The p53/miR-145a Axis Promotes Cellular Senescence and Inhibits Osteogenic Differentiation by Targeting Cbfb in Mesenchymal Stem Cells

Xia, Chao; Jiang, Tianyuan; Wang, Yonghui; Rothenberg, Marc E.; Hu, Yan; Gao, Yanhong

doi:10.3389/fendo.2020.609186

Cited by 12 publications

(12 citation statements)

References 51 publications

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“…Mechanisms underlying senescent induced changes in MSCs have since then been addressed in multiple studies, identifying important mediators of MSC senescence [ 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ]. For instance, several miRNAs have been identified that are involved in regulating senescence and the balance between osteoblastic and adipocytic differentiation of BMSCs [ 52 , 55 , 60 , 61 ]. Lian et al investigated an involvement of miR-29a in age-related bone loss [ 61 ].…”

Section: Cellular Senescencementioning

confidence: 99%

“…In vivo, ZFAS1 knockdown was associated with increased bone mass [ 60 ]. Finally, two groups investigated mechanisms involved in regulating osteogenesis and adipogenesis in BMSCs in vitro and identified miR-363-3p [ 54 ] and miR-245a [ 55 ] as regulators of senescence. miR-363-3p targets tumor necrosis factor receptor-associated factor 3 (TRAF3), which promotes BMSCs differentiation to osteoblast and suppresses senescence and differentiation to adipocytes [ 54 ].…”

Section: Cellular Senescencementioning

confidence: 99%

“…miR-363-3p targets tumor necrosis factor receptor-associated factor 3 (TRAF3), which promotes BMSCs differentiation to osteoblast and suppresses senescence and differentiation to adipocytes [ 54 ]. miR-145a was shown to be upregulated by p53, a positive regulator of senescence and negative regulator of osteogenic differentiation of BMSCs [ 55 ].…”

Section: Cellular Senescencementioning

confidence: 99%

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Age Related Osteoporosis: Targeting Cellular Senescence

Föger-Samwald

Kerschan‐Schindl

Butylina

et al. 2022

IJMS

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Age-related chronic diseases are an enormous burden to modern societies worldwide. Among these, osteoporosis, a condition that predisposes individuals to an increased risk of fractures, substantially contributes to increased mortality and health-care costs in elderly. It is now well accepted that advanced chronical age is one of the main risk factors for chronical diseases. Hence, targeting fundamental aging mechanisms such as senescence has become a promising option in the treatment of these diseases. Moreover, for osteoporosis, the main pathophysiological concepts arise from menopause causing estrogen deficiency, and from aging. Here, we focus on recent advances in the understanding of senescence-related mechanisms contributing to age-related bone loss. Furthermore, treatment options for senile osteoporosis targeting senescent cells are reviewed.

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Section: Cellular Senescencementioning

confidence: 99%

Section: Cellular Senescencementioning

confidence: 99%

Section: Cellular Senescencementioning

confidence: 99%

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Age Related Osteoporosis: Targeting Cellular Senescence

Föger-Samwald

Kerschan‐Schindl

Butylina

et al. 2022

IJMS

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“…MiRNAs, endogenous small noncoding RNA molecules, have been reported to play crucial roles in mediating the cellular senescence of stem cells [ 24 , 25 , 71 ], examples include microRNA-206 [ 15 ], let-7, miRNA-23a, miRNA-26a, miRNA-30a [ 72 ], microRNA-34a-3p [ 73 ], miRNA-145a [ 27 ], miRNA-1292 [ 26 ], miRNA-15a/15b [ 74 ], miRNA-155-5p [ 43 ], and miRNA-199a-5p [ 49 ]. Using microarray and bioinformatic analysis, we compared miRNA expression levels in OM-MSCs cultured in normoxia and hypoxia.…”

Section: Resultsmentioning

confidence: 99%

“…MiRNAs have been proven to play an important role in cellular senescence [ 24 , 25 ]. Overexpression of miR-1292 in adipose-derived MSCs promoted cellular senescence and restrained osteogenesis [ 26 ], overexpression of miR-145a accelerated bone marrow-derived MSCs senescence [ 27 ], and miR-378 transfection effectively promoted bone marrow-derived MSC survival [ 28 ]. Whether miRNAs play important roles in the senescence of normoxia and hypoxia OM-MSCs remains to be further studied.…”

Section: Introductionmentioning

confidence: 99%

Hypoxic preconditioning rejuvenates mesenchymal stem cells and enhances neuroprotection following intracerebral hemorrhage via the miR-326-mediated autophagy

Liu

et al. 2021

Stem Cell Res Ther

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Background Intracerebral hemorrhage (ICH) is a major public health concern, and mesenchymal stem cells (MSCs) hold great potential for treating ICH. However, the quantity and quality of MSCs decline in the cerebral niche, limiting the potential efficacy of MSCs. Hypoxic preconditioning is suggested to enhance the survival of MSCs and augment the therapeutic efficacy of MSCs in ICH. MicroRNAs (miRNAs) are known to mediate cellular senescence. However, the precise mechanism by which miRNAs regulate the senescence of hypoxic MSCs remains to be further studied. In the present study, we evaluated whether hypoxic preconditioning enhances the survival and therapeutic effects of olfactory mucosa MSC (OM-MSC) survival and therapeutic effects in ICH and investigated the mechanisms by which miRNA ameliorates hypoxic OM-MSC senescence. Methods In the in vivo model, ICH was induced in mice by administration of collagenase IV. At 24 h post-ICH, 5 × 105 normoxia or hypoxia OM-MSCs or saline was administered intracerebrally. The behavioral outcome, neuronal apoptosis, and OM-MSC survival were evaluated. In the in vitro model, OM-MSCs were exposed to hemin. Cellular senescence was examined by evaluating the expressions of P16INK4A, P21, P53, and by β-galactosidase staining. Microarray and bioinformatic analyses were performed to investigate the differences in the miRNA expression profiles between the normoxia and hypoxia OM-MSCs. Autophagy was confirmed using the protein expression levels of LC3, P62, and Beclin-1. Results In the in vivo model, transplanted OM-MSCs with hypoxic preconditioning exhibited increased survival and tissue-protective capability. In the in vitro model, hypoxia preconditioning decreased the senescence of OM-MSCs exposed to hemin. Bioinformatic analysis identified that microRNA-326 (miR-326) expression was significantly increased in the hypoxia OM-MSCs compared with that of normoxia OM-MSCs. Upregulation of miR-326 alleviated normoxia OM-MSC senescence, whereas miR-326 downregulation increased hypoxia OM-MSC senescence. Furthermore, we showed that miR-326 alleviated cellular senescence by upregulating autophagy. Mechanistically, miR-326 promoted the autophagy of OM-MSCs via the PI3K signaling pathway by targeting polypyrimidine tract-binding protein 1 (PTBP1). Conclusions Our study shows that hypoxic preconditioning delays OM-MSC senescence and augments the therapeutic efficacy of OM-MSCs in ICH by upregulating the miR-326/PTBP1/PI3K-mediated autophagy.

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Slo1 deficiency impaired skeletal muscle regeneration and slow‐twitch fibre formation

Xia

Wang

Jiang

et al. 2023

J cachexia sarcopenia muscle

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Background It has been observed that Slo1 knockout mice have reduced motor function, and people with certain Slo1 mutations have movement problems, but there is no answer whether the movement disorder is caused by the loss of Slo1 in the nervous system, or skeletal muscle, or both. Here, to ascertain in which tissues Slo1 functions to regulate motor function and offer deeper insight in treating related movement disorder, we generated skeletal muscle‐specific Slo1 knockout mice, studied the functional changes in Slo1‐deficient skeletal muscle and explored the underlying mechanism. Methods We used skeletal muscle‐specific Slo1 knockout mice (Myf5‐Cre; Slo1flox/flox mice, called CKO) as in vivo models to examine the role of Slo1 in muscle growth and muscle regeneration. The forelimb grip strength test was used to assess skeletal muscle function and treadmill exhaustion test was used to test whole‐body endurance. Mouse primary myoblasts derived from CKO (myoblast/CKO) mice were used to extend the findings to in vitro effects on myoblast differentiation and fusion. Quantitative real‐time PCR, western blot and immunofluorescence approaches were used to analyse Slo1 expression during myoblast differentiation and muscle regeneration. To investigate the involvement of genes in the regulation of muscle dysfunction induced by Slo1 deletion, RNA‐seq analysis was performed in primary myoblasts. Immunoprecipitation and mass spectrometry were used to identify the protein interacting with Slo1. A dual‐luciferase reporter assay was used to identify whether Slo1 deletion affects NFAT activity. Results We found that the body weight and size of CKO mice were not significantly different from those of Slo1flox/flox mice (called WT). Deficiency of Slo1 in muscles leads to reduced endurance (~30% reduction, P < 0.05) and strength (~30% reduction, P < 0.001). Although there was no difference in the general morphology of the muscles, electron microscopy revealed a considerable reduction in the content of mitochondria in the soleus muscle (~40% reduction, P < 0.01). We found that Slo1 was expressed mainly on the cell membrane and showed higher expression in slow‐twitch fibres. Slo1 protein expression is progressively reduced during muscle postnatal development and regeneration after injury, and the expression is strongly reduced during myoblast differentiation. Slo1 deletion impaired myoblast differentiation and slow‐twitch fibre formation. Mechanistically, RNA‐seq analysis showed that Slo1 influences the expression of genes related to myogenic differentiation and slow‐twitch fibre formation. Slo1 interacts with FAK to influence myogenic differentiation, and Slo1 deletion diminishes NFAT activity. Conclusions Our data reveal that Slo1 deficiency impaired skeletal muscle regeneration and slow‐twitch fibre formation.

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The p53/miR-145a Axis Promotes Cellular Senescence and Inhibits Osteogenic Differentiation by Targeting Cbfb in Mesenchymal Stem Cells

Cited by 12 publications

References 51 publications

Age Related Osteoporosis: Targeting Cellular Senescence

Age Related Osteoporosis: Targeting Cellular Senescence

Hypoxic preconditioning rejuvenates mesenchymal stem cells and enhances neuroprotection following intracerebral hemorrhage via the miR-326-mediated autophagy

Slo1 deficiency impaired skeletal muscle regeneration and slow‐twitch fibre formation

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