scholarly journals RIPK1 Coordinates Bone Marrow Mesenchymal Stem Cell Survival by Maintaining Mitochondrial Homeostasis via p53

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Qing Tian ◽  
Chen Cao ◽  
Weijian Qiu ◽  
Han Wu ◽  
Lijun Zhou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Mitochondrial Dysfunction ◽  
Molecular Mechanisms ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Bone Marrow Mscs ◽  
Induced Apoptosis

Survival of mesenchymal stem cells in the bone marrow is essential for bone marrow microenvironment homeostasis, but the molecular mechanisms remain poorly understood. RIPK1 has emerged as a critical molecule of programmed cell death in tissue homeostasis. However, little is known about the regulation of RIPK1 on bone marrow mesenchymal stem cells (MSCs). Here, we have investigated for the first time the role of RIPK1 in bone marrow MSCs. We have found that RIPK1 knockdown suppressed proliferation, differentiation, and migration in bone marrow MSCs. Furthermore, RIPK1 knockdown resulted in the opening of mitochondrial permeability transition pore (mPTP) and mtDNA damage, leading to mitochondrial dysfunction, and consequently induced apoptosis and necroptosis in bone marrow MSCs. Moreover, we identified that the p53-PUMA axis pathway was involved in mitochondrial dysfunction in RIPK1-deficient bone marrow MSCs. Together, our findings highlighted that RIPK1 was indispensable for bone marrow MSC survival.

scholarly journals Hepatitis B Virus Replication Is Associated with an HBx-Dependent Mitochondrion-Regulated Increase in Cytosolic Calcium Levels

2007 ◽  
Vol 81 (21) ◽  
pp. 12061-12065 ◽  
Author(s):  
Stephanie L. McClain ◽  
Amy J. Clippinger ◽  
Rebecca Lizzano ◽  
Michael J. Bouchard
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Molecular Mechanisms ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cytosolic Calcium ◽  
Hbv Replication ◽  
B Virus

ABSTRACT The nonstructural hepatitis B virus (HBV) protein HBx has an important role in HBV replication and in HBV-associated liver disease. Many activities have been linked to HBx expression; however, the molecular mechanisms underlying many of these activities are unknown. One proposed HBx function is the regulation of cytosolic calcium. We analyzed calcium levels in HepG2 cells that expressed HBx or replicating HBV, and we demonstrated that HBx, expressed in the absence of other HBV proteins or in the context of HBV replication, elevates cytosolic calcium. We linked this elevation of cytosolic calcium to the association of HBx with the mitochondrial permeability transition pore.

Exosomal MicroRNA-204 Derived from Bone Marrow Mesenchymal Stem Cells (BMSCs) Inhibits Cell Proliferation and Induces Apoptosis Through NF-κB Signaling Pathway in Breast Cancer

2022 ◽  
Vol 12 (2) ◽  
pp. 273-278
Author(s):  
Daqing Jiang ◽  
Xianxin Xie ◽  
Cong Wang ◽  
Weijie Li ◽  
Jianjun He
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Mesenchymal Stem Cells ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Marrow Mesenchymal Stem Cells ◽  
Induced Apoptosis ◽  
Signaling Activation

Our study intends to assess the relationship between exosomes derived from bone marrow mesenchymal stem cells (BMSC-exo) and breast cancer. BMSC-exo were isolated and characterized by transmission electron microscopy. After transfection of BMSCs with miR-204 inhibitor, breast cancer cells were incubated with BMSC-exo followed by analysis of cell proliferation by CCK-8 assay, cell apoptosis by flow cytometry, and expression of apoptosis-related protein and NF-κB signaling by western blot. The co-culture of BMSC-exo with breast cancer cells enhanced miR-204 transcription, inhibited cell proliferation and induced apoptosis. Further, BMSC-exo accelerated apoptosis as demonstrated by the increased level of Bax and casepase-3 and decreased Bcl-2 expression, as well as reduced NF-κB signaling activity. But knockdown of miR-204 abolished the effect of BMSC-exo on apoptosis and proliferation with NF-κB signaling activation. In conclusion, miR-204 from BMSC-exo restrains growth of breast cancer cell and might be a novel target for treating breast cancer.

Abstract 3782: β2-Adrenergic Receptor Signaling Positively Modulates Pro-Survival Kinases and Ameliorates Mitochondrial Dysfunction during Doxorubicin Cardiotoxicity

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Giovanni Fajardo ◽  
Mingming Zhao ◽  
Gerald Berry ◽  
Daria Mochly-Rosen ◽  
Daniel Bernstein
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Surface Receptors ◽  
Β2 Adrenergic Receptor ◽  
Improvement In Survival ◽  
Complex I Activity

β2-adrenergic receptors (β2-ARs) modulate cardioprotection through crosstalk with multiple pathways. We have previously shown that β2-ARs are cardioprotective during acute exposure to Doxorubicin (DOX). DOX cardiotoxicity is mediated through a Ca 2+ -dependent opening of the mitochondrial permeability transition pore (MPT) and mitochondrial dysfunction, however the upstream signals linking cell surface receptors and the MPT are not clear. The purpose of this study was to assess crosstalk between β2-AR signaling and mitochondrial function in DOX toxicity. DOX 10 mg/kg was administered to β2−/− and WT mice. Whereas there was no mortality in WT, 85% of β2−/− mice died within 30 min (n=20). Pro- and anti-survival kinases were assessed by immunobloting. At baseline, β2−/− showed normal levels of ϵPKC, but a 16% increase in δPKC compared to WT (p<0.05). After DOX, β2−/− showed a 64% decrease in ϵPKC (p<0.01) and 22% increase in δPKC (p<0.01). The ϵPKC activator ΨϵRACK decreased mortality by 40% in β2−/− mice receiving DOX; there was no improvement in survival with the δPKC inhibitor δV1–1. After DOX, AKT activity was decreased by 76% (p<0.01) in β2−/− but not in WT. The α1-AR blocker prazosin, inhibiting signaling through Gαq, restored AKT activity and reduced DOX mortality by 47%. We next assessed the role of mitochondrial dysfunction in β2−/− mediated DOX toxicity. DOX treated β2−/− mice, but not WT, show marked vacuolization of mitochondrial cristae. Complex I activity decreased 31% in β2−/− mice with DOX; but not in WT. Baseline rate of Ca2+ release and peak [Ca2+]i ratio were increased 85% and 17% respectively in β2−/− myocytes compared to WT. Verapamil decreased mortality by 27% in DOX treated β2−/− mice. Cyclosporine, a blocker of both MPT and calcineurin, reduced DOX mortality to 50%. In contrast, FK506, a blocker of calcineurin but not the MPT, did not reduce DOX mortality. Cyclosporine prevented the decrease in AKT activity in β2−/− whereas FK506 did not. These findings suggest that β2-ARs modulate pro-survival kinases and attenuate mitochondrial dysfunction during DOX cardiotoxicity; absence of β2-ARs enhances DOX toxicity via negative regulation of survival kinases and enhancement of intracellular Ca2+, sensitizing mitochondria to opening of the MPT.

scholarly journals Melatonin Reverses the Loss of Stemness Induced by TNF-α in Human Bone Marrow Mesenchymal Stem Cells through Upregulation of YAP Expression

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Xudong Wang ◽  
Tongzhou Liang ◽  
Jincheng Qiu ◽  
Xianjian Qiu ◽  
Bo Gao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Molecular Mechanisms ◽  
Inflammatory Factor ◽  
Cell Transplant ◽  
Alizarin Red ◽  
Marrow Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are promising candidates for tissue regeneration and disease treatment. However, long-term in vitro culture results in loss of MSC stemness. The inflammation that occurs at stem cell transplant sites (such as that resulting from TNF-α) is a contributing factor for stem cell treatment failure. Currently, there is little evidence regarding the protective role of melatonin with regard to the negative effects of TNF-α on the stemness of MSCs. In this study, we report a melatonin-based method to reduce the inflammatory effects on the stemness of bone marrow mesenchymal stem cells (BMMSCs). The results of colony formation assays, Alizarin red staining, western blotting, and reverse transcription-polymerase chain reactions suggest that melatonin can reverse the inflammatory damage caused by TNF-α treatment in the third, seventh, and tenth generations of primary BMMSCs (vs. control and the TNF-α-treated group). Meanwhile, a detailed analysis of the molecular mechanisms showed that the melatonin receptor and YAP signaling pathway are closely related to the role that melatonin plays in negative inflammatory effects against BMMSCs. In addition, in vivo experiments showed that melatonin could reverse the damage caused by TNF-α on bone regeneration by BMMSCs in nude mice. Overall, our results suggest that melatonin can reverse the loss of stemness caused by inflammatory factor TNF-α in BMMSCs. Our results also provide a practical strategy for the application of BMMSCs in tissue engineering and cell therapy.

Kartogenin enhances the therapeutic effect of bone marrow mesenchymal stem cells derived exosomes in cartilage repair

Nanomedicine ◽  
2020 ◽  
Vol 15 (3) ◽  
pp. 273-288 ◽  
Author(s):  
Chun Liu ◽  
Yun Li ◽  
Zhijian Yang ◽  
Zhiyou Zhou ◽  
Zhihao Lou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Therapeutic Effect ◽  
Bone Marrow Mscs ◽  
In Vivo Experiments ◽  
Marrow Mesenchymal Stem Cells ◽  
Cartilage Diseases

The effectiveness of mesenchymal stem cells (MSC) in the treatment of cartilage diseases has been demonstrated to be attributed to the paracrine mechanisms, especially the mediation of exosomes. But the exosomes derived from unsynchronized MSCs may be nonhomogeneous and the therapeutic effect varies between samples. Aim: To produce homogeneous and more effective exosomes for the regeneration of cartilage. Materials & methods: In this study we produced specific exosomes from bone marrow MSCs (BMSC) through kartogenin (KGN) preconditioning and investigated their performance in either in vitro or in vivo experiments. Results & conclusion: The exosomes derived from KGN-preconditioned BMSCs (KGN-BMSC-Exos) performed more effectively than the exosomes derived from BMSCs (BMSC-Exos). KGN preconditioning endowed BMSC-Exos with stronger chondral matrix formation and less degradation.

scholarly journals MicroRNA-346-5p Regulates Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells by Inhibiting Transmembrane Protein 9

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Yicai Zhang ◽  
Yi Sun ◽  
Jinlong Liu ◽  
Yu Han ◽  
Jinglong Yan
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Osteogenic Differentiation ◽  
Protein Level ◽  
Molecular Mechanisms ◽  
Transmembrane Protein ◽  
Luciferase Reporter ◽  
Alizarin Red ◽  
Protein Levels

The molecular mechanisms how bone marrow-derived mesenchymal stem cells (BMSCs) differentiate into osteoblast need to be investigated. MicroRNAs (miRNAs) contribute to the osteogenic differentiation of BMSCs. However, the effect of miR-346-5p on osteogenic differentiation of BMSCs is not clear. This study is aimed at elucidating the underlying mechanism by which miR-346-5p regulates osteogenic differentiation of human BMSCs. Results of alkaline phosphatase (ALP) and Alizarin Red S (ARS) staining indicated that upregulation of miR-346-5p suppressed osteogenic differentiation of BMSCs, whereas downregulation of miR-346-5p enhanced this process. The protein levels of the osteoblastic markers Osterix and Runt-related transcription factor 2 (Runx2) were decreased in cells treated with miR-346-5p mimic at day 7 and day 14 after being differentiated. By contrast, downregulation of miR-346-5p elevated the protein levels of Osterix and Runx2. Moreover, a dual-luciferase reporter assay revealed that Transmembrane Protein 9 (TMEM9) was a target of miR-346-5p. In addition, the Western Blot results demonstrated that the TMEM9 protein level was significantly reduced by the miR-346-5p mimic whereas downregulation of miR-346-5p improved the protein level of TMEM9. These results together demonstrated that miR-346-5p served a key role in BMSC osteogenic differentiation of through targeting TMEM9, which may provide a novel target for clinical treatments of bone injury.

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