scholarly journals Mesenchymal Stem Cell-Derived Exosome Therapy of Microbial Diseases: From Bench to Bed

2022 ◽  
Vol 12 ◽  
Author(s):  
Xiaolan Wu ◽  
Shanshan Jin ◽  
Chengye Ding ◽  
Yu Wang ◽  
Danqing He ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Targeted Drug Delivery ◽  
Infectious Complications ◽  
Economic Losses ◽  
Microbial Diseases ◽  
Comprehensive Overview ◽  
Routes Of Administration ◽  
Underlying Mechanisms ◽  
Antimicrobial Treatments

Microbial diseases are a global health threat, leading to tremendous casualties and economic losses. The strategy to treat microbial diseases falls into two broad categories: pathogen-directed therapy (PDT) and host-directed therapy (HDT). As the typical PDT, antibiotics or antiviral drugs directly attack bacteria or viruses through discerning specific molecules. However, drug abuse could result in antimicrobial resistance and increase infectious disease morbidity. Recently, the exosome therapy, as a HDT, has attracted extensive attentions for its potential in limiting infectious complications and targeted drug delivery. Mesenchymal stem cell-derived exosomes (MSC-Exos) are the most broadly investigated. In this review, we mainly focus on the development and recent advances of the application of MSC-Exos on microbial diseases. The review starts with the difficulties and current strategies in antimicrobial treatments, followed by a comprehensive overview of exosomes in aspect of isolation, identification, contents, and applications. Then, the underlying mechanisms of the MSC-Exo therapy in microbial diseases are discussed in depth, mainly including immunomodulation, repression of excessive inflammation, and promotion of tissue regeneration. In addition, we highlight the latest progress in the clinical translation of the MSC-Exo therapy, by summarizing related clinical trials, routes of administration, and exosome modifications. This review will provide fundamental insights and future perspectives on MSC-Exo therapy in microbial diseases from bench to bedside.

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

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.

Intra-articular Mesenchymal Stem Cell Therapy for the Human Joint: A Systematic Review

2017 ◽  
Vol 46 (14) ◽  
pp. 3550-3563 ◽  
Author(s):  
James A. McIntyre ◽  
Ian A. Jones ◽  
Bo Han ◽  
C. Thomas Vangsness
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Cochrane Library ◽  
Entire Body ◽  
Comprehensive Overview ◽  
Safety And Efficacy ◽  
Mesenchymal Stem Cell Therapy ◽  
Chondral Defects

Background: Stem cell therapy is emerging as a potential treatment of osteoarthritis (OA) and chondral defects (CDs). However, there is a great deal of heterogeneity in the literature. The indications for stem cell use, the ideal tissue source, and the preferred outcome measures for stem cell–based treatments have yet to be determined. Purpose: To provide clinicians with a comprehensive overview of the entire body of the current human literature investigating the safety and efficacy of intra-articular mesenchymal stem cell (MSC) therapy in all joints. Methods: To provide a comprehensive overview of the current literature, all clinical studies investigating the safety and efficacy of intra-articular MSC therapy were included. PubMed, MEDLINE, and Cochrane Library databases were searched for published human clinical trials involving the use of MSCs for the treatment of OA and CDs in all joints. A total of 3867 publications were screened. Results: Twenty-eight studies met the criteria to be included in this review. Fourteen studies treating osteoarthritis and 14 studies treating focal chondral defects were included. MSCs originating from bone marrow (13), adipose tissue (12), synovial tissue (2), or peripheral blood (2) were administered to 584 distinct individuals. MSCs were administered into the knee (523 knees), foot/ankle (61), and hip (5). The mean follow-up time was 24.4 months after MSC therapy. All studies reported improvement from baseline in at least 1 clinical outcome measure, and no study reported major adverse events attributable to MSC therapy. Discussion: The studies included in this review suggest that intra-articular MSC therapy is safe. While clinical and, in some cases, radiological improvements were reported for both OA and CD trials, the overall quality of the literature was poor, and heterogeneity and lack of reproducibility limit firm conclusions regarding the efficacy of these treatments. Conclusion: This review provides strong evidence that autologous intra-articular MSC therapy is safe, with generally positive clinical outcomes.

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 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, 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. 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 H2O2 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 ◽  
Author(s):  
Qian Zhang ◽  
Xianfeng Cheng ◽  
Haizhou Zhang ◽  
Tao Zhang ◽  
Zhengjun Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Signal Pathway ◽  
Cell Counting ◽  
Mouse Bone Marrow ◽  
Ros Production ◽  
Stress Injury ◽  
Underlying Mechanisms

Abstract BackgroundBone 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.MethodsMst1 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.ResultsMst1 inhibition reduced ROS production, increased antioxidant enzyme SOD1/2, CAT, 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.ConclusionMst1 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.

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