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1
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Gyöngyösi M, Guthrie J, Hasimbegovic E, Han E, Riesenhuber M, Hamzaraj K, Bergler-Klein J, Traxler D, Emmert MY, Hackl M, Derdak S, Lukovic D. Critical analysis of descriptive microRNA data in the translational research on cardioprotection and cardiac repair: lost in the complexity of bioinformatics. Basic Res Cardiol 2025:10.1007/s00395-025-01104-1. [PMID: 40205177 DOI: 10.1007/s00395-025-01104-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 03/21/2025] [Accepted: 03/24/2025] [Indexed: 04/11/2025]
Abstract
The unsuccessful translation of cardiac regeneration and cardioprotection from animal experiments to clinical applications in humans has raised the question of whether microRNA bioinformatics can narrow the gap between animal and human research outputs. We reviewed the literature for the period between 2000 and 2024 and found 178 microRNAs involved in cardioprotection and cardiac regeneration. On analyzing the orthologs and annotations, as well as downstream regulation, we observed species-specific differences in the diverse regulation of the microRNAs and related genes and transcriptomes, the influence of the experimental setting on the microRNA-guided biological responses, and database-specific bioinformatics results. We concluded that, in addition to reducing the number of in vivo experiments, following the 3R animal experiment rules, the bioinformatics approach allows the prediction of several currently unknown interactions between pathways, coding and non-coding genes, proteins, and downstream regulatory elements. However, a comprehensive analysis of the miRNA-mRNA-protein networks needs a profound bioinformatics and mathematical education and training to appropriately design an experimental study, select the right bioinformatics tool with programming language skills and understand and display the bioinformatics output of the results to translate the research data into clinical practice. In addition, using in-silico approaches, a risk of deviating from the in vivo processes exists, with adverse consequences on the translational research.
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Affiliation(s)
- Mariann Gyöngyösi
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.
| | - Julia Guthrie
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Zimmermannplatz 10, 1090, Vienna, Austria
| | - Ena Hasimbegovic
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | - Emilie Han
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | - Martin Riesenhuber
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | - Kevin Hamzaraj
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | - Jutta Bergler-Klein
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | - Denise Traxler
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | - Maximilian Y Emmert
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charite (DHZC), Berlin, Germany
| | | | - Sophia Derdak
- Core Facilities, Medical University of Vienna, Vienna, Austria
| | - Dominika Lukovic
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
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2
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Cai WF, Jiang L, Liang J, Dutta S, Huang W, He X, Wu Z, Paul C, Gao X, Xu M, Kanisicak O, Zheng J, Wang Y. HAX1-Overexpression Augments Cardioprotective Efficacy of Stem Cell-Based Therapy Through Mediating Hippo-Yap Signaling. Stem Cell Rev Rep 2024; 20:1569-1586. [PMID: 38713406 PMCID: PMC11319392 DOI: 10.1007/s12015-024-10729-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2024] [Indexed: 05/08/2024]
Abstract
Although stem/progenitor cell therapy shows potential for myocardial infarction repair, enhancing the therapeutic efficacy could be achieved through additional genetic modifications. HCLS1-associated protein X-1 (HAX1) has been identified as a versatile modulator responsible for cardio-protective signaling, while its role in regulating stem cell survival and functionality remains unknown. In this study, we investigated whether HAX1 can augment the protective potential of Sca1+ cardiac stromal cells (CSCs) for myocardial injury. The overexpression of HAX1 significantly increased cell proliferation and conferred enhanced resistance to hypoxia-induced cell death in CSCs. Mechanistically, HAX1 can interact with Mst1 (a prominent conductor of Hippo signal transduction) and inhibit its kinase activity for protein phosphorylation. This inhibition led to enhanced nuclear translocation of Yes-associated protein (YAP) and activation of downstream therapeutic-related genes. Notably, HAX1 overexpression significantly increased the pro-angiogenic potential of CSCs, as demonstrated by elevated expression of vascular endothelial growth factors. Importantly, implantation of HAX1-overexpressing CSCs promoted neovascularization, protected against functional deterioration, and ameliorated cardiac fibrosis in ischemic mouse hearts. In conclusion, HAX1 emerges as a valuable and efficient inducer for enhancing the effectiveness of cardiac stem or progenitor cell therapeutics.
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Affiliation(s)
- Wen-Feng Cai
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267-0529, USA
| | - Lin Jiang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267-0529, USA
| | - Jialiang Liang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267-0529, USA
| | - Suchandrima Dutta
- Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, 45267-0529, USA
| | - Wei Huang
- Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, 45267-0529, USA
| | - Xingyu He
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267-0529, USA
| | - Zhichao Wu
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267-0529, USA
- Department of Cardiovascular Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No.107 Yanjiang West Road, Guangzhou, 510120, Guangdong, China
| | - Christian Paul
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267-0529, USA
| | - Xiang Gao
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267-0529, USA
| | - Meifeng Xu
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267-0529, USA
| | - Onur Kanisicak
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267-0529, USA
| | - Junmeng Zheng
- Department of Cardiovascular Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No.107 Yanjiang West Road, Guangzhou, 510120, Guangdong, China.
| | - Yigang Wang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267-0529, USA.
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3
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Haider KH. Priming mesenchymal stem cells to develop "super stem cells". World J Stem Cells 2024; 16:623-640. [PMID: 38948094 PMCID: PMC11212549 DOI: 10.4252/wjsc.v16.i6.623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/04/2024] [Accepted: 05/20/2024] [Indexed: 06/25/2024] Open
Abstract
The stem cell pre-treatment approaches at cellular and sub-cellular levels encompass physical manipulation of stem cells to growth factor treatment, genetic manipulation, and chemical and pharmacological treatment, each strategy having advantages and limitations. Most of these pre-treatment protocols are non-combinative. This editorial is a continuum of Li et al's published article and Wan et al's editorial focusing on the significance of pre-treatment strategies to enhance their stemness, immunoregulatory, and immunosuppressive properties. They have elaborated on the intricacies of the combinative pre-treatment protocol using pro-inflammatory cytokines and hypoxia. Applying a well-defined multi-pronged combinatorial strategy of mesenchymal stem cells (MSCs), pre-treatment based on the mechanistic understanding is expected to develop "Super MSCs", which will create a transformative shift in MSC-based therapies in clinical settings, potentially revolutionizing the field. Once optimized, the standardized protocols may be used with slight modifications to pre-treat different stem cells to develop "super stem cells" with augmented stemness, functionality, and reparability for diverse clinical applications with better outcomes.
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Affiliation(s)
- Khawaja Husnain Haider
- Department of Basic Sciences, Sulaiman AlRajhi University, AlQaseem 52736, Saudi Arabia.
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4
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Zhang H, Shen Y, Kim IM, Liu Y, Cai J, Berman AE, Nilsson KR, Weintraub NL, Tang Y. Electrical Stimulation Increases the Secretion of Cardioprotective Extracellular Vesicles from Cardiac Mesenchymal Stem Cells. Cells 2023; 12:cells12060875. [PMID: 36980214 PMCID: PMC10047597 DOI: 10.3390/cells12060875] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/06/2023] [Accepted: 03/08/2023] [Indexed: 03/16/2023] Open
Abstract
Clinical trials have shown that electric stimulation (ELSM) using either cardiac resynchronization therapy (CRT) or cardiac contractility modulation (CCM) approaches is an effective treatment for patients with moderate to severe heart failure, but the mechanisms are incompletely understood. Extracellular vesicles (EV) produced by cardiac mesenchymal stem cells (C-MSC) have been reported to be cardioprotective through cell-to-cell communication. In this study, we investigated the effects of ELSM stimulation on EV secretion from C-MSCs (C-MSCELSM). We observed enhanced EV-dependent cardioprotection conferred by conditioned medium (CM) from C-MSCELSM compared to that from non-stimulated control C-MSC (C-MSCCtrl). To investigate the mechanisms of ELSM-stimulated EV secretion, we examined the protein levels of neutral sphingomyelinase 2 (nSMase2), a key enzyme of the endosomal sorting complex required for EV biosynthesis. We detected a time-dependent increase in nSMase2 protein levels in C-MSCELSM compared to C-MSCCtrl. Knockdown of nSMase2 in C-MSC by siRNA significantly reduced EV secretion in C-MSCELSM and attenuated the cardioprotective effect of CM from C-MSCELSM in HL-1 cells. Taken together, our results suggest that ELSM-mediated increases in EV secretion from C-MSC enhance the cardioprotective effects of C-MSC through an EV-dependent mechanism involving nSMase2.
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Affiliation(s)
- Haitao Zhang
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Yan Shen
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Il-man Kim
- Cell Biology and Physiology, School of Medicine, Indiana University, Indianapolis, IN 47405, USA
| | - Yutao Liu
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Jingwen Cai
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Adam E. Berman
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Kent R. Nilsson
- Medical College of Georgia, Augusta University/University of Georgia Partnership, Athens, GA 30602, USA
| | - Neal L. Weintraub
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Yaoliang Tang
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- Correspondence:
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The context-dependent role of transforming growth factor-β/miR-378a-3p/connective tissue growth factor in vascular calcification: a translational study. Aging (Albany NY) 2023; 15:830-845. [PMID: 36787443 PMCID: PMC9970315 DOI: 10.18632/aging.204518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 02/06/2023] [Indexed: 02/16/2023]
Abstract
BACKGROUND Vascular calcification (VC) constitutes an important vascular pathology with prognostic importance. The pathogenic role of transforming growth factor-β (TGF-β) in VC remains unclear, with heterogeneous findings that we aimed to evaluate using experimental models and clinical specimens. METHODS Two approaches, exogenous administration and endogenous expression upon osteogenic media (OM) exposure, were adopted. Aortic smooth muscle cells (ASMCs) were subjected to TGF-β1 alone, OM alone, or both, with calcification severity determined. We evaluated miR-378a-3p and TGF-β1 effectors (connective tissue growth factor; CTGF) at different periods of calcification. Results were validated in an ex vivo model and further in sera from older adults without or with severe aortic arch calcification. RESULTS TGF-β1 treatment induced a significant dose-responsive increase in ASMC calcification without or with OM at the mature but not early or mid-term VC period. On the other hand, OM alone induced VC accompanied by suppressed TGF-β1 expressions over time; this phenomenon paralleled the declining miR-378a-3p and CTGF expressions since early VC. TGF-β1 treatment led to an upregulation of CTGF since early VC but not miR-378a-3p until mid-term VC, while miR-378a-3p overexpression suppressed CTGF expressions without altering TGF-β1 levels. The OM-induced down-regulation of TGF-β1 and CTGF was also observed in the ex vivo models, with compatible results identified from human sera. CONCLUSIONS We showed that TGF-β1 played a context-dependent role in VC, involving a time-dependent self-regulatory loop of TGF-β1/miR-378a-3p/CTGF signaling. Our findings may assist subsequent studies in devising potential therapeutics against VC.
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6
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Wang Y, Xue Y, Guo HD. Intervention effects of traditional Chinese medicine on stem cell therapy of myocardial infarction. Front Pharmacol 2022; 13:1013740. [PMID: 36330092 PMCID: PMC9622800 DOI: 10.3389/fphar.2022.1013740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 10/03/2022] [Indexed: 11/13/2022] Open
Abstract
Cardiovascular diseases are the leading cause of global mortality, in which myocardial infarction accounts for 46% of total deaths. Although good progress has been achieved in medication and interventional techniques, a proven method to repair the damaged myocardium has not yet been determined. Stem cell therapy for damaged myocardial repair has evolved into a promising treatment for ischemic heart disease. However, low retention and poor survival of the injected stem cells are the major obstacles to achieving the intended therapeutic effects. Chinese botanical and other natural drug substances are a rich source of effective treatment for various diseases. As such, numerous studies have revealed the role of Chinese medicine in stem cell therapy for myocardial infarction treatment, including promoting proliferation, survival, migration, angiogenesis, and differentiation of stem cells. Here, we discuss the potential and limitations of stem cell therapy, as well as the regulatory mechanism of Chinese medicines underlying stem cell therapy. We focus on the evidence from pre-clinical trials and clinical practices, and based on traditional Chinese medicine theories, we further summarize the mechanisms of Chinese medicine treatment in stem cell therapy by the commonly used prescriptions. Despite the pre-clinical evidence showing that traditional Chinese medicine is helpful in stem cell therapy, there are still some limitations of traditional Chinese medicine therapy. We also systematically assess the detailed experimental design and reliability of included pharmacological research in our review. Strictly controlled animal models with multi-perspective pharmacokinetic profiles and high-grade clinical evidence with multi-disciplinary efforts are highly demanded in the future.
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Affiliation(s)
- Yu Wang
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuezhen Xue
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Hai-dong Guo
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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7
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Afjeh-Dana E, Naserzadeh P, Moradi E, Hosseini N, Seifalian AM, Ashtari B. Stem Cell Differentiation into Cardiomyocytes: Current Methods and Emerging Approaches. Stem Cell Rev Rep 2022; 18:2566-2592. [PMID: 35508757 DOI: 10.1007/s12015-021-10280-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/05/2021] [Indexed: 12/26/2022]
Abstract
Cardiovascular diseases (CVDs) are globally known to be important causes of mortality and disabilities. Common treatment strategies for CVDs, such as pharmacological therapeutics impose serious challenges due to the failure of treatments for myocardial necrosis. By contrast, stem cells (SCs) based therapies are seen to be promising approaches to CVDs treatment. In such approaches, cardiomyocytes are differentiated from SCs. To fulfill SCs complete potential, the method should be appointed to generate cardiomyocytes with more mature structure and well-functioning operations. For heart repairing applications, a greatly scalable and medical-grade cardiomyocyte generation must be used. Nonetheless, there are some challenges such as immune rejection, arrhythmogenesis, tumorigenesis, and graft cell death potential. Herein, we discuss the types of potential SCs, and commonly used methods including embryoid bodies related techniques, co-culture, mechanical stimulation, and electrical stimulation and their applications, advantages and limitations in this field. An estimated 17.9 million people died from CVDs in 2019, representing 32 % of all global deaths. Of these deaths, 85 % were due to heart attack and stroke.
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Affiliation(s)
- Elham Afjeh-Dana
- Radiation Biology Research Centre, Iran University of Medical Sciences, Tehran, Iran
| | - Parvaneh Naserzadeh
- Radiation Biology Research Centre, Iran University of Medical Sciences, Tehran, Iran
| | - Elham Moradi
- Radiation Biology Research Centre, Iran University of Medical Sciences, Tehran, Iran.,Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran
| | - Nasrin Hosseini
- Neuroscience Research Centre, Iran University of Medical Sciences, Tehran, Iran.
| | - Alexander Marcus Seifalian
- Nanotechnology & Regenerative Medicine Commercialisation Centre (NanoRegMed Ltd), London BioScience Innovation Centre, London, UK
| | - Behnaz Ashtari
- Radiation Biology Research Centre, Iran University of Medical Sciences, Tehran, Iran. .,Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran. .,Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran.
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8
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MicroRNAs and exosomes: Cardiac stem cells in heart diseases. Pathol Res Pract 2021; 229:153701. [PMID: 34872024 DOI: 10.1016/j.prp.2021.153701] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 11/09/2021] [Accepted: 11/18/2021] [Indexed: 12/20/2022]
Abstract
Treating cardiovascular diseases with cardiac stem cells (CSCs) is a valid treatment among various stem cell-based therapies. With supplying the physiological need for cardiovascular cells as their main function, under pathological circumstances, CSCs can also reproduce the myocardial cells. Although studies have identified many of CSCs' functions, our knowledge of molecular pathways that regulate these functions is not complete enough. Either physiological or pathological studies have shown, stem cells proliferation and differentiation could be regulated by microRNAs (miRNAs). How miRNAs regulate CSC behavior is an interesting area of research that can help us study and control the function of these cells in vitro; an achievement that may be beneficial for patients with cardiovascular diseases. The secretome of stem and progenitor cells has been studied and it has been determined that exosomes are the main source of their secretion which are very small vesicles at the nanoscale and originate from endosomes, which are secreted into the extracellular space and act as key signaling organelles in intercellular communication. Mesenchymal stem cells, cardiac-derived progenitor cells, embryonic stem cells, induced pluripotent stem cells (iPSCs), and iPSC-derived cardiomyocytes release exosomes that have been shown to have cardioprotective, immunomodulatory, and reparative effects. Herein, we summarize the regulation roles of miRNAs and exosomes in cardiac stem cells.
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9
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Bioactive Scaffolds in Stem Cell-Based Therapies for Myocardial Infarction: a Systematic Review and Meta-Analysis of Preclinical Trials. Stem Cell Rev Rep 2021; 18:2104-2136. [PMID: 34463903 DOI: 10.1007/s12015-021-10186-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/12/2021] [Indexed: 10/20/2022]
Abstract
The use of bioactive scaffolds in conjunction with stem cell therapies for cardiac repair after a myocardial infarction shows significant promise for clinical translation. We performed a systematic review and meta-analysis of preclinical trials that investigated the use of bioactive scaffolds to support stem cell-aided cardiac regeneration, in comparison to stem cell treatment alone. Cochrane Library, Medline, Embase, PubMed, Scopus, Web of Science, and grey literature were searched through April 23, 2020 and 60 articles were included in the final analysis. The overall effect size observed in scaffold and stem cell-treated small animals compared to stem cell-treated controls for ejection fraction (EF) was 7.98 [95% confidence interval (CI): 6.36, 9.59] and for fractional shortening (FS) was 5.50 [95% CI: 4.35, 6.65] in small animal models. The largest improvements in EF and FS were observed when hydrogels were used (MD = 8.45 [95% CI: 6.46, 10.45] and MD = 5.76 [95% CI: 4.46, 7.05], respectively). Subgroup analysis revealed that cardiac progenitor cells had the largest effect size for FS, and was significant from pluripotent, mesenchymal and endothelial stem cell types. In large animal studies, the overall improvement of EF favoured the use of stem cell-embedded scaffolds compared to direct injection of cells (MD = 10.49 [95% CI: 6.30, 14.67]). Significant publication bias was present in the small animal trials for EF and FS. This study supports the use of bioactive scaffolds to aid in stem cell-based cardiac regeneration. Hydrogels should be further investigated in larger animal models for clinical translation.
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10
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Chou SE, Lee KL, Wei PK, Cheng JY. Screening anti-metastasis drugs by cell adhesion-induced color change in a biochip. LAB ON A CHIP 2021; 21:2955-2970. [PMID: 34132296 DOI: 10.1039/d1lc00039j] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Metastasis is a frequent complication of cancer and accounts for more than 60% of patients' mortality. Despite technological advancements, treatment options are still limited. Ion channels participate in the regulation of cell adhesion, whilst the regulation of cell adhesion further controls metastasis formation. However, to develop a new ion channel inhibitor targeting metastasis takes tremendous effort and resources; therefore, drug repurposing is an emerging strategy in oncology. In previous studies, we have developed a metal-based nanoslit surface plasmon resonance (SPR) platform to examine the influence of drugs on the cell adhesion process. In this work, we developed a scanner-based cell adhesion kinetic examination (CAKE) system that is capable of monitoring the cell adhesion process by measuring color changes of SPR biosensors. The system's performance was demonstrated by screening the anti-metastasis ability of compounds from a commercial ion-channel inhibitor library. Out of the 274 compounds from the inhibitor library, zinc pyrithione (ZPT) and terfenadine were demonstrated to influence CL1-5 cell adhesion. The cell responses to the two compounds were then compared with those by traditional cell adhesion assays where similar behavior was observed. Further investigation of the two compounds using wound healing and transwell assays was performed and inhibitions of both cell migration and invasion by the two compounds were also observed. The results indicate that ZPT and terfenadine are potential candidates for anti-metastasis drugs. Our work has demonstrated the label-free drug screening ability of our CAKE system for finding potential drugs for cancer treatment.
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Affiliation(s)
- Shih-En Chou
- Research Center for Applied Sciences, Academia Sinica Taiwan, Taipei, 11529, Taiwan.
| | - Kuang-Li Lee
- Research Center for Applied Sciences, Academia Sinica Taiwan, Taipei, 11529, Taiwan.
| | - Pei-Kuen Wei
- Research Center for Applied Sciences, Academia Sinica Taiwan, Taipei, 11529, Taiwan. and Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan
| | - Ji-Yen Cheng
- Research Center for Applied Sciences, Academia Sinica Taiwan, Taipei, 11529, Taiwan. and Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan and Department of Mechanical and Mechatronic Engineering, National Taiwan Ocean University, Keelung, 20224, Taiwan and College of Engineering, Chang Gung University, Taoyuan, 33302, Taiwan
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11
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Use of electroconductive biomaterials for engineering tissues by 3D printing and 3D bioprinting. Essays Biochem 2021; 65:441-466. [PMID: 34296738 DOI: 10.1042/ebc20210003] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 06/16/2021] [Accepted: 06/21/2021] [Indexed: 12/13/2022]
Abstract
Existing methods of engineering alternatives to restore or replace damaged or lost tissues are not satisfactory due to the lack of suitable constructs that can fit precisely, function properly and integrate into host tissues. Recently, three-dimensional (3D) bioprinting approaches have been developed to enable the fabrication of pre-programmed synthetic tissue constructs that have precise geometries and controlled cellular composition and spatial distribution. New bioinks with electroconductive properties have the potential to influence cellular fates and function for directed healing of different tissue types including bone, heart and nervous tissue with the possibility of improved outcomes. In the present paper, we review the use of electroconductive biomaterials for the engineering of tissues via 3D printing and 3D bioprinting. Despite significant advances, there remain challenges to effective tissue replacement and we address these challenges and describe new approaches to advanced tissue engineering.
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12
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Du H, Zhao Y, Li H, Wang DW, Chen C. Roles of MicroRNAs in Glucose and Lipid Metabolism in the Heart. Front Cardiovasc Med 2021; 8:716213. [PMID: 34368265 PMCID: PMC8339264 DOI: 10.3389/fcvm.2021.716213] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 06/21/2021] [Indexed: 12/22/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that participate in heart development and pathological processes mainly by silencing gene expression. Overwhelming evidence has suggested that miRNAs were involved in various cardiovascular pathological processes, including arrhythmias, ischemia-reperfusion injuries, dysregulation of angiogenesis, mitochondrial abnormalities, fibrosis, and maladaptive remodeling. Various miRNAs could regulate myocardial contractility, vascular proliferation, and mitochondrial function. Meanwhile, it was reported that miRNAs could manipulate nutrition metabolism, especially glucose and lipid metabolism, by regulating insulin signaling pathways, energy substrate transport/metabolism. Recently, increasing studies suggested that the abnormal glucose and lipid metabolism were closely associated with a broad spectrum of cardiovascular diseases (CVDs). Therefore, maintaining glucose and lipid metabolism homeostasis in the heart might be beneficial to CVD patients. In this review, we summarized the present knowledge of the functions of miRNAs in regulating cardiac glucose and lipid metabolism, as well as highlighted the miRNA-based therapies targeting cardiac glucose and lipid metabolism.
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Affiliation(s)
- Hengzhi Du
- Division of Cardiology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Yanru Zhao
- Division of Cardiology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Huaping Li
- Division of Cardiology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Dao Wen Wang
- Division of Cardiology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Chen Chen
- Division of Cardiology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
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13
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Lan H, Xue Q, Liu Y, Jin K, Fang X, Shao H. The emerging therapeutic role of mesenchymal stem cells in anthracycline-induced cardiotoxicity. Cell Tissue Res 2021; 384:1-12. [PMID: 33433685 DOI: 10.1007/s00441-020-03364-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 11/24/2020] [Indexed: 12/22/2022]
Abstract
Mesenchymal stem cell (MSC)-based tissue regeneration therapy has been extensively investigated for cardiac regeneration over the past two decades. Numerous animal and clinical investigations demonstrated the efficacy of various types of MSCs towards myocardial protection and restoration against anthracycline-induced cardiotoxicity (AIC). It has been established that local or systemic administration of MSCs considerably improved the cardiac function, while ameliorating inflammatory responses and myocardial fibrosis. Several factors influence the outcomes of MSC treatment for AIC, including MSC types, dosages, and routes and duration of administration. In this review, we discuss the recent (from 2015 to 2020) experimental and clinical research on the preventive and regeneration efficacy of different types of MSCs (with or without supporting agents) against AIC, as well as the key factors responsible for MSC-mediated cardiac repair. In addition, challenges and future perspectives of MSC-based cardiac regeneration therapy are also outlined.
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Affiliation(s)
- Huanrong Lan
- Department of Breast and Thyroid Surgery, Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, People's Republic of China
| | - Qi Xue
- Department of Cardiology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, People's Republic of China
| | - Yuyao Liu
- Department of Colorectal Surgery, Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, People's Republic of China
| | - Ketao Jin
- Department of Colorectal Surgery, Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, People's Republic of China
| | - Xingliang Fang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Shaoxing University (Shaoxing Municipal Hospital), Shaoxing, 312000, Zhejiang Province, People's Republic of China
| | - Hong Shao
- Department of Cardiology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, People's Republic of China.
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14
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Gelatin-based hydrogels combined with electrical stimulation to modulate neonatal rat cardiomyocyte beating and promote maturation. Biodes Manuf 2020. [DOI: 10.1007/s42242-020-00100-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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15
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Gorabi AM, Bianconi V, Pirro M, Banach M, Sahebkar A. Regulation of cardiac stem cells by microRNAs: State-of-the-art. Biomed Pharmacother 2019; 120:109447. [PMID: 31580971 DOI: 10.1016/j.biopha.2019.109447] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 09/05/2019] [Accepted: 09/06/2019] [Indexed: 12/27/2022] Open
Abstract
Stem cells have a therapeutic potential in various medical conditions. In cases without sufficient response to conventional drug treatments, stem cells represent a next generation therapeutic strategy in cardiovascular diseases. Cardiac stem cells (CSCs), among a wide variety of stem cell sources, have been identified as a valid option for stem cell-based therapy in cardiovascular diseases. CSCs mainly act as a cell source to supply the physiological need for cardiovascular cells. However, they have been demonstrated to reproduce the myocardial cells under pathological settings. Despite their roles and functions have somewhat been clarified, molecular pathways underlying the regulatory mechanisms of CSCs are still not fully elucidated. Several studies have recently shown that different microRNAs (miRNAs) play a substantial role in regulating and controlling both the physiological and pathological proliferation and differentiation of stem cells. MiRNAs are small non-coding RNA molecules that regulate gene expression and may undergo aberrant expression levels during pathological conditions. Understanding the way through which miRNAs regulate CSC behavior may open up new horizons in modulating these cells in vitro to devise sophisticated approaches for treating patients with cardiovascular diseases. In this review article, we tried to discuss available evidence about the role of miRNAs in regulating CSCs.
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Affiliation(s)
- Armita Mahdavi Gorabi
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Vanessa Bianconi
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Matteo Pirro
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, Lodz, Poland; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
| | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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16
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Maxwell JT, Trac D, Shen M, Brown ME, Davis ME, Chao MS, Supapannachart KJ, Zaladonis CA, Baker E, Li ML, Zhao J, Jacobs DI. Electrical Stimulation of pediatric cardiac-derived c-kit + progenitor cells improves retention and cardiac function in right ventricular heart failure. Stem Cells 2019; 37:1528-1541. [PMID: 31574184 PMCID: PMC6916193 DOI: 10.1002/stem.3088] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 07/18/2019] [Accepted: 08/29/2019] [Indexed: 12/20/2022]
Abstract
Nearly 1 in every 120 children born has a congenital heart defect. Although surgical therapy has improved survival, many of these children go on to develop right ventricular heart failure (RVHF). The emergence of cardiovascular regenerative medicine as a potential therapeutic strategy for pediatric HF has provided new avenues for treatment with a focus on repairing or regenerating the diseased myocardium to restore cardiac function. Although primarily tried using adult cells and adult disease models, stem cell therapy is relatively untested in the pediatric population. Here, we investigate the ability of electrical stimulation (ES) to enhance the retention and therapeutic function of pediatric cardiac-derived c-kit+ progenitor cells (CPCs) in an animal model of RVHF. Human CPCs isolated from pediatric patients were exposed to chronic ES and implanted into the RV myocardium of rats. Cardiac function and cellular retention analysis showed electrically stimulated CPCs (ES-CPCs) were retained in the heart at a significantly higher level and longer time than control CPCs and also significantly improved right ventricular functional parameters. ES also induced upregulation of extracellular matrix and adhesion genes and increased in vitro survival and adhesion of cells. Specifically, upregulation of β1 and β5 integrins contributed to the increased retention of ES-CPCs. Lastly, we show that ES induces CPCs to release higher levels of pro-reparative factors in vitro. These findings suggest that ES can be used to increase the retention, survival, and therapeutic effect of human c-kit+ progenitor cells and can have implications on a variety of cell-based therapies. Stem Cells 2019;37:1528-1541.
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Affiliation(s)
- Joshua T. Maxwell
- Division of Pediatric Cardiology, Department of PediatricsEmory University School of MedicineAtlantaGeorgiaUSA
- Children's Heart Research & Outcomes (HeRO) CenterChildren's Healthcare of Atlanta & Emory UniversityAtlantaGeorgiaUSA
| | - David Trac
- Wallace H. Coulter Department of Biomedical EngineeringGeorgia Institute of Technology & Emory University School of MedicineAtlantaGeorgiaUSA
| | - Ming Shen
- Division of Pediatric Cardiology, Department of PediatricsEmory University School of MedicineAtlantaGeorgiaUSA
- Children's Heart Research & Outcomes (HeRO) CenterChildren's Healthcare of Atlanta & Emory UniversityAtlantaGeorgiaUSA
| | - Milton E. Brown
- Wallace H. Coulter Department of Biomedical EngineeringGeorgia Institute of Technology & Emory University School of MedicineAtlantaGeorgiaUSA
| | - Michael E. Davis
- Division of Pediatric Cardiology, Department of PediatricsEmory University School of MedicineAtlantaGeorgiaUSA
- Children's Heart Research & Outcomes (HeRO) CenterChildren's Healthcare of Atlanta & Emory UniversityAtlantaGeorgiaUSA
- Wallace H. Coulter Department of Biomedical EngineeringGeorgia Institute of Technology & Emory University School of MedicineAtlantaGeorgiaUSA
| | - Myra S. Chao
- Emory University College of Arts and SciencesAtlantaGeorgiaUSA
| | | | | | - Emily Baker
- Emory University College of Arts and SciencesAtlantaGeorgiaUSA
| | - Martin L. Li
- Emory University College of Arts and SciencesAtlantaGeorgiaUSA
| | - Jennifer Zhao
- Cornell University College of Arts and SciencesIthacaNew YorkUSA
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17
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Song SY, Yoo J, Go S, Hong J, Sohn HS, Lee JR, Kang M, Jeong GJ, Ryu S, Kim SHL, Hwang NS, Char K, Kim BS. Cardiac-mimetic cell-culture system for direct cardiac reprogramming. Theranostics 2019; 9:6734-6744. [PMID: 31660065 PMCID: PMC6815967 DOI: 10.7150/thno.35574] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 08/05/2019] [Indexed: 12/19/2022] Open
Abstract
Rationale: Cardiovascular diseases often cause substantial heart damage and even heart failure due to the limited regenerative capacity of adult cardiomyocytes. The direct cardiac reprogramming of fibroblasts could be a promising therapeutic option for these patients. Although exogenous transcriptional factors can induce direct cardiac reprogramming, the reprogramming efficiency is too low to be used clinically. Herein, we introduce a cardiac-mimetic cell-culture system that resembles the microenvironment in the heart and provides interactions with cardiomyocytes and electrical cues to the cultured fibroblasts for direct cardiac reprogramming. Methods: Nano-thin and nano-porous membranes and heart like electric stimulus were used in the cardiac-mimetic cell-culture system. The human neonatal dermal fibroblasts containing cardiac transcription factors were plated on the membrane and cultured with the murine cardiomyocyte in the presence of the electric stimulus. The reprogramming efficiency was evaluated by qRT-PCR and immunocytochemistry. Results: Nano-thin and nano-porous membranes in the culture system facilitated interactions between fibroblasts and cardiomyocytes in coculture. The cellular interactions and electric stimulation supplied by the culture system dramatically enhanced the cardiac reprogramming efficiency of cardiac-specific transcriptional factor-transfected fibroblasts. Conclusion: The cardiac-mimetic culture system may serve as an effective tool for producing a feasible number of reprogrammed cardiomyocytes from fibroblasts.
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18
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Hathaway QA, Durr AJ, Shepherd DL, Pinti MV, Brandebura AN, Nichols CE, Kunovac A, Goldsmith WT, Friend SA, Abukabda AB, Fink GK, Nurkiewicz TR, Hollander JM. miRNA-378a as a key regulator of cardiovascular health following engineered nanomaterial inhalation exposure. Nanotoxicology 2019; 13:644-663. [PMID: 30704319 PMCID: PMC6629495 DOI: 10.1080/17435390.2019.1570372] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 11/13/2018] [Accepted: 12/12/2018] [Indexed: 12/31/2022]
Abstract
Nano-titanium dioxide (nano-TiO2), though one of the most utilized and produced engineered nanomaterials (ENMs), diminishes cardiovascular function through dysregulation of metabolism and mitochondrial bioenergetics following inhalation exposure. The molecular mechanisms governing this cardiac dysfunction remain largely unknown. The purpose of this study was to elucidate molecular mediators that connect nano-TiO2 exposure with impaired cardiac function. Specifically, we were interested in the role of microRNA (miRNA) expression in the resulting dysfunction. Not only are miRNA global regulators of gene expression, but also miRNA-based therapeutics provide a realistic treatment modality. Wild type and MiRNA-378a knockout mice were exposed to nano-TiO2 with an aerodynamic diameter of 182 ± 1.70 nm and a mass concentration of 11.09 mg/m3 for 4 h. Cardiac function, utilizing the Vevo 2100 Imaging System, electron transport chain complex activities, and mitochondrial respiration assessed cardiac and mitochondrial function. Immunoblotting and qPCR examined molecular targets of miRNA-378a. MiRNA-378a-3p expression was increased 48 h post inhalation exposure to nano-TiO2. Knockout of miRNA-378a preserved cardiac function following exposure as revealed by preserved E/A ratio and E/SR ratio. In knockout animals, complex I, III, and IV activities (∼2- to 6-fold) and fatty acid respiration (∼5-fold) were significantly increased. MiRNA-378a regulated proteins involved in mitochondrial fusion, transcription, and fatty acid metabolism. MiRNA-378a-3p acts as a negative regulator of mitochondrial metabolic and biogenesis pathways. MiRNA-378a knockout animals provide a protective effect against nano-TiO2 inhalation exposure by altering mitochondrial structure and function. This is the first study to manipulate a miRNA to attenuate the effects of ENM exposure.
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Affiliation(s)
- Quincy A. Hathaway
- Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV, USA
- Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, WV, USA
- Toxicology Working Group, West Virginia University School of Medicine, Morgantown, WV, USA
| | - Andrya J. Durr
- Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV, USA
- Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, WV, USA
| | - Danielle L. Shepherd
- Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV, USA
- Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, WV, USA
| | - Mark V. Pinti
- Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV, USA
- Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, WV, USA
| | - Ashley N. Brandebura
- Rockefeller Neuroscience Institute, West Virginia University School of Medicine, Morgantown, WV, USA
- Department of Biochemistry, West Virginia University School of Medicine, Morgantown, WV, USA
| | - Cody E. Nichols
- Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
| | - Amina Kunovac
- Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV, USA
- Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, WV, USA
| | - William T. Goldsmith
- Toxicology Working Group, West Virginia University School of Medicine, Morgantown, WV, USA
- Department of Physiology, Pharmacology & Neuroscience, Morgantown, WV, USA
| | - Sherri A. Friend
- National Institute for Occupational Safety and Health, Morgantown, WV, USA
| | - Alaeddin B. Abukabda
- Toxicology Working Group, West Virginia University School of Medicine, Morgantown, WV, USA
- Department of Physiology, Pharmacology & Neuroscience, Morgantown, WV, USA
| | - Garrett K. Fink
- Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV, USA
| | - Timothy R. Nurkiewicz
- Toxicology Working Group, West Virginia University School of Medicine, Morgantown, WV, USA
- Department of Physiology, Pharmacology & Neuroscience, Morgantown, WV, USA
| | - John M. Hollander
- Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV, USA
- Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, WV, USA
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19
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Circulating microRNA-378 levels serve as a novel biomarker for assessing the severity of coronary stenosis in patients with coronary artery disease. Biosci Rep 2019; 39:BSR20182016. [PMID: 31064817 PMCID: PMC6522732 DOI: 10.1042/bsr20182016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 04/05/2019] [Accepted: 05/02/2019] [Indexed: 01/22/2023] Open
Abstract
Background: Circulating microRNAs (miRNA) are steady preserved in blood plasma. Multiple evidences have shown that miRNAs play a crucial role in cardiovascular disease including miRNA-378, which has been illustrated to participate in diverse physiological and pathological processes of cardiovascular disease. In the present study, we aim to explore the expression of plasma miRNA-378 and its clinical significance in patients with coronary artery disease (CAD). Methods: MiRNA-378 expression in blood plasma was performed by quantitative real-time PCR (qRT-PCR) in 215 CAD patients and 52 matched controls of healthy populations. Medical information of all patients including the results of coronary angiography (CAG) was acquired through hospital information system (HIS). Spearman’s correlation, binary linear regression, and covariance analysis were used to examine the association between miRNA-378 and relative clinical risk factors. Receiver operating characteristic curve analysis was applied to evaluate the value of miRNA-378 in predicting the disease severity of coronary lesion. Results: Plasma miR-378 expression was significantly down-regulated in CAD patients compared with healthy controls. Relative miR-378 level was shown conversely correlated with Gensini score, which present the severity of coronary artery lesions. Moreover, it is indicated that miR-378 expression can effectively distinguish patients with or without coronary artery stenosis. Conclusions: Plasma miR-378 levels appear to be a promising non-invasive biomarker, but require to be further validated by a large cohort study in future.
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20
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Hou HS, Lee KL, Wang CH, Hsieh TH, Sun JJ, Wei PK, Cheng JY. Simultaneous assessment of cell morphology and adhesion using aluminum nanoslit-based plasmonic biosensing chips. Sci Rep 2019; 9:7204. [PMID: 31076598 PMCID: PMC6510726 DOI: 10.1038/s41598-019-43442-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 04/24/2019] [Indexed: 11/13/2022] Open
Abstract
A variety of physiological and pathological processes rely on cell adhesion, which is most often tracked by changes in cellular morphology. We previously reported a novel gold nanoslit-based biosensor that is capable of real-time and label-free monitoring of cell morphological changes and cell viability. However, the preparation of gold biosensors is inefficient, complicated and costly. Recently, nanostructure-based aluminum (Al) sensors have been introduced for biosensing applications. The Al-based sensor has a longer decay length and is capable of analyzing large-sized mass such as cells. Here, we developed two types of double-layer Al nanoslit-based plasmonic biosensors, which were nanofabricated and used to evaluate the correlation between metastatic potency and adhesion of lung cancer and melanoma cell lines. Cell adhesion was determined by Fano resonance signals that were induced by binding of the cells to the nanoslit. The peak and dip of the Fano resonance spectrum respectively reflected long- and short-range cellular changes, allowing us to simultaneously detect and distinguish between focal adhesion and cell spreading. Also, the Al nanoslit-based biosensor chips were used to evaluate the inhibitory effects of drugs on cancer cell spreading. We are the first to report the use of double layer Al nanoslit-based biosensors for detection of cell behavior, and such devices may become powerful tools for anti-metastasis drug screening in the future.
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Affiliation(s)
- Hsien-San Hou
- Research Center for Applied Sciences, Academia Sinica, Taipei, 11529, Taiwan
| | - Kuang-Li Lee
- Research Center for Applied Sciences, Academia Sinica, Taipei, 11529, Taiwan
| | - Chen-Hung Wang
- Research Center for Applied Sciences, Academia Sinica, Taipei, 11529, Taiwan
| | - Tung-Han Hsieh
- Research Center for Applied Sciences, Academia Sinica, Taipei, 11529, Taiwan
| | - Juan-Jie Sun
- Research Center for Applied Sciences, Academia Sinica, Taipei, 11529, Taiwan
| | - Pei-Kuen Wei
- Research Center for Applied Sciences, Academia Sinica, Taipei, 11529, Taiwan.,Institute of Biophotonics, National Yang-Ming University, Taipei, 11221, Taiwan
| | - Ji-Yen Cheng
- Research Center for Applied Sciences, Academia Sinica, Taipei, 11529, Taiwan. .,Institute of Biophotonics, National Yang-Ming University, Taipei, 11221, Taiwan. .,Department of Mechanical and Mechatronic Engineering, National Taiwan Ocean University, Keelung, 20224, Taiwan. .,College of Engineering, Chang Gung University, Taoyuan, 33302, Taiwan.
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21
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Shabani P, Ghazizadeh Z, Gorgani-Firuzjaee S, Molazem M, Rajabi S, Vahdat S, Azizi Y, Doosti M, Aghdami N, Baharvand H. Cardioprotective effects of omega-3 fatty acids and ascorbic acid improve regenerative capacity of embryonic stem cell-derived cardiac lineage cells. Biofactors 2019; 45:427-438. [PMID: 30907984 DOI: 10.1002/biof.1501] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Accepted: 02/15/2019] [Indexed: 12/23/2022]
Abstract
One of the major issues in cell therapy of myocardial infarction (MI) is early death of engrafted cells in a harsh oxidative stress environment, which limits the potential therapeutic utility of this strategy in the clinical setting. Increasing evidence implicates beneficial effects of omega-3 fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and ascorbic acid (AA) in cardiovascular diseases, in particular their role in ameliorating fibrosis. In the current study, we aim to assess the cytoprotective role of EPA + DHA and AA in protecting embryonic stem cell (ESC)-derived cardiac lineage cells and amelioration of fibrosis. Herein, we have shown that preincubation of the cells with EPA + DHA + AA prior to H2 O2 treatment attenuated generation of reactive oxygen species (ROS) and enhanced cell viability. Gene expression analysis revealed that preincubation with EPA + DHA + AA followed by H2 O2 treatment, upregulated heme oxygenase-1 (HO-1) along with cardiac markers (GATA4, myosin heavy chain, α isoform [MYH6]), connexin 43 [CX43]) and attenuated oxidative stress-induced upregulation of fibroblast markers (vimentin and collagen type 1 [Col1]). Alterations in gene expression patterns were followed by marked elevation of cardiac troponin (TNNT2) positive cells and reduced numbers of vimentin positive cells. An injection of EPA + DHA + AA-pretreated ESC-derived cardiac lineage cells into the ischemic myocardium of a rat model of MI significantly reduced fibrosis compared to the vehicle group. This study provided evidence that EPA + DHA + AA may be an appropriate preincubation regimen for regenerative purposes. © 2019 BioFactors, 45(3):427-438, 2019.
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Affiliation(s)
- Parisa Shabani
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Biochemistry, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Zaniar Ghazizadeh
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Sattar Gorgani-Firuzjaee
- Department of Laboratory Sciences, Faculty of Para Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Mohammad Molazem
- Department of Radiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Sarah Rajabi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Sadaf Vahdat
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
| | - Yaser Azizi
- Physiology Research Center, Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahmood Doosti
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nasser Aghdami
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Hossein Baharvand
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Developmental Biology, University of Science and Culture, Tehran, Iran
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22
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Huang W, Liang J, Feng Y, Jia Z, Jiang L, Cai W, Paul C, Gu JG, Stambrook PJ, Millard RW, Zhu XL, Zhu P, Wang Y. Heterogeneity of adult masseter muscle satellite cells with cardiomyocyte differentiation potential. Exp Cell Res 2018; 371:20-30. [PMID: 29842877 PMCID: PMC7291879 DOI: 10.1016/j.yexcr.2018.05.028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Revised: 05/21/2018] [Accepted: 05/24/2018] [Indexed: 01/25/2023]
Abstract
Although resident cardiac stem cells have been reported, regeneration of functional cardiomyocytes (CMs) remains a challenge. The present study identifies an alternative progenitor source for CM regeneration without the need for genetic manipulation or invasive heart biopsy procedures. Unlike limb skeletal muscles, masseter muscles (MM) in the mouse head are developed from Nkx2-5 mesodermal progenitors. Adult masseter muscle satellite cells (MMSCs) display heterogeneity in developmental origin and cell phenotypes. The heterogeneous MMSCs that can be characterized by cell sorting based on stem cell antigen-1 (Sca1) show different lineage potential. While cardiogenic potential is preserved in Sca1+ MMSCs as shown by expression of cardiac progenitor genes (including Nkx2-5), skeletal myogenic capacity is maintained in Sca1- MMSCs with Pax7 expression. Sca1+ MMSC-derived beating cells express cardiac genes and exhibit CM-like morphology. Electrophysiological properties of MMSC-derived CMs are demonstrated by calcium transients and action potentials. These findings show that MMSCs could serve as a novel cell source for cardiomyocyte replacement.
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Affiliation(s)
- Wei Huang
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jialiang Liang
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Yuliang Feng
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Zhanfeng Jia
- Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Lin Jiang
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Wenfeng Cai
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Christian Paul
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jianguo G Gu
- Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Peter J Stambrook
- Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Ronald W Millard
- Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Xiao-Lan Zhu
- Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Ping Zhu
- Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
| | - Yigang Wang
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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23
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Yuan Y, Du W, Liu J, Ma W, Zhang L, Du Z, Cai B. Stem Cell-Derived Exosome in Cardiovascular Diseases: Macro Roles of Micro Particles. Front Pharmacol 2018; 9:547. [PMID: 29904347 PMCID: PMC5991072 DOI: 10.3389/fphar.2018.00547] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 05/08/2018] [Indexed: 12/15/2022] Open
Abstract
The stem cell-based therapy has emerged as the promising therapeutic strategies for cardiovascular diseases (CVDs). Recently, increasing evidence suggest stem cell-derived active exosomes are important communicators among cells in the heart via delivering specific substances to the adjacent/distant target cells. These exosomes and their contents such as certain proteins, miRNAs and lncRNAs exhibit huge beneficial effects on preventing heart damage and promoting cardiac repair. More importantly, stem cell-derived exosomes are more effective and safer than stem cell transplantation. Therefore, administration of stem cell-derived exosomes will expectantly be an alternative stem cell-based therapy for the treatment of CVDs. Furthermore, modification of stem cell-derived exosomes or artificial synthesis of exosomes will be the new therapeutic tools for CVDs in the future. In addition, stem cell-derived exosomes also have been implicated in the diagnosis and prognosis of CVDs. In this review, we summarize the current advances of stem cell-derived exosome-based treatment and prognosis for CVDs, including their potential benefits, underlying mechanisms and limitations, which will provide novel insights of exosomes as a new tool in clinical therapeutic translation in the future.
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Affiliation(s)
- Ye Yuan
- Department of Clinical Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China
| | - Weijie Du
- Department of Clinical Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China
| | - Jiaqi Liu
- Department of Pharmacology, College of Pharmacy, Mudanjiang Medical University, Mudanjiang, China
| | - Wenya Ma
- Department of Clinical Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China
| | - Lai Zhang
- Department of Clinical Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China
| | - Zhimin Du
- Department of Clinical Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China
| | - Benzhi Cai
- Department of Clinical Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China
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Ma R, Liang J, Huang W, Guo L, Cai W, Wang L, Paul C, Yang HT, Kim HW, Wang Y. Electrical Stimulation Enhances Cardiac Differentiation of Human Induced Pluripotent Stem Cells for Myocardial Infarction Therapy. Antioxid Redox Signal 2018; 28:371-384. [PMID: 27903111 PMCID: PMC5770128 DOI: 10.1089/ars.2016.6766] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIMS Electrical stimulation (EleS) can promote cardiac differentiation, but the underlying mechanism is not well known. This study investigated the effect of EleS on cardiomyocyte (CM) differentiation of human induced pluripotent stem cells (hiPSCs) and evaluated the therapeutic effects for the treatment of myocardial infarction (MI). RESULTS Cardiac differentiation of hiPSCs was induced with EleS after embryoid body formation. Spontaneously beating hiPSCs were observed as early at 2 days when treated with EleS compared with control treatment. The cardiac differentiation efficiency of hiPSCs was significantly enhanced by EleS. In addition, the functional maturation of hiPSC-CMs under EleS was confirmed by calcium indicators, intracellular Ca2+ levels, and expression of structural genes. Mechanistically, EleS mediated cardiac differentiation of hiPSCs through activation of Ca2+/PKC/ERK pathways, as revealed by RNA sequencing, quantitative polymerase chain reaction, and Western blotting. After transplantation in immunodeficient MI mice, EleS-preconditioned hiPSC-derived cells significantly improved cardiac function and attenuated expansion of infarct size. The preconditioned hiPSC-derived CMs were functionally integrated with the host heart. INNOVATION We show EleS as an efficacious time-saving approach for CM generation. The global RNA profiling shows that EleS can accelerate cardiac differentiation of hiPSCs through activation of multiple pathways. The cardiac-mimetic electrical signals will provide a novel approach to generate functional CMs and facilitate cardiac tissue engineering for successful heart regeneration. CONCLUSION EleS can enhance efficiency of cardiac differentiation in hiPSCs and promote CM maturation. The EleS-preconditioned CMs emerge as a promising approach for clinical application in MI treatment. Antioxid. Redox Signal. 28, 371-384.
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Affiliation(s)
- Ruilian Ma
- 1 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Jialiang Liang
- 1 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Wei Huang
- 1 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Linlin Guo
- 1 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Wenfeng Cai
- 1 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Lei Wang
- 1 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Christian Paul
- 1 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Huang-Tian Yang
- 2 Key Laboratory of Stem Cell Biology and Laboratory of Molecular Cardiology, Institute of Health Sciences, Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) and Shanghai Jiao Tong University School of Medicine (SJTUSM) , Shanghai, China
| | - Ha Won Kim
- 1 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Yigang Wang
- 1 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio
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25
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Yoon JK, Lee TI, Bhang SH, Shin JY, Myoung JM, Kim BS. Stretchable Piezoelectric Substrate Providing Pulsatile Mechanoelectric Cues for Cardiomyogenic Differentiation of Mesenchymal Stem Cells. ACS APPLIED MATERIALS & INTERFACES 2017; 9:22101-22111. [PMID: 28560866 DOI: 10.1021/acsami.7b03050] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Ex vivo induction of cardiomyogenic differentiation of mesenchymal stem cells (MSCs) before implantation would potentiate therapeutic efficacy of stem cell therapies for ischemic heart diseases because MSCs rarely undergo cardiomyogenic differentiation following implantation. In cardiac microenvironments, electric pulse and cyclic mechanical strain are sequentially produced. However, no study has applied the pulsatile mechanoelectric cues (PMEC) to stimulate cardiomyogenic differentiation of MSCs ex vivo. In this study, we developed a stretchable piezoelectric substrate (SPS) that can provide PMEC to human MSCs (hMSCs) for cardiomyogenic differentiation ex vivo. Our data showed that hMSCs subjected to PMEC by SPS underwent promoted cardiac phenotype development: cell alignment and the expression of cardiac markers (i.e., cardiac transcription factors, structural proteins, ion channel proteins, and gap junction proteins). The enhanced cardiac phenotype development was mediated by the upregulation of cardiomyogenic differentiation-related autocrine factor expression, focal adhesion kinase, and extracellular signal-regulated kinases signaling pathways. Thus, SPS providing electrical and mechanical regulation of stem cells may be utilized to potentiate hMSC therapies for myocardial infarction and provide a tool for the study of stem cell biology.
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Affiliation(s)
| | - Tae Il Lee
- Department of BioNano Technology, Gachon University , Seongnam 13557, Republic of Korea
| | - Suk Ho Bhang
- School of Chemical Engineering, Sungkyunkwan University , Suwon 16419, Republic of Korea
| | | | - Jae-Min Myoung
- Department of Materials Science and Engineering, Yonsei University , Seoul 03722, Republic of Korea
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26
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Exosomes Derived from Embryonic Stem Cells as Potential Treatment for Cardiovascular Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 998:187-206. [DOI: 10.1007/978-981-10-4397-0_13] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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27
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Fang YC, Yeh CH. Role of microRNAs in Vascular Remodeling. Curr Mol Med 2016; 15:684-96. [PMID: 26391551 PMCID: PMC5384354 DOI: 10.2174/1566524015666150921105031] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Revised: 09/06/2015] [Accepted: 09/18/2015] [Indexed: 12/20/2022]
Abstract
Besides being involved in the gradual formation of blood vessels during embryonic development, vascular remodeling also contributes to the progression of various cardiovascular diseases, such as; myocardial infarction, heart failure, atherosclerosis, pulmonary artery hypertension, restenosis, aneurysm, etc. The integrated mechanisms; proliferation of medial smooth muscle cell, dysregulation of intimal endothelial cell, activation of adventitial fibroblast, inflammation of macrophage, and the participation of extracellular matrix proteins are important factors in vascular remodeling. In the recent studies, microRNAs (miRs) have been shown to be expressed in all of these cell-types and play important roles in the mechanisms of vascular remodeling. Therefore, some miRs may be involved in prevention and others in the aggravation of the vascular lesions. miRs are small, endogenous, conserved, single-stranded, non-coding RNAs; which degrade target RNAs or inhibit translation post-transcriptionally. In this paper, we reviewed the function and mechanisms of miRs, which are highly expressed in various cells types, especially endothelial and smooth muscle cells, which are closely involved in the process of vascular remodeling. We also assess the functions of these miRs in the hope that they may provide new possibilities of diagnosis and treatment choices for the related diseases.
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Affiliation(s)
| | - C-H Yeh
- Department of Thoracic & Cardiovascular Surgery, Chang Gung Memorial Hospital at Keelung, 222 Mai-Chin Road, Keelung, 204, Taiwan.
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28
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Rouabhia M, Park HJ, Zhang Z. Electrically Activated Primary Human Fibroblasts Improve In Vitro and In Vivo Skin Regeneration. J Cell Physiol 2016; 231:1814-21. [PMID: 26661681 DOI: 10.1002/jcp.25289] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 12/10/2015] [Indexed: 12/14/2022]
Abstract
Electrical stimulation (ES) changes cellular behaviors and thus constitutes a potential strategy to promote wound healing. However, well-controlled in vitro findings have yet to be translated to in vivo trials. This study was to demonstrate the feasibility and advantages of transplanting electrically activated cells (E-Cells) to help wound healing. Primary human skin fibroblasts were activated through well defined ES and cultured with keratinocytes to generate engineered human skin (EHS), which were transplanted to nu/nu mice. The electrically activated EHS grafts were analyzed at 20 and 30 days post-grafting, showing faster wound closure, thick epidermis, vasculature, and functional basement membrane containing laminin and type IV collagen that were totally produced by the implanted human cells. Because a variety of cells can be electrically activated, E-Cells may become a new cell source and the transplantation of E-Cells may represent a new strategy in wound healing and tissue engineering. J. Cell. Physiol. 231: 1814-1821, 2016. © 2015 Wiley Periodicals, Inc.
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Affiliation(s)
- Mahmoud Rouabhia
- Groupe de Recherche en Écologie Buccale, Faculté de Médecine Dentaire, Université Laval, Québec, Canada
| | - Hyun Jin Park
- Groupe de Recherche en Écologie Buccale, Faculté de Médecine Dentaire, Université Laval, Québec, Canada.,Département de Chirurgie, Faculté de Médecine, Axe Médecine Régénératrice, Centre de Recherche du CHU de Québec, Université Laval, Québec, Canada
| | - Ze Zhang
- Département de Chirurgie, Faculté de Médecine, Axe Médecine Régénératrice, Centre de Recherche du CHU de Québec, Université Laval, Québec, Canada
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29
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Campbell CR, Berman AE, Weintraub NL, Tang YL. Electrical stimulation to optimize cardioprotective exosomes from cardiac stem cells. Med Hypotheses 2016; 88:6-9. [PMID: 26880625 DOI: 10.1016/j.mehy.2015.12.022] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 12/25/2015] [Indexed: 01/18/2023]
Abstract
Injured or ischemic cardiac tissue has limited intrinsic capacity for regeneration. While stem cell transplantation is a promising approach to stimulating cardiac repair, its success in humans has thus far been limited. Harnessing the therapeutic benefits of stem cells requires a better understanding of their mechanisms of action and methods to optimize their function. Cardiac stem cells (CSC) represent a particularly effective cellular source for cardiac repair, and pre-conditioning CSC with electrical stimulation (EleS) was demonstrated to further enhance their function, although the mechanisms are unknown. Recent studies suggest that transplanted stem cells primarily exert their effects through communicating with endogenous tissues via the release of exosomes containing cardioprotective molecules such as miRNAs, which upon uptake by recipient cells may stimulate survival, proliferation, and angiogenesis. Exosomes are also effective therapeutic agents in isolation and may provide a feasible alternative to stem cell transplantation. We hypothesize that EleS enhances CSC-mediated cardiac repair through its beneficial effects on production of cardioprotective exosomes. Moreover, we hypothesize that the beneficial effects of biventricular pacing in patients with heart failure may in part result from EleS-induced preconditioning of endogenous CSC to promote cardiac repair. With future research, our hypothesis may provide applications to optimize stem cell therapy and augment current pacing protocols, which may significantly advance the treatment of patients with heart disease.
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Affiliation(s)
- C R Campbell
- Vascular Biology Center, Department of Medicine, Medical College of Georgia/Georgia Regents University, 1459 Laney Walker Boulevard, Augusta, GA 30912, United States
| | - A E Berman
- Vascular Biology Center, Department of Medicine, Medical College of Georgia/Georgia Regents University, 1459 Laney Walker Boulevard, Augusta, GA 30912, United States
| | - N L Weintraub
- Vascular Biology Center, Department of Medicine, Medical College of Georgia/Georgia Regents University, 1459 Laney Walker Boulevard, Augusta, GA 30912, United States
| | - Y L Tang
- Vascular Biology Center, Department of Medicine, Medical College of Georgia/Georgia Regents University, 1459 Laney Walker Boulevard, Augusta, GA 30912, United States.
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30
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Critical Roles of Reactive Oxygen Species in Age-Related Impairment in Ischemia-Induced Neovascularization by Regulating Stem and Progenitor Cell Function. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:7095901. [PMID: 26697140 PMCID: PMC4677240 DOI: 10.1155/2016/7095901] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 08/12/2015] [Indexed: 12/18/2022]
Abstract
Reactive oxygen species (ROS) regulate bone marrow microenvironment for stem and progenitor cells functions including self-renewal, differentiation, and cell senescence. In response to ischemia, ROS also play a critical role in mediating the mobilization of endothelial progenitor cells (EPCs) from the bone marrow to the sites of ischemic injury, which contributes to postnatal neovascularization. Aging is an unavoidable biological deteriorative process with a progressive decline in physiological functions. It is associated with increased oxidative stress and impaired ischemia-induced neovascularization. This review discusses the roles of ROS in regulating stem and progenitor cell function, highlighting the impact of unbalanced ROS levels on EPC dysfunction and the association with age-related impairment in ischemia-induced neovascularization. Furthermore, it discusses strategies that modulate the oxidative levels of stem and progenitor cells to enhance the therapeutic potential for elderly patients with cardiovascular disease.
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31
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32
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Okada M, Kim HW, Matsu-ura K, Wang YG, Xu M, Ashraf M. Abrogation of Age-Induced MicroRNA-195 Rejuvenates the Senescent Mesenchymal Stem Cells by Reactivating Telomerase. Stem Cells 2015; 34:148-59. [PMID: 26390028 DOI: 10.1002/stem.2211] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 08/19/2015] [Accepted: 08/24/2015] [Indexed: 12/14/2022]
Abstract
Previously, we reported that a novel subpopulation of young mesenchymal stem cells (YMSCs) existed in old bone marrow, which possessed high antiaging properties as well as excellent efficacy for cardiac repair. MicroRNAs (miRNAs) have emerged as key regulators in post-transcriptional gene expression programs, and however, it is unknown whether miRNAs directly control stem cell senescence. Here we present the first evidence that miR-195 overexpressed in old MSCs (OMSCs) induces stem cell senescence deteriorating their regenerative ability by directly deactivating telomerase reverse transcriptase (Tert), and abrogation of miR-195 can reverse stem cell aging. MiRNAs profiling analysis in YMSCs and OMSCs by microarray showed that miR-140, miR-146a/b, and miR-195 were significantly upregulated in OMSCs, which led us to hypothesize that these are age-induced miRNAs involved in stem cell senescence. Of these miRNAs, we found miR-195 directly targeted 3'-untranslated region of Tert gene by computational target prediction analysis and luciferase assay, and knockdown of miR-195 significantly increased Tert expression in OMSCs. Strikingly, miR-195 inhibition significantly induced telomere relengthening in OMSCs along with reduced expression of senescence-associated β-galactosidase. Moreover, silencing miR-195 in OMSCs by transfection of miR-195 inhibitor significantly restored antiaging factors expression including Tert and Sirt1 as well as phosphorylation of Akt and FOXO1. Notably, abrogation of miR-195 markedly restored proliferative abilities in OMSCs. Transplantation of OMSCs with knocked out miR-195 reduced infarction size and improved LV function. In conclusion, rejuvenation of aged stem cells by miR-195 inhibition would be a promising autologous therapeutic strategy for cardiac repair in the elderly patients.
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Affiliation(s)
- Motoi Okada
- Department of Pathology and Lab of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, 45267, USA
| | - Ha Won Kim
- Department of Pathology and Lab of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, 45267, USA
| | - Kaoru Matsu-ura
- Department of Pathology and Lab of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, 45267, USA
| | - Yi-Gang Wang
- Department of Pathology and Lab of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, 45267, USA
| | - Meifeng Xu
- Department of Pathology and Lab of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, 45267, USA
| | - Muhammad Ashraf
- Department of Pathology and Lab of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, 45267, USA
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33
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Alex A, Li A, Tanzi RE, Zhou C. Optogenetic pacing in Drosophila melanogaster. SCIENCE ADVANCES 2015; 1:e1500639. [PMID: 26601299 PMCID: PMC4646813 DOI: 10.1126/sciadv.1500639] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 08/12/2015] [Indexed: 05/19/2023]
Abstract
Electrical stimulation is currently the gold standard for cardiac pacing. However, it is invasive and nonspecific for cardiac tissues. We recently developed a noninvasive cardiac pacing technique using optogenetic tools, which are widely used in neuroscience. Optogenetic pacing of the heart provides high spatial and temporal precisions, is specific for cardiac tissues, avoids artifacts associated with electrical stimulation, and therefore promises to be a powerful tool in basic cardiac research. We demonstrated optogenetic control of heart rhythm in a well-established model organism, Drosophila melanogaster. We developed transgenic flies expressing a light-gated cation channel, channelrhodopsin-2 (ChR2), specifically in their hearts and demonstrated successful optogenetic pacing of ChR2-expressing Drosophila at different developmental stages, including the larva, pupa, and adult stages. A high-speed and ultrahigh-resolution optical coherence microscopy imaging system that is capable of providing images at a rate of 130 frames/s with axial and transverse resolutions of 1.5 and 3.9 μm, respectively, was used to noninvasively monitor Drosophila cardiac function and its response to pacing stimulation. The development of a noninvasive integrated optical pacing and imaging system provides a novel platform for performing research studies in developmental cardiology.
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Affiliation(s)
- Aneesh Alex
- Department of Electrical and Computer Engineering, Lehigh University, Bethlehem, PA 18015, USA
- Center for Photonics and Nanoelectronics, Lehigh University, Bethlehem, PA 18015, USA
| | - Airong Li
- Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
| | - Rudolph E. Tanzi
- Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
- Corresponding author. E-mail: (R.E.T.); (C.Z.)
| | - Chao Zhou
- Department of Electrical and Computer Engineering, Lehigh University, Bethlehem, PA 18015, USA
- Center for Photonics and Nanoelectronics, Lehigh University, Bethlehem, PA 18015, USA
- Bioengineering Program, Lehigh University, Bethlehem, PA 18015, USA
- Corresponding author. E-mail: (R.E.T.); (C.Z.)
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Purvis N, Bahn A, Katare R. The Role of MicroRNAs in Cardiac Stem Cells. Stem Cells Int 2015; 2015:194894. [PMID: 25802528 PMCID: PMC4329769 DOI: 10.1155/2015/194894] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2014] [Revised: 12/14/2014] [Accepted: 01/05/2015] [Indexed: 12/12/2022] Open
Abstract
Stem cells are considered as the next generation drug treatment in patients with cardiovascular disease who are resistant to conventional treatment. Among several stem cells used in the clinical setting, cardiac stem cells (CSCs) which reside in the myocardium and epicardium of the heart have been shown to be an effective option for the source of stem cells. In normal circumstances, CSCs primarily function as a cell store to replace the physiologically depleted cardiovascular cells, while under the diseased condition they have been shown to experimentally regenerate the diseased myocardium. In spite of their major functional role, molecular mechanisms regulating the CSCs proliferation and differentiation are still unknown. MicroRNAs (miRs) are small, noncoding RNA molecules that regulate gene expression at the posttranscriptional level. Recent studies have demonstrated the important role of miRs in regulating stem cell proliferation and differentiation, as well as other physiological and pathological processes related to stem cell function. This review summarises the current understanding of the role of miRs in CSCs. A deeper understanding of the mechanisms by which miRs regulate CSCs may lead to advances in the mode of stem cell therapies for the treatment of cardiovascular diseases.
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Affiliation(s)
- Nima Purvis
- Department of Physiology-Heart Otago, Otago School of Medical Sciences, University of Otago, Dunedin 9010, New Zealand
| | - Andrew Bahn
- Department of Physiology-Heart Otago, Otago School of Medical Sciences, University of Otago, Dunedin 9010, New Zealand
| | - Rajesh Katare
- Department of Physiology-Heart Otago, Otago School of Medical Sciences, University of Otago, Dunedin 9010, New Zealand
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35
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Zheng D, Liao S, Zhu G, Luo G, Xiao S, He J, Pei Z, Li G, Zhou Y. CD38 is a putative functional marker for side population cells in human nasopharyngeal carcinoma cell lines. Mol Carcinog 2015; 55:300-11. [PMID: 25630761 DOI: 10.1002/mc.22279] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Revised: 11/21/2014] [Accepted: 12/05/2014] [Indexed: 11/09/2022]
Abstract
Cancer stem cells (CSCs) are thought to be responsible for cancer progression and therapeutic resistance but identification of this subpopulation requires selective markers. Fortunately, side population (SP) cells analysis brings a novel method to CSCs study. In this study, we identified SP cells, which are demonstrated rich in CSCs, in four nasopharyngeal carcinoma (NPC) cell lines. We investigated SP cells from HK-1 NPC cell line and showed CSCs characteristics in this subpopulation. SP cells displayed greater proliferation and invasion and expressed high levels of CSCs markers than NSP cells. Furthermore, our microRNA microarray analysis of SP versus NSP cells revealed that CD38-related miRNAs were down-regulated in SP cell, but the mRNA and protein level of CD38 were highly expressed in SP cells. We further searched for molecules interacting with CD38 and identified ZAP70, which was also well expressed in SP cells at both mRNA and protein levels. Our results uncover a CD38 pathway that may regulate the proliferation and migration of SP cells from HK-1 NPC cell line.
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Affiliation(s)
- Danwei Zheng
- Human Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China.,Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, P. R. China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
| | - Shan Liao
- Human Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China.,Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, P. R. China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
| | - Guangchao Zhu
- Human Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China.,Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, P. R. China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
| | - Gengqiu Luo
- Department of Pathology, Basic School of Medicine, Central South University, Changsha, Hunan Province, P. R. China
| | - Songshu Xiao
- Department of Gynecology and Obstetrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
| | - Junyu He
- Human Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China.,Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, P. R. China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
| | - Zhen Pei
- Human Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China.,Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, P. R. China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
| | - Guiyuan Li
- Human Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China.,Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, P. R. China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
| | - Yanhong Zhou
- Human Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China.,Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, P. R. China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
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Krist B, Florczyk U, Pietraszek-Gremplewicz K, Józkowicz A, Dulak J. The Role of miR-378a in Metabolism, Angiogenesis, and Muscle Biology. Int J Endocrinol 2015; 2015:281756. [PMID: 26839547 PMCID: PMC4709675 DOI: 10.1155/2015/281756] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 11/30/2015] [Indexed: 02/06/2023] Open
Abstract
MicroRNA-378a (miR-378a, previously known as miR-378) is one of the small noncoding RNA molecules able to regulate gene expression at posttranscriptional level. Its two mature strands, miR-378a-3p and miR-378a-5p, originate from the first intron of the peroxisome proliferator-activated receptor gamma, coactivator 1 beta (ppargc1b) gene encoding PGC-1β. Embedding in the sequence of this transcriptional regulator of oxidative energy metabolism implies involvement of miR-378a in metabolic pathways, mitochondrial energy homeostasis, and related biological processes such as muscle development, differentiation, and regeneration. On the other hand, modulating the expression of proangiogenic factors such as vascular endothelial growth factor, angiopoietin-1, or interleukin-8, influencing inflammatory reaction, and affecting tumor suppressors, such as SuFu and Fus-1, miR-378a is considered as a part of an angiogenic network in tumors. In the latter, miR-378a can evoke broader actions by enhancing cell survival, reducing apoptosis, and promoting cell migration and invasion. This review describes the current knowledge on miR-378a linking oxidative/lipid metabolism, muscle biology, and blood vessel formation.
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Affiliation(s)
- Bart Krist
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30–387 Krakow, Poland
| | - Urszula Florczyk
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30–387 Krakow, Poland
| | - Katarzyna Pietraszek-Gremplewicz
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30–387 Krakow, Poland
| | - Alicja Józkowicz
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30–387 Krakow, Poland
| | - Jozef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30–387 Krakow, Poland
- *Jozef Dulak:
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Xing Y, Hou J, Guo T, Zheng S, Zhou C, Huang H, Chen Y, Sun K, Zhong T, Wang J, Li H, Wang T. microRNA-378 promotes mesenchymal stem cell survival and vascularization under hypoxic-ischemic conditions in vitro. Stem Cell Res Ther 2014; 5:130. [PMID: 25418617 PMCID: PMC4446090 DOI: 10.1186/scrt520] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 11/12/2014] [Indexed: 12/18/2022] Open
Abstract
Introduction Mesenchymal stem cells (MSCs) transplantation has been demonstrated to be an effective strategy for the treatment of cardiovascular disease. However, the low survival rate of MSCs at local diseased tissue reduces the therapeutic efficacy. We therefore investigated the influence of MicroRNA-378 (miR-378) transfection on MSCs survival and vascularization under hypoxic-ischemic condition in vitro. Methods MSCs were isolated from bone marrow of Sprague–Dawley rats and cultured in vitro. The third passage of MSCs were divided into the miR-378 group and control group. For the miR-378 group, cells were transfected with miR-378 mimic. Both groups experienced exposure to hypoxia (1% O2) and serum deprivation for 24 hours, using normoxia (20% O2) as a negative control during the process. After 24 hours of reoxygenation (20% O2), cell proliferation and apoptosis were evaluated. Expressions of apoptosis and angiogenesis related genes were detected. Both groups were further co-cultured with human umbilical vein endothelial cells to promote vascular differentiation for another 6 hours. Vascular density was assessed thereafter. Results Compared with the control group, MSCs transfected with miR-378 showed more rapid growth. Their proliferation rates were much higher at 72 h and 96 h under hypoxic condition (257.33% versus 246.67%, P <0.01; 406.84% versus 365.39%, P <0.05). Cell apoptosis percentage in the miR-378 group was significantly declined under normoxic and hypoxic condition (0.30 ± 0.10% versus 0.50 ± 0.10%, P <0.05; 0.60 ± 0.40% versus 1.70 ± 0.20%, P <0.01). The miR-378 group formed a larger number of vascular branches on matrigel. BCL2 level was decreased accompanied with an upregulated expression of BAX in the two experimental groups under the hypoxic environment. BAX expression was reduced in the miR-378 group under the hypoxic environment. In the miR-378 group, there was a decreased expression of tumor necrosis factor-α on protein level and a reduction of TUSC-2 under normoxic environment. Their expressions were both downregulated under hypoxic environment. For the angiogenesis related genes, enhanced expressions of vascular endothelial growth factorα, platelet derived growth factor-β and transforming growth factor-β1 could be detected both in normoxic and hypoxic-ischemic conditions. Conclusion MiR-378 transfection could effectively promote MSCs survival and vascularization under hypoxic-ischemic condition in vitro.
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Chang D, Wen Z, Wang Y, Cai W, Wani M, Paul C, Okano T, Millard RW, Wang Y. Ultrastructural features of ischemic tissue following application of a bio-membrane based progenitor cardiomyocyte patch for myocardial infarction repair. PLoS One 2014; 9:e107296. [PMID: 25310410 PMCID: PMC4195599 DOI: 10.1371/journal.pone.0107296] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Accepted: 08/08/2014] [Indexed: 01/09/2023] Open
Abstract
Background and Objective Implantation of cell-sheets into damaged regions of the heart after myocardial infarction (MI) has been shown to improve heart function. However, the tissue morphology following application of induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CM) has not been studied in detail at the level afforded by electron microscopy. We hypothesized that increasing the number of CM derived from iPSC would increase the effectiveness of cell-sheets used to treat ischemic cardiomyopathy. We report here on the ultrastructural features after application of a bio-membrane ‘cell patch’. Methods iPSC-derived progenitor cells were transduced using lentivirus vectors with or without NCX1 promoter. iPSC-CM sheets were transplanted over the transmural MI region in a mouse model of regional ischemic cardiomyopathy. Mice were divided into four groups, 1) Sham; 2) MI; 3) MI + iPSC without NCX1 treated cells (MI + iPSCNull) and 4) MI + iPSC receiving NCX1 promoter treated cells (MI + iPSCNCX1). Echocardiography was performed 4 weeks after cell patch application, followed by histological and transmission electron microscopy (TEM) analysis. Results Large numbers of transplanted CM were observed with significant improvements in left ventricular performance and remodeling in group 4 as compared with group 3. No teratoma formation was detected in any of the treatment groups. Conclusion Manipulation of iPSC yields large numbers of iPSC-CM and favorable morphological and ultrastructural tissue changes. These changes have the potential to enhance current methods used for restoration of cardiac function after MI.
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Affiliation(s)
- Dehua Chang
- Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America
| | - Zhili Wen
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America
| | - Yuhua Wang
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America
| | - Wenfeng Cai
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America
| | - Mashhood Wani
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America
| | - Christian Paul
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America
| | - Teruo Okano
- Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan
| | - Ronald W. Millard
- Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, Ohio, United States of America
| | - Yigang Wang
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America
- * E-mail:
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Srijaya TC, Ramasamy TS, Kasim NHA. Advancing stem cell therapy from bench to bedside: lessons from drug therapies. J Transl Med 2014; 12:243. [PMID: 25182194 PMCID: PMC4163166 DOI: 10.1186/s12967-014-0243-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2014] [Accepted: 08/26/2014] [Indexed: 12/20/2022] Open
Abstract
The inadequacy of existing therapeutic tools together with the paucity of organ donors have always led medical researchers to innovate the current treatment methods or to discover new ways to cure disease. Emergence of cell-based therapies has provided a new framework through which it has given the human world a new hope. Though relatively a new concept, the pace of advancement clearly reveals the significant role that stem cells will ultimately play in the near future. However, there are numerous uncertainties that are prevailing against the present setting of clinical trials related to stem cells: like the best route of cell administration, appropriate dosage, duration and several other applications. A better knowledge of these factors can substantially improve the effectiveness of disease cure or organ repair using this latest therapeutic tool. From a certain perspective, it could be argued that by considering certain proven clinical concepts and experience from synthetic drug system, we could improve the overall efficacy of cell-based therapies. In the past, studies on synthetic drug therapies and their clinical trials have shown that all the aforementioned factors have critical ascendancy over its therapeutic outcomes. Therefore, based on the knowledge gained from synthetic drug delivery systems, we hypothesize that by employing many of the clinical approaches from synthetic drug therapies to this new regenerative therapeutic tool, the efficacy of stem cell-based therapies can also be improved.
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Affiliation(s)
| | - Thamil Selvee Ramasamy
- />Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Noor Hayaty Abu Kasim
- />Department of Restorative Dentistry, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
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Zhao Y, Liu XZ, Tian WW, Guan YF, Wang P, Miao CY. Extracellular visfatin has nicotinamide phosphoribosyltransferase enzymatic activity and is neuroprotective against ischemic injury. CNS Neurosci Ther 2014; 20:539-47. [PMID: 24750959 DOI: 10.1111/cns.12273] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Revised: 03/12/2014] [Accepted: 03/26/2014] [Indexed: 12/25/2022] Open
Abstract
AIM Visfatin, a novel adipokine, is predominantly produced by visceral adipose tissue and exists in intracellular and extracellular compartments. The intracellular form of visfatin is proved to be nicotinamide phosphoribosyltransferase (NAMPT) and exhibits neuroprotection through maintaining intracellular NAD(+) pool. However, whether extracellular form of visfatin has NAMPT activity and the effect of extracellular visfatin in cerebral ischemia are unknown. METHODS AND RESULTS Plasma concentrations of visfatin, NAD(+) , and ATP were increased in mice upon cerebral ischemia. Cultured glia, but not neuron, was able to secrete visfatin. Oxygen-glucose deprivation (OGD) stress increased the secretion of visfatin from glia. Extracellular recombinant mouse wild-type visfatin, but not mouse H247A-mutant enzymatic-dead visfatin, had NAMPT enzymatic function in vitro. Treatment of wild-type visfatin, but not H247A-mutant enzymatic-dead visfatin, significantly attenuated detrimental effect of OGD on the cell viability and apoptosis in both cultured mouse neuron and glia. Treatment of neutralizing antibody, abolished the protective effect of extracellular visfatin on cell viability, but failed to block the antiapoptotic effect of extracellular visfatin. At last, we observed that plasma visfatin concentrations decreased in 6-month-old but not 3-month-old SHR-SP compared with that in age-matched Wistar-Kyoto rats. Inhibition of NAMPT enzymatic function of visfatin (by FK866) accelerated the occurrence of stroke in SHR-SP. CONCLUSIONS Extracellular visfatin has NAMPT enzymatic activity and maybe be neuroprotective just as intracellular visfatin in cerebral ischemic injury.
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Affiliation(s)
- Yan Zhao
- Department of Pharmacology, Second Military Medical University, Shanghai, China
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