Infusion of MSCs has been performed to evaluate their safety and therapeutic efficacy in diseases of the immune[ 3 ], hematological[ 4 ], cardiovascular[ 5 , 6 ], nervous[ 7 , 8 ], respiratory[ 9 ], digestive[ 10 ], skeletal[ 11 ], endocrine[ 12 ], and reproductive[ 13 ] systems[ 14 ]. To date, more than 1000 MSC-based clinical trials have been registered in the United States National Institute of Health database[ 15 , 16 ].…”

Metformin-Induced MicroRNA-34a-3p Downregulation Alleviates Senescence in Human Dental Pulp Stem Cells by Targeting CAB39 through the AMPK/mTOR Signaling Pathway

“…Furthermore, CAB39, a component of the trimeric LKB1-STRAD-CAB39 complex, contributes to the stabilization of LKB1 to STRAD binding and is recognized as an upstream activator of AMPK due to its role in activating AMPK signaling by phosphorylating AMPK α 1 on residue Thr-172 [ 42 ]. It has been reported that CAB39 is associated with MSC senescence, which occurs in an AMPK-dependent manner [ 43 ]. In the current study, our results showed a decrease in the expression of CAB39 and p-AMPK and an increase in the expression of p-mTOR in aging DPSCs when compared to young DPSCs.…”