scholarly journals Mesenchymal stem cell–derived exosomal microRNA-34c-5p ameliorates renal pericyte activation by inhibiting core fucosylation

2020 ◽  
Author(s):  
Hu Xuemei ◽  
Nan Shen ◽  
Anqi Liu ◽  
Weidong Wang ◽  
Lihua Zhang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Interstitial Fibrosis ◽  
Kidney Diseases ◽  
Post Translational Modification ◽  
Microvascular Damage ◽  
Egfr Ligand ◽  
Underlying Mechanisms ◽  
Signaling Activation ◽  
Core Fucosylation

Abstract Renal interstitial fibrosis (RIF) is an incurable pathological lesion in progressive chronic kidney diseases. Myofibroblast proliferation and microvascular damage are two important events in RIF, and pericytes are a major source of myofibroblasts in the kidney. However, the underlying mechanisms remain poorly characterized. We report that core fucosylation (CF), a post-translational modification of proteins, is essential for pericyte activation by regulating profibrotic and antifibrotic signaling pathways as a “hub-like” target. Mesenchymal stem cell (MSC)-derived exosomes reside specifically in the obstructed kidney and deliver microRNA (miR)-34c-5p to inhibit CF, reducing pericyte activation and renal fibrosis. Furthermore, we clarify that the CD81–EGFR ligand–receptor complex aids the entry of exosomal miR-34c-5p into pericytes. Our results reveal a novel mechanism of pericyte activation based on CF and suggest a potential use of MSC exosomes as a new therapeutic strategy for RIF by inhibiting CF, the hub-like target of profibrotic signaling activation.

scholarly journals Wnt-mediated endothelial transformation into mesenchymal stem cell–like cells induces chemoresistance in glioblastoma

2020 ◽  
Vol 12 (532) ◽  
pp. eaay7522 ◽  
Author(s):  
Menggui Huang ◽  
Duo Zhang ◽  
Janet Y. Wu ◽  
Kun Xing ◽  
Eujin Yeo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Malignant Tumors ◽  
Therapeutic Resistance ◽  
Tumor Resistance ◽  
Genetic Ablation ◽  
Cytotoxic Treatment ◽  
Signaling Activation ◽  
Mesenchymal Transformation

Therapeutic resistance remains a persistent challenge for patients with malignant tumors. Here, we reveal that endothelial cells (ECs) acquire transformation into mesenchymal stem cell (MSC)–like cells in glioblastoma (GBM), driving tumor resistance to cytotoxic treatment. Transcriptome analysis by RNA sequencing (RNA-seq) revealed that ECs undergo mesenchymal transformation and stemness-like activation in GBM microenvironment. Furthermore, we identified a c-Met–mediated axis that induces β-catenin phosphorylation at Ser675 and Wnt signaling activation, inducing multidrug resistance–associated protein-1(MRP-1) expression and leading to EC stemness-like activation and chemoresistance. Last, genetic ablation of β-catenin in ECs overcome GBM tumor resistance to temozolomide (TMZ) chemotherapy in vivo. Combination of Wnt inhibition and TMZ chemotherapy eliminated tumor-associated ECs, inhibited GBM growth, and increased mouse survival. These findings identified a cell plasticity–based, microenvironment-dependent mechanism that controls tumor chemoresistance, and suggest that targeting Wnt/β-catenin–mediated EC transformation and stemness activation may overcome therapeutic resistance in GBM.

scholarly journals Adult mesenchymal stem cell ageing interplays with depressed mitochondrial Ndufs6

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Yuelin Zhang ◽  
Liyan Guo ◽  
Shuo Han ◽  
Ling Chen ◽  
Cheng Li ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Adult Stem Cells ◽  
Adult Stem Cell ◽  
Mitochondrial Ros ◽  
Ros Accumulation ◽  
Sulfur Protein ◽  
Aged State ◽  
Novel Strategy ◽  
Underlying Mechanisms

AbstractMesenchymal stem cell (MSC)-based therapy has emerged as a novel strategy to treat many degenerative diseases. Accumulating evidence shows that the function of MSCs declines with age, thus limiting their regenerative capacity. Nonetheless, the underlying mechanisms that control MSC ageing are not well understood. We show that compared with bone marrow-MSCs (BM-MSCs) isolated from young and aged samples, NADH dehydrogenase (ubiquinone) iron-sulfur protein 6 (Ndufs6) is depressed in aged MSCs. Similar to that of Ndufs6 knockout (Ndufs6−/−) mice, MSCs exhibited a reduced self-renewal and differentiation capacity with a tendency to senescence in the presence of an increased p53/p21 level. Downregulation of Ndufs6 by siRNA also accelerated progression of wild-type BM-MSCs to an aged state. In contrast, replenishment of Ndufs6 in Ndufs6−/−-BM-MSCs significantly rejuvenated senescent cells and restored their proliferative ability. Compared with BM-MSCs, Ndufs6−/−-BM-MSCs displayed increased intracellular and mitochondrial reactive oxygen species (ROS), and decreased mitochondrial membrane potential. Treatment of Ndufs6−/−-BM-MSCs with mitochondrial ROS inhibitor Mito-TEMPO notably reversed the cellular senescence and reduced the increased p53/p21 level. We provide direct evidence that impairment of mitochondrial Ndufs6 is a putative accelerator of adult stem cell ageing that is associated with excessive ROS accumulation and upregulation of p53/p21. It also indicates that manipulation of mitochondrial function is critical and can effectively protect adult stem cells against senescence.

scholarly journals Dissecting Molecular Mechanisms Underlying H2O2-induced Apoptosis of Mouse Bone Marrow Mesenchymal Stem Cell: Role of Mst1 Inhibition.

2020 ◽  
Author(s):  
Qian Zhang ◽  
Xianfeng Cheng ◽  
Haizhou Zhang ◽  
Tao Zhang ◽  
Zhengjun Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Signal Pathway ◽  
Cell Counting ◽  
Ros Production ◽  
Stress Injury ◽  
Underlying Mechanisms

Abstract Background: Bone marrow mesenchymal stem cell (BM-MSC) has been shown to treat pulmonary arterial hypertension (PAH). However, excessive reactive oxygen species (ROS) increases the apoptosis of BM-MSCs, leading to poor survival and engraft efficiency. Thus, improving the ability of BM-MSCs to scavenge ROS may considerably enhance the effectiveness of transplantation therapy. Mammalian Ste20-like kinase 1 (Mst1) is a pro-apoptotic molecule which increases ROS production. The aim of this study is to uncover whether Mst1 inhibition enhanced the tolerance of BM-MSCs under H2O2 condition and the underlying mechanisms. Methods: Mst1 expression in BM-MSCs was inhibited via transfection with adenoviruses expressing a short hairpin (sh) RNA directed against Mst1 (Ad-sh-Mst1) and exposure to H 2 O 2 . Cell viability was detected by Cell counting Kit 8 (CCK-8) assay, and cell apoptosis was analyzed by Annexin V-FITC/PI, Caspase 3 Activity Assay kits, and pro caspase 3 expression. ROS level was evaluated by the ROS probe DCFH-DA, mitochondrial membrane potential (ΔΨm) assay, SOD1/2, CAT, and GPx expression. Autophagy was assessed using transmission electron microscopy, stubRFP-sensGFP-LC3 lentivirus and autophagy-related protein expression. The autophagy/Keap1/Nrf2 signal in H 2 O 2 -treated BM-MSC/sh-Mst1 was also measured. Results: Mst1 inhibition reduced ROS production, increased antioxidant enzyme SOD1/2, CAT, GPx expression, maintained ΔΨm, and alleviated cell apoptosis in H 2 O 2 -treated BM-MSCs. In addition, this phenomenon was closely correlated with the autophagy/Keap1/Nrf2 signal pathway. The autophagy inhibitor, the antioxidant pathway Keap1/Nrf2, was also blocked when autophagy was inhibited by 3-MA. However, Keap1 or Nrf2 knockout via siRNA had no effect on autophagy activation or suppression. Conclusion: Mst1 inhibition mediates the cytoprotective benefit of mBM-MSCs against H 2 O 2 oxidative stress injury. The underlying mechanisms involve autophagy activation and the Keap1/Nrf2 signal pathway.

scholarly journals Dissecting molecular mechanisms underlying H2O2-induced apoptosis of mouse bone marrow mesenchymal stem cell: role of Mst1 inhibition

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Qian Zhang ◽  
Xianfeng Cheng ◽  
Haizhou Zhang ◽  
Tao Zhang ◽  
Zhengjun Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Signal Pathway ◽  
Cell Counting ◽  
Ros Production ◽  
Stress Injury ◽  
Underlying Mechanisms

Abstract Background Bone marrow mesenchymal stem cell (BM-MSC) has been shown to treat pulmonary arterial hypertension (PAH). However, excessive reactive oxygen species (ROS) increases the apoptosis of BM-MSCs, leading to poor survival and engraft efficiency. Thus, improving the ability of BM-MSCs to scavenge ROS may considerably enhance the effectiveness of transplantation therapy. Mammalian Ste20-like kinase 1 (Mst1) is a pro-apoptotic molecule which increases ROS production. The aim of this study is to uncover the underlying mechanisms the effect of Mst1 inhibition on the tolerance of BM-MSCs under H2O2 condition. Methods Mst1 expression in BM-MSCs was inhibited via transfection with adenoviruses expressing a short hairpin (sh) RNA directed against Mst1 (Ad-sh-Mst1) and exposure to H2O2. Cell viability was detected by Cell Counting Kit 8 (CCK-8) assay, and cell apoptosis was analyzed by Annexin V-FITC/PI, Caspase 3 Activity Assay kits, and pro caspase 3 expression. ROS level was evaluated by the ROS probe DCFH-DA, mitochondrial membrane potential (ΔΨm) assay, SOD1/2, CAT, and GPx expression. Autophagy was assessed using transmission electron microscopy, stubRFP-sensGFP-LC3 lentivirus, and autophagy-related protein expression. The autophagy/Keap1/Nrf2 signal in H2O2-treated BM-MSC/sh-Mst1 was also measured. Results Mst1 inhibition reduced ROS production; increased antioxidant enzyme SOD1/2, CAT, and GPx expression; maintained ΔΨm; and alleviated cell apoptosis in H2O2-treated BM-MSCs. In addition, this phenomenon was closely correlated with the autophagy/Keap1/Nrf2 signal pathway. Moreover, the antioxidant pathway Keap1/Nrf2 was also blocked when autophagy was inhibited by the autophagy inhibitor 3-MA. However, Keap1 or Nrf2 knockout via siRNA had no effect on autophagy activation or suppression. Conclusion Mst1 inhibition mediated the cytoprotective action of mBM-MSCs against H2O2-induced oxidative stress injury. The underlying mechanisms involve autophagy activation and the Keap1/Nrf2 signal pathway. Graphical abstract

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