scholarly journals Chronic High Dose Alcohol Induces Osteopenia via Activation of mTOR Signaling in Bone Marrow Mesenchymal Stem Cells

Stem Cells ◽  
2016 ◽  
Vol 34 (8) ◽  
pp. 2157-2168 ◽  
Author(s):  
Yao Liu ◽  
Xiaoxing Kou ◽  
Chider Chen ◽  
Wenjing Yu ◽  
Yingying Su ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Mtor Signaling ◽  
High Dose ◽  
Marrow Mesenchymal Stem Cells

scholarly journals Melatonin Inhibits the Ferroptotic Pathway in Rat Bone Marrow Mesenchymal Stem Cells by Activating the PI3K-AKT-mTOR Signaling Axis to Attenuate Steroid-induced Osteoporosis

2021 ◽  
Author(s):  
meng li ◽  
ning yang ◽  
li hao ◽  
wei zhou ◽  
lei li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
High Dose ◽  
Treatment Pathways ◽  
Marrow Mesenchymal Stem Cells

Abstract ObjectivesSteroid-induced osteoporosis (SIOP) is a secondary osteoporosis, which is a systemic bone disease characterized by low bone mass, bone microstructure damage, increased bone fragility, and easy fracture. However, the specific mechanism remains unclear. Glucocorticoid-induced death of osteoblasts and bone marrow mesenchymal stem cells (BMSCs) is an important factor in SIOP. Ferroptosis is an iron-dependent programmed cell death that differs from apoptosis, cell necrosis, and autophagy, which can be induced by many factors. Herein, we aimed to explore whether glucocorticoids (GCs) cause ferroptosis in BMSCs and determine possible treatment pathways and mechanisms of action. Melatonin (MT), a hormone secreted by the pineal gland, displays strong antioxidant abilities to scavenge free radicals and alleviates ferroptosis in many tissues and organs. MethodsIn this study, we used high-dose dexamethasone (DEX) to observe whether glucocorticoids induced ferroptosis in BMSCs. We then assessed whether MT can inhibit the ferroptotic pathway, thereby providing early protection against GC-induced SIOP, and investigated the signaling pathways involved.ResultsIn vitro experiments showed that MT intervention significantly improved GC-induced ferroptosis in BMSCs and significantly improved SIOP in vivo. Pathway analysis showed that MT improves ferroptosis by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) axis. MT upregulates expression of PI3K, which is an important regulator of ferroptosis resistance. PI3K activators mimic the anti-ferroptosis effect of MT, but after blocking the PI3K pathway, the effect of MT is weakened. Obviously, MT can protect against SIOP induced by GC. Notably, even after GC-induced ferroptosis begins, MT can confer protection against SIOP. ConclusionOur research confirms that GC-induced ferroptosis is closely related to SIOP. Melatonin can inhibit ferroptosis by activating the PI3K-AKT-mTOR signaling pathway, thereby reducing the occurrence of steroid-induced osteoporosis. Therefore, MT may provide a novel strategy for preventing and treating SIOP.

scholarly journals Bone marrow mesenchymal stem cells promote remyelination in spinal cord by driving oligodendrocyte progenitor cell differentiation via TNFα/RelB-Hes1 pathway: a rat model study of 2,5-hexanedione-induced neurotoxicity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shuangyue Li ◽  
Huai Guan ◽  
Yan Zhang ◽  
Sheng Li ◽  
Kaixin Li ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Statistical Significance ◽  
High Dose ◽  
Sprague Dawley ◽  
Oligodendrocyte Progenitor ◽  
Hes1 Expression ◽  
Marrow Mesenchymal Stem Cells

Abstract Background N-hexane, with its metabolite 2,5-hexanedine (HD), is an industrial hazardous material. Chronic hexane exposure causes segmental demyelination in the peripheral nerves, and high-dose intoxication may also affect central nervous system. Demyelinating conditions are difficult to treat and stem cell therapy using bone marrow mesenchymal stem cells (BMSCs) is a promising novel strategy. Our previous study found that BMSCs promoted motor function recovery in rats modeling hexane neurotoxicity. This work aimed to explore the underlying mechanisms and focused on the changes in spinal cord. Methods Sprague Dawley rats were intoxicated with HD (400 mg/kg/day, i.p, for 5 weeks). A bolus of BMSCs (5 × 107 cells/kg) was injected via tail vein. Demyelination and remyelination of the spinal cord before and after BMSC treatment were examined microscopically. Cultured oligodendrocyte progenitor cells (OPCs) were incubated with HD ± BMSC-derived conditional medium (BMSC-CM). OPC differentiation was studied by immunostaining and morphometric analysis. The expressional changes of Hes1, a transcription factor negatively regulating OPC-differentiation, were studied. The upstream Notch1 and TNFα/RelB pathways were studied, and some key signaling molecules were measured. The correlation between neurotrophin NGF and TNFα was also investigated. Statistical significance was evaluated using one-way ANOVA and performed using SPSS 13.0. Results  The demyelinating damage by HD and remyelination by BMSCs were evidenced by electron microscopy, LFB staining and NG2/MBP immunohistochemistry. In vitro cultured OPCs showed more differentiation after incubation with BMSC-CM. Hes1 expression was found to be significantly increased by HD and decreased by BMSC or BMSC-CM. The change of Hes1 was found, however, independent of Notch1 activation, but dependent on TNFα/RelB signaling. HD was found to increase TNFα, RelB and Hes1 expression, and BMSCs were found to have the opposite effect. Addition of recombinant TNFα to OPCs or RelB overexpression similarly caused upregulation of Hes1 expression. The secretion of NGF by BMSC and activation of NGF receptor was found important for suppression of TNFα production in OPCs. Conclusions  Our findings demonstrated that BMSCs promote remyelination in the spinal cord of HD-exposed rats via TNFα/RelB-Hes1 pathway, providing novel insights for evaluating and further exploring the therapeutical effect of BMSCs on demyelinating neurodegenerative disease.

Effect of Substance P on Bone Marrow Mesenchymal Stem Cells Differentiation in High Glucose Environment

2020 ◽  
Vol 10 (2) ◽  
pp. 252-258
Author(s):  
HeTong Yu ◽  
Yanjun Li ◽  
Xiaowei Ren ◽  
Huanhuan Zhao ◽  
Chong Nan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Mesenchymal Stem Cells ◽  
Substance P ◽  
High Glucose ◽  
Mtor Signaling ◽  
Alp Activity ◽  
Ampk Phosphorylation ◽  
Marrow Mesenchymal Stem Cells

Bone marrow mesenchymal stem cells (BMSCs) can be used to treat bone defects. The neuropeptide substance P (SP) plays an important role in a variety of life activities. However, the effect of SP on BMSCs differentiation in high glucose environment remains unclear. Rat BMSCs were isolated and divided into control group; high glucose group; and SP group. The secretion of SP was detected by ELISA; cell proliferation was detected by MTT assay; apoptosis activity was detected by Cas-pase3 activity kit. Real time PCR was performed to measure Bax and Bcl-2 expression. Alizarin red staining was to detect calcified nodule formation. Western blot was done to measure AMPK/mTOR signaling protein expression. In high glucose environment, SP secretion was significantly decreased, along with increased cell proliferation, Caspase3 activity and Bax expression. Meanwhile, Bcl-2 expression, ALP activity and calcified nodules formation was significantly decreased with reduced AMPK phosphorylation and increased mTOR expression (P < 0.05). SP addition in high glucose environment significantly promoted SP secretion and cell proliferation, decreased Caspase3 activity and Bax expression, increased Bcl-2 expression, ALP activity and calcification nodules formation with increased AMPK phosphorylation and decreased mTOR expression (P < 0.05). In high glucose environment, SP secretion is decreased in BMSCs. Up-regulation of SP in BMSCs cells in high glucose environment inhibit the apoptosis of BMSCs and promote cell proliferation and osteogenesis by regulating AMPK/mTOR signaling pathway.

Role of autophagy and mTOR signaling in neural differentiation of bone marrow mesenchymal stem cells

2014 ◽  
Vol 38 (11) ◽  
pp. 1337-1343 ◽  
Author(s):  
Yanfei Li ◽  
Cuiqin Wang ◽  
Guangyu Zhang ◽  
Xiaohan Wang ◽  
Ranran Duan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Neural Differentiation ◽  
Mtor Signaling ◽  
Marrow Mesenchymal Stem Cells

scholarly journals Transplantation of Bone Marrow Mesenchymal Stem Cells Prevents Radiation-Induced Artery Injury by Suppressing Oxidative Stress and Inflammation

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Yanjun Shen ◽  
Xin Jiang ◽  
Lingbin Meng ◽  
Chengcheng Xia ◽  
Lihong Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Protective Effect ◽  
Human Bone ◽  
Human Bone Marrow ◽  
High Dose ◽  
Marrow Mesenchymal Stem Cells ◽  
Radiation Induced

The present study aims to explore the protective effect of human bone marrow mesenchymal stem cells (hBMSCs) on radiation-induced aortic injury (RIAI). hBMSCs were isolated and cultured from human bone marrow. Male C57/BL mice were irradiated with a dose of 18-Gy 6MV X-ray and randomly treated with either vehicle or hBMSCs through tail vein injection with a dose of 103 or 104 cells/g of body weight (low or high dose of hBMSCs) within 24 h. Aortic inflammation, oxidative stress, and vascular remodeling were assessed by immunohistochemical staining at 3, 7, 14, 28, and 84 days after irradiation. The results revealed irradiation caused aortic cell apoptosis and fibrotic remodeling indicated by aortic thickening, collagen accumulation, and increased expression of profibrotic cytokines (CTGF and TGF-β). Further investigation showed that irradiation resulted in elevated expression of inflammation-related molecules (TNF-α and ICAM-1) and oxidative stress indicators (4-HNE and 3-NT). Both of the low and high doses of hBMSCs alleviated the above irradiation-induced pathological changes and elevated the antioxidant enzyme expression of HO-1 and catalase in the aorta. The high dose even showed a better protective effect. In conclusion, hBMSCs provide significant protection against RIAI possibly through inhibition of aortic oxidative stress and inflammation. Therefore, hBMSCs can be used as a potential therapy to treat RIAI.

scholarly journals Shenfu Injection: A Famous Chinese Prescription That Promotes HCN4 Activity in Bone Marrow Mesenchymal Stem Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Xinjun Zhao ◽  
Qingmin Chu ◽  
Wei Wu ◽  
Hui Wu ◽  
Song Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Low Dose ◽  
High Dose ◽  
Patch Clamp Technique ◽  
Camp Content ◽  
Shenfu Injection ◽  
Whole Cell Patch Clamp ◽  
Marrow Mesenchymal Stem Cells

We investigated the effects of Shenfu Injection (SFI) on HCN4 activity in bone marrow mesenchymal stem cells (BMSCs). The sample of BMSCs was divided into six groups: a control group, a high-dose SFI group (0.25 ml/ml), a middle-dose SFI group (0.1 ml/ml), a low-dose SFI group (0.05 ml/ml), an adenovirus-encoded control vector group, and an adenovirus-encoded HCN4 group. Cell ultrastructure was observed using a transmission electron microscope. Quantitative reverse transcription PCR (RT-qPCR) was performed to detect HCN4 expression, and HCN4 activity was detected using the whole-cell patch clamp technique. An enzyme-linked immunosorbent assay was performed to detect cAMP content. Application of flow cytometry confirmed that the isolated cells showed BMSC-like phenotypes. Differentiation of BMSCs in both the SFI and the adenovirus-encoding HCN4 groups occurred according to the cellular ultrastructure. Application of the whole-cell patch clamp technique revealed that SFI could activate the inward pacing current of BMSCs in a concentration-dependent manner. The RT-qPCR results showed that HCN4 expression was significantly higher in the high-dose SFI group than in the medium- and low-dose groups, whereas the cAMP content in the overexpressed HCN4 group decreased significantly; this content in the high-dose SFI group increased significantly. In conclusion, SFI promotes HCN4 activity in BMSCs, which could explain its treatment effect when administered to patients with cardiovascular diseases.

Metformin Weakens the Angiogenic Potential of Human Bone Marrow Mesenchymal Stem Cells (hBMSCs) by Activating Mammalian Target of Rapamycin (mTOR) Signaling

2021 ◽  
Vol 11 (10) ◽  
pp. 2030-2036
Author(s):  
Lihua Chen ◽  
Ji’e Shi ◽  
Xiu Qu
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Pcr Analysis ◽  
Angiogenic Potential ◽  
Marrow Mesenchymal Stem Cells

To study metformin’s effect on the angiogenesis of human bone marrow mesenchymal stem cells (hBMSCs). Cells were treated with metformin (0.5, 1, 10, 50, 100, 200 and 500 βM) for 14 days, followed by analysis of cell viability and total fatty acid profile, level of VEGFR-2, Tie-2, VE-Cadherin and mTOR signaling protein, cell differentiation by microtubule generation and cell migration by transwell assay. Metformin dose dependently decreased cell survival and reduced palmitate, oleate, stearate and linoleate content. In addition, it downregulated VEGFR-2 and Tie-2 and decreased the angiogenic potential of BMSCs and down-regulated VE-Cadherin. Western blot and PCR analysis showed that metformin activated mTOR signaling and up-regulated the transcription of autophagyrelated genes. Metformin can reduce BMSCs angiogenic potential by regulating mTOR signal pathway.

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