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

Hong, Yan; He, Haiwei; Jiang, Guojun; Zhang, Hao; Tao, Wuyuan; Ding, Yue; Yuan, Dongsheng; Liu, Jing; Fan, Huimin; Lin, Fang‐Yue; Liang, Xiaoting; Li, Xin; Zhang, Yuelin

doi:10.1111/acel.13128

Cited by 67 publications

(40 citation statements)

References 39 publications

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“…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.…”

Section: Msc-based Mitochondrial Therapeuticsmentioning

confidence: 99%

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

Ren

Chen

et al. 2020

Front. Cell Dev. Biol.

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Mesenchymal stem cells (MSCs) are pivotal to tissue homeostasis, repair, and regeneration due to their potential for self-renewal, multilineage differentiation, and immune modulation. Mitochondria are highly dynamic organelles that maintain their morphology via continuous fission and fusion, also known as mitochondrial dynamics. MSCs undergo specific mitochondrial dynamics during proliferation, migration, differentiation, apoptosis, or aging. Emerging evidence suggests that mitochondrial dynamics are key contributors to stem cell fate determination. The coordination of mitochondrial fission and fusion is crucial for cellular function and stress responses, while abnormal fission and/or fusion causes MSC dysfunction. This review focuses on the role of mitochondrial dynamics in MSC commitment under physiological and stress conditions. We highlight mechanistic insights into modulating mitochondrial dynamics and mitochondrial strategies for stem cell-based regenerative medicine. These findings shed light on the contribution of mitochondrial dynamics to MSC fate and MSC-based tissue repair.

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Section: Msc-based Mitochondrial Therapeuticsmentioning

confidence: 99%

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

Ren

Chen

et al. 2020

Front. Cell Dev. Biol.

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Qiao³

et al. 2021

Stem Cells International

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Dental pulp stem cells (DPSCs) are ideal seed cells for the regeneration of dental tissues. However, DPSC senescence restricts its clinical applications. Metformin (Met), a common prescription drug for type 2 diabetes, is thought to influence the aging process. This study is aimed at determining the effects of metformin on DPSC senescence. Young and aging DPSCs were isolated from freshly extracted human teeth. Flow cytometry confirmed that DPSCs expressed characteristic surface antigen markers of mesenchymal stem cells (MSCs). Cell Counting Kit-8 (CCK-8) assay showed that a concentration of 100 μM metformin produced the highest increase in the proliferation of DPSCs. Metformin inhibited senescence in DPSCs as evidenced by senescence-associated β-galactosidase (SA-β-gal) staining and the expression levels of senescence-associated proteins. Additionally, metformin significantly suppressed microRNA-34a-3p (miR-34a-3p) expression, elevated calcium-binding protein 39 (CAB39) expression, and activated the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway. Dual-luciferase reporter assay confirmed that CAB39 is a direct target for miR-34a-3p. Furthermore, transfection of miR-34a-3p mimics promoted the senescence of DPSCs, while metformin treatment or Lenti-CAB39 transfection inhibited cellular senescence. In conclusion, these results indicated that metformin could alleviate the senescence of DPSCs by downregulating miR-34a-3p and upregulating CAB39 through the AMPK/mTOR signaling pathway. This study elucidates on the inhibitory effect of metformin on DPSC senescence and its potential as a therapeutic target for senescence treatment.

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“…Our previous study showed that miR-155-5p inhibits mitochondrial fission in MSCs via the Cab39/AMPK signaling pathway, resulting in cellular senescence. Inhibition of miR-155-5p has been shown to rejuvenate aged-MSCs and enhance their cardioprotective effects on myocardial infarction in mice [ 16 ]. It has been reported that the level of miR-199a-5p is significantly increased in patients with IPF and in mice with bleomycin-induced lung fibrosis [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of miR-199a-5p rejuvenates aged mesenchymal stem cells derived from patients with idiopathic pulmonary fibrosis and improves their therapeutic efficacy in experimental pulmonary fibrosis

et al. 2021

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Background Idiopathic pulmonary fibrosis (IPF) is an age-related disease with no cure. Mesenchymal stem cell (MSC)-based therapy has emerged as a novel strategy for IPF treatment. Nevertheless, MSCs derived from patients with IPF (IPF-MSCs) become senescent, thereby reducing their beneficial effects in IPF. MicroRNAs (miRNAs) mediate the senescence of MSCs, but the underlying mechanisms are not fully understood. We investigated the mechanisms by which miR-199a-5p regulates IPF-MSC senescence and whether its inhibition could rejuvenate IPF-MSCs and enhance their therapeutic efficacy. Methods Control-MSCs and IPF-MSCs were isolated from the adipose tissue of age-matched healthy and IPF donors, respectively. Cell senescence was examined by senescence-associated β-galactosidase (SA-β-gal) staining. The level of miR-199a-5p was measured by RT-PCR. Autophagy was determined using a transmission electron microscope (TEM). The therapeutic efficacy of anti-miR-199a-5p-IPF-MSCs was assessed using a mouse model of bleomycin-induced lung fibrosis. Results Despite similar surface makers, IPF-MSCs exhibited increased cellular senescence and decreased proliferative capacity compared with control-MSCs. The expression of miR-199a-5p was significantly enhanced in the serum of IPF patients and IPF-MSCs compared with that of healthy donors and control-MSCs. The upregulation of miR-199a-5p induced senescence of control-MSCs, whereas the downregulation rescued IPF-MSC senescence. Mechanistically, miR-155-5p suppressed autophagy of MSCs via the AMPK signaling pathway by downregulating the expression of Sirtuin 1(Sirt1), resulting in cellular senescence. Accordingly, miR-155-5p inhibition promoted autophagy and ameliorated IPF-MSC senescence by activating the Sirt1/AMPK signaling pathway. Compared with IPF-MSCs, the transplantation of anti-miR-199a-5p-IPF-MSCs increased the ability to prevent progression of pulmonary fibrosis in bleomycin-treated mice. Conclusions Our study shows that miR-199a-5p regulates MSC senescence in patients with IPF by regulating the Sirt1/AMPK signaling pathway and miR-199a-5p is a novel target to rejuvenate IPF-MSCs and enhance their beneficial effects.

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

Cited by 67 publications

References 39 publications

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

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

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

Inhibition of miR-199a-5p rejuvenates aged mesenchymal stem cells derived from patients with idiopathic pulmonary fibrosis and improves their therapeutic efficacy in experimental pulmonary fibrosis

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