Alkbh1‐mediated DNA N6‐methyladenine modification regulates bone marrow mesenchymal stem cell fate during skeletal aging

Cai, Guangping; Liu, Yalin; Luo, Liping; Xiao, Yamei; Tong, Jiang; Yuan, Jian; Wang, Min

doi:10.1111/cpr.13178

Cited by 30 publications

(28 citation statements)

References 61 publications

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“…The crosstalk between RNA modification and oxidative stress has been investigated in various human diseases [ 15 ]. Additionally, RNA modification exerts a crucial role in differentiation of BMSCs [ 16 ]. Enhancing BMSC function is a critical step in optimizing stem cell-mediated bone repair.…”

Section: Introductionmentioning

confidence: 99%

Leukemia Inhibitory Factor Facilitates Self-Renewal and Differentiation and Attenuates Oxidative Stress of BMSCs by Activating PI3K/AKT Signaling

Liang

Zhou

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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Objective. Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) remains a hopeful therapeutic approach for bone defect reconstruction. Herein, we investigated the effects and mechanisms of leukemia inhibitory factor (LIF) in the function and viability of hypoxic BMSCs as well as bone defect repair. Methods. The effects of LIF on apoptosis (flow cytometry, TUNEL staining), mitochondrial activity (JC-1 staining), proliferation (colony formation, EdU staining), and differentiation (CD105, CD90, and CD29 via flow sorting) were examined in hypoxic BMSCs. LIF, LIFR, gp130, Keap1, Nrf2, antioxidant enzymes (SOD1, catalase, GPx-3), bone-specific matrix proteins (ALP, BSP, OCN), PI3K, and Akt were detected via immunoblotting or immunofluorescent staining. BMSCs combined with biphasic calcium phosphate scaffolds were implanted into calvarial bone defect mice, and the therapeutic effect of LIF on bone defect was investigated. Results. Hypoxic BMSCs had increased apoptosis and oxidative stress and reduced mitochondrial activity. Additionally, LIF, LIFR, and gp130 were upregulated and PI3K/Akt activity was depressed in hypoxic BMSCs. Upregulated LIF alleviated apoptosis and oxidative stress and heightened mitochondrial activity and PI3K/Akt signaling in hypoxic BMSCs. Additionally, LIF overexpression promoted self-renewal and osteogenic differentiation of BMSCs with hypoxic condition. Mechanically, LIF facilitated self-renewal and differentiation as well as attenuated oxidative stress of BMSCs through enhancing PI3K/AKT signaling activity. Implantation of LIF-overexpressed BMSC-loaded BCP scaffolds promoted osteogenesis as well as alleviated oxidative stress and apoptosis through PI3K/Akt signaling. Conclusion. Our findings demonstrate that LIF facilitates self-renewal and differentiation and attenuates oxidative stress of BMSCs by PI3K/AKT signaling.

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Section: Introductionmentioning

confidence: 99%

Leukemia Inhibitory Factor Facilitates Self-Renewal and Differentiation and Attenuates Oxidative Stress of BMSCs by Activating PI3K/AKT Signaling

Liang

Zhou

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Our study that m6A methylation of SOCS3 regulate the senescence of SkMSCs through JAK2-STAT3 signaling. Epigenetic modi cation of m6A has a powerful in uence on cellular senescence and affects the cell fate and leads to the overexpression of target protein in aged mice to relieve age-related disease; however, further exploration of the molecular mechanisms remain is required 41,42 . Our data provides the evidence that SOCS3 binds to JAK2 and promote its degradation.…”

Section: Discussionmentioning

confidence: 99%

N6-methyladenosine-mediated changes in SOCS3 expression regulate skeletal muscle stem cell senescence

Zhu

Lian

Chen

et al. 2022

Preprint

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N6-methyladenosine (m6A)-associated mechanisms are involved in cellular metabolic activities; however, their role in skeletal muscle stem cell (SkMSC) senescence is unknown. In this study, m6A RNA modification and METTL3 expression were decreased in aged SkMSCs from mice. Transcriptional analysis of m6A modification further revealed that suppressor of cytokine signaling 3 (SOCS3) was downregulated in aged SkMSCs, and that downregulation of METTL3 promoted SkMSC senescence. In addition, the upregulation of METTL3 alleviated the senescence of SkMSCs. Mechanistically, deletion of m6A modifications promoted senescence and inhibited SOCS3 expression, whereas downregulation of SOCS3 promoted senescence. Moreover, insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) was identified as an important regulator in the recognition and stabilization of m6A modified SOCS3 expression. IGF2BP1 binds to SOCS3 and reinforces its stability by suppressing the phosphorylation of JAK2/STAT3. Therefore, METTL3 inhibits SkMSC senescence through m6A modification-dependent stabilization of SOCS3 expression and inhibition of JAK2-STAT3 signaling. This study thus highlights a novel mechanism underlying SkMSC senescence.

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“…Histochemical and immunohistochemical staining were conducted as previously described ( Cai et al, 2022 ; Yang et al, 2020 ). Femora were collected and fixed with 4% paraformaldehyde for 1 day at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

Long noncoding RNA Gm31629 promotes bone regeneration by maintaining bone marrow mesenchymal stem cells activity

Cai

Xiao

Yang

et al. 2022

PeerJ

Self Cite

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Background Long noncoding RNA Gm31629 can regulate hypothalamic neural stem cells (htNSCs) senescence and the aging process. However, the effect of Gm31629 on the senescence of bone marrow mesenchymal stem cells (BMSCs) and bone regeneration is unclear. In the present study, we investigated the effects of Gm31629 on the senescence of BMSCs and bone regeneration. Methods Gm31629 knockout (Gm31629-KO) and wild-type (WT) mice were used to establish a bone regeneration model. The Brdu labelling, CCK8 assay, wound healing assay, β-gal staining and osteogenic differentiation assay were used to assess the effects of Gm31629 on the functions of BMSCs. Micro-computed tomography (CT), histochemical and immunohistochemical staining were used to evaluate the ability of bone regeneration. The mimic of Gm31629, theaflavin 3-gallate, was used to investigate its role on the senescence of BMSCs and bone regeneration. Results The expression of Gm31629 reduced in BMSCs of middle-aged mice was compared with that of young mice. The deletion of Gm31629 was sufficient to drive the senescence of BMSCs, resulting in impaired bone regeneration in mice. Mechanistically, Gm31629 could interact with Y-box protein 1(YB-1) and delay its degradation, decreasing the transcription of p16INK4A of BMSCs. We also found that theaflavin 3-gallate could alleviate the senescence of BMSCs and promote bone regeneration in middle-aged mice. Conclusion These results indicated that Gm31629 played an important role on BMSCs senescence and bone regeneration and provided a therapeutic target to promote bone regeneration.

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Alkbh1‐mediated DNA N6‐methyladenine modification regulates bone marrow mesenchymal stem cell fate during skeletal aging

Cited by 30 publications

References 61 publications

Leukemia Inhibitory Factor Facilitates Self-Renewal and Differentiation and Attenuates Oxidative Stress of BMSCs by Activating PI3K/AKT Signaling

Leukemia Inhibitory Factor Facilitates Self-Renewal and Differentiation and Attenuates Oxidative Stress of BMSCs by Activating PI3K/AKT Signaling

N6-methyladenosine-mediated changes in SOCS3 expression regulate skeletal muscle stem cell senescence

Long noncoding RNA Gm31629 promotes bone regeneration by maintaining bone marrow mesenchymal stem cells activity

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