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1
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Zhang J. Non-coding RNAs and angiogenesis in cardiovascular diseases: a comprehensive review. Mol Cell Biochem 2024; 479:2921-2953. [PMID: 38306012 DOI: 10.1007/s11010-023-04919-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 12/18/2023] [Indexed: 02/03/2024]
Abstract
Non-coding RNAs (ncRNAs) have key roles in the etiology of many illnesses, including heart failure, myocardial infarction, stroke, and in physiological processes like angiogenesis. In transcriptional regulatory circuits that control heart growth, signaling, and stress response, as well as remodeling in cardiac disease, ncRNAs have become important players. Studies on ncRNAs and cardiovascular disease have made great progress recently. Here, we go through the functions of non-coding RNAs (ncRNAs) like circular RNAs (circRNAs), and microRNAs (miRNAs) as well as long non-coding RNAs (lncRNAs) in modulating cardiovascular disorders.
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Affiliation(s)
- Jie Zhang
- Medical School, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
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2
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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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3
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Ahmed ZT, Zain Al-Abeden MS, Al Abdin MG, Muqresh MA, Al Jowf GI, Eijssen LMT, Haider KH. Dose-response relationship of MSCs as living Bio-drugs in HFrEF patients: a systematic review and meta-analysis of RCTs. Stem Cell Res Ther 2024; 15:165. [PMID: 38867306 PMCID: PMC11170815 DOI: 10.1186/s13287-024-03713-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 04/01/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have emerged as living biodrugs for myocardial repair and regeneration. Recent randomized controlled trials (RCTs) have reported that MSC-based therapy is safe and effective in heart failure patients; however, its dose-response relationship has yet to be established. We aimed to determine the optimal MSC dose for treating HF patients with reduced ejection fraction (EF) (HFrEF). METHODS The preferred reporting items for systematic reviews and meta-analyses (PRISMA) and Cochrane Handbook guidelines were followed. Four databases and registries, i.e., PubMed, EBSCO, clinicaltrials.gov, ICTRP, and other websites, were searched for RCTs. Eleven RCTs with 1098 participants (treatment group, n = 606; control group, n = 492) were selected based on our inclusion/exclusion criteria. Two independent assessors extracted the data and performed quality assessments. The data from all eligible studies were plotted for death, major adverse cardiac events (MACE), left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and 6-minute walk distance (6-MWD) as safety, efficacy, and performance parameters. For dose-escalation assessment, studies were categorized as low-dose (< 100 million cells) or high-dose (≥ 100 million cells). RESULTS MSC-based treatment is safe across low and high doses, with nonsignificant effects. However, low-dose treatment had a more significant protective effect than high-dose treatment. Subgroup analysis revealed the superiority of low-dose treatment in improving LVEF by 3.01% (95% CI; 0.65-5.38%) compared with high-dose treatment (-0.48%; 95% CI; -2.14-1.18). MSC treatment significantly improved the 6-MWD by 26.74 m (95% CI; 3.74-49.74 m) in the low-dose treatment group and by 36.73 m (95% CI; 6.74-66.72 m) in the high-dose treatment group. The exclusion of studies using ADRCs resulted in better safety and a significant improvement in LVEF from low- and high-dose MSC treatment. CONCLUSION Low-dose MSC treatment was safe and superior to high-dose treatment in restoring efficacy and functional outcomes in heart failure patients, and further analysis in a larger patient group is warranted.
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Affiliation(s)
- Ziyad T Ahmed
- College of Medicine, Sulaiman Al Rajhi University, Al-Bukairiyah, 52726, Saudi Arabia
| | | | | | - Mohamad Ayham Muqresh
- College of Medicine, Sulaiman Al Rajhi University, Al-Bukairiyah, 52726, Saudi Arabia
| | - Ghazi I Al Jowf
- Department of Public Health, College of Applied Medical Sciences, King Faisal University, Al-Ahsa, 31982, Saudi Arabia
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre, Maastricht, 6200 MD, The Netherlands
- European Graduate School of Neuroscience, Maastricht University, Maastricht, 6200 MD, The Netherlands
| | - Lars M T Eijssen
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre, Maastricht, 6200 MD, The Netherlands
- Department of Bioinformatics- BiGCaT, School of Nutrition and Translational Research in Metabolism (NUTRIM), Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, 6200 MD, The Netherlands
- European Graduate School of Neuroscience, Maastricht University, Maastricht, 6200 MD, The Netherlands
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Frljak S, Gozdowska R, Klimczak-Tomaniak D, Kucia M, Kuch M, Jadczyk T, Vrtovec B, Sanz-Ruiz R. Stem Cells in Heart Failure: Future Perspective. CARDIOVASCULAR APPLICATIONS OF STEM CELLS 2023:491-514. [DOI: 10.1007/978-981-99-0722-9_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Al-Omar MT, Alnajjar MT, Ahmed ZT, Salaas FMI, Alrefaei TSM, Haider KH. Endothelial progenitor cell-derived small extracellular vesicles for myocardial angiogenesis and revascularization. J Clin Transl Res 2022; 8:476-487. [PMID: 36457898 PMCID: PMC9709527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/23/2022] [Accepted: 10/20/2022] [Indexed: 06/17/2023] Open
Abstract
BACKGROUND Endothelial progenitor cells (EPCs) have been well-studied for their differentiation potential and paracrine activity in vitro and in experimental animal studies. EPCs are the precursors of endothelial cells (ECs) and a rich source of pro-angiogenic factors, and hence, possess enormous potential to treat ischemic heart through myocardial angiogenesis. Their proven safety and efficacy observed during the pre-clinical and clinical studies have portrayed them as a near ideal cell type for cell-based therapy of ischemic heart disease.In response to the chemical cues from the ischemic heart, EPCs from the bone marrow and peripheral circulation home-in to the ischemic myocardium and participate in the intrinsic repair process at the molecular and cellular levels through paracrine activity and EC differentiation. EPCs also release small extracellular vesicles (sEVs) loaded with bioactive molecules as part of their paracrine activity for intercellular communication to participate in the reparative process in the heart. AIM This literature review is based on the published data regarding the characteristic features of EPC-derived sEVs and their proteomic and genomic payload, besides facilitating safe and effective repair of the ischemic myocardium. In light of the encouraging published data, translational and clinical assessment of EPC-derived sEVs is warranted. We report the recent experimental animal studies and their findings using EPC-derived sEVs on cardiac angiogenesis and preservation of cardiac function. RELEVANCE FOR PATIENTS With the promising results from pre-clinical studies, clinical trials should be conducted to assess the clinical utility of EPC-derived sEVs in the treatment of the ischemic myocardium.
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Affiliation(s)
- Maher T. Al-Omar
- Department of Basic Sciences, College of Medicine, Sulaiman Al Rajhi University, Al-Bukairyah 52726, Saudi Arabia
| | - Mahmoud T. Alnajjar
- Department of Basic Sciences, College of Medicine, Sulaiman Al Rajhi University, Al-Bukairyah 52726, Saudi Arabia
| | - Ziyad T. Ahmed
- Department of Basic Sciences, College of Medicine, Sulaiman Al Rajhi University, Al-Bukairyah 52726, Saudi Arabia
| | - Faris M. I. Salaas
- Department of Basic Sciences, College of Medicine, Sulaiman Al Rajhi University, Al-Bukairyah 52726, Saudi Arabia
| | - Tamim S. M. Alrefaei
- Department of Basic Sciences, College of Medicine, Sulaiman Al Rajhi University, Al-Bukairyah 52726, Saudi Arabia
| | - Khawaja H. Haider
- Department of Basic Sciences, College of Medicine, Sulaiman Al Rajhi University, Al-Bukairyah 52726, Saudi Arabia
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6
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Zaccagnini G, Greco S, Voellenkle C, Gaetano C, Martelli F. miR-210 hypoxamiR in Angiogenesis and Diabetes. Antioxid Redox Signal 2022; 36:685-706. [PMID: 34521246 DOI: 10.1089/ars.2021.0200] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Significance: microRNA-210 (miR-210) is the master hypoxia-inducible miRNA (hypoxamiR) since it has been found to be significantly upregulated under hypoxia in a wide range of cell types. Recent advances: Gene ontology analysis of its targets indicates that miR-210 modulates several aspects of cellular response to hypoxia. Due to its high pleiotropy, miR-210 not only plays a protective role by fine-tuning mitochondrial metabolism and inhibiting red-ox imbalance and apoptosis, but it can also promote cell proliferation, differentiation, and migration, substantially contributing to angiogenesis. Critical issues: As most miRNAs, modulating different gene pathways, also miR-210 can potentially lead to different and even opposite effects, depending on the physio-pathological contexts in which it acts. Future direction: The use of miRNAs as therapeutics is a fast growing field. This review aimed at highlighting the role of miR-210 in angiogenesis in the context of ischemic cardiovascular diseases and diabetes in order to clarify the molecular mechanisms underpinning miR-210 action. Particular attention will be dedicated to experimentally validated miR-210 direct targets involved in cellular processes related to angiogenesis and diabetes mellitus, such as mitochondrial metabolism, redox balance, apoptosis, migration, and adhesion. Antioxid. Redox Signal. 36, 685-706.
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Affiliation(s)
- Germana Zaccagnini
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Simona Greco
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Christine Voellenkle
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Carlo Gaetano
- Laboratorio di Epigenetica, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
| | - Fabio Martelli
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy
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Sarathkumar E, Victor M, Menon JA, Jibin K, Padmini S, Jayasree RS. Nanotechnology in cardiac stem cell therapy: cell modulation, imaging and gene delivery. RSC Adv 2021; 11:34572-34588. [PMID: 35494731 PMCID: PMC9043027 DOI: 10.1039/d1ra06404e] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 10/04/2021] [Indexed: 12/11/2022] Open
Abstract
The wide arena of applications opened by nanotechnology is multidimensional. It is already been proven that its prominence can continuously influence human life. The role of stem cells in curing degenerative diseases is another major area of research. Cardiovascular diseases are one of the major causes of death globally. Nanotechnology-assisted stem cell therapy could be used to tackle the challenges faced in the management of cardiovascular diseases. In spite of the positive indications and proven potential of stem cells to differentiate into cardiomyocytes for cardiac repair and regeneration during myocardial infarction, this therapeutic approach still remains in its infancy due to several factors such as non-specificity of injected cells, insignificant survival rate, and low cell retention. Attempts to improve stem cell therapy using nanoparticles have shown some interest among researchers. This review focuses on the major hurdles associated with cardiac stem cell therapy and the role of nanoparticles to overcome the major challenges in this field, including cell modulation, imaging, tracking and gene delivery. This review summarizes the potential challenges present in cardiac stem cell therapy and the major role of nanotechnology to overcome these challenges including cell modulation, tracking and imaging of stem cells.![]()
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Affiliation(s)
- Elangovan Sarathkumar
- Division of Biophotonics and Imaging, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Biomedical Technology Wing Trivandrum India
| | - Marina Victor
- Division of Biophotonics and Imaging, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Biomedical Technology Wing Trivandrum India
| | | | - Kunnumpurathu Jibin
- Division of Biophotonics and Imaging, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Biomedical Technology Wing Trivandrum India
| | - Suresh Padmini
- Sree Narayana Institute of Medical Sciences Kochi Kerala India
| | - Ramapurath S Jayasree
- Division of Biophotonics and Imaging, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Biomedical Technology Wing Trivandrum India
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Omega-3 fatty acid protects cardiomyocytes against hypoxia-induced injury through targeting MiR-210-3p/CASP8AP2 axis. Mol Cell Biochem 2021; 476:2999-3007. [PMID: 33791918 DOI: 10.1007/s11010-021-04141-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 03/19/2021] [Indexed: 10/21/2022]
Abstract
MicroRNAs (miRs) regulate diverse biological functions in both normal and pathological cellular conditions by post-transcriptional regulation of various genes expression. Nevertheless, the role of miRs in regulating the protective functions of omega-3 fatty acid in relation to hypoxia in cardiomyocytes remains unknown. The aim of this study was to investigate the effects of omega-3 fatty acid supplementation on cardiomyocyte apoptosis and further delineate the mechanisms underlying microRNA-210 (miRNA-210)-induced cardiomyocyte apoptosis in vitro. H9C2 cultured cells were first subjected to hypoxia followed by a subsequent treatment with main component of the Omega-3 fatty acid, Docosahexaenoic Acid (DHA). Cell apoptosis were detected by flow cytometry and the expression of miR-210-3p were detected by RT-qPCR and caspase-8-associated protein 2 (CASP8AP2) at protein levels by immunoblotting. Dual luciferase assay was used to verify the mutual effect between miR-210-3p and the 3'-untranslated region (UTR) of CASP8AP2 gene. DHA was shown to reduce apoptosis in H9C2 cells subjected to hypoxia. While DHA caused a significant increase in the expression of miR-210-3p, there was a marked reduction in the protein expression of CASP8AP2. MiR-210-3p and CASP8AP2 were significantly increased in H9C2 cardiomyocyte subjected to hypoxia. Overexpression of miR-210-3p could ameliorate hypoxia-induced apoptosis in H9C2 cells. MiR-210-3p negatively regulated CASP8AP2 expression at the transcriptional level. Both miR-210-3p mimic and CASP8AP2 siRNA could efficiently inhibit apoptosis in H9C2 cardiomyocyte subjected to hypoxia. We provide strong evidence showing that Omega-3 fatty acids can attenuate apoptosis in cardiomyocyte under hypoxic conditions via the up-regulation of miR-210-3p and targeting CASP8AP2 signaling pathway.
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Fukuda S, Akiyama M, Niki Y, Kawatsura R, Harada H, Nakahama KI. Inhibitory effects of miRNAs in astrocytes on C6 glioma progression via connexin 43. Mol Cell Biochem 2021; 476:2623-2632. [PMID: 33660186 DOI: 10.1007/s11010-021-04118-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 02/20/2021] [Indexed: 12/20/2022]
Abstract
In many types of tumor cells, cell communication via gap junction is decreased or missing. Therefore, cancer cells acquire unique cytosolic environments that differ from those of normal cells. This study assessed the differences in microRNA (miRNA) expression between cancer and normal cells. MicroRNA microarray analysis revealed five miRNAs that were highly expressed in normal astrocytes compared with that in C6 gliomas. To determine whether these miRNAs could pass through gap junctions, connexin 43 was expressed in C6 glioma cells and co-cultured with normal astrocytes. The co-culture experiment showed the possibility that miR-152-3p and miR-143-3p propagate from normal astrocytes to C6 glioma in connexin 43-dependent and -independent manners, respectively. Moreover, we established C6 glioma cells that expressed miR-152-3p or miR-143-3p. Although the proliferation of these miRNA-expressing C6 glioma cells did not differ from that of empty vectors introduced in C6 glioma cells, cell migration and invasion were significantly decreased in C6 glioma cells expressing miR-152-3p or miR-143-3p. These results suggest the possibility that miRNA produced by normal cells attenuates tumor progression through connexin 43-dependent and -independent mechanisms.
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Affiliation(s)
- Shuhei Fukuda
- Department of Cellular Physiological Chemistry, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.,Department of Oral and Maxillofacial Surgery, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Masako Akiyama
- Research Administration Division, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Yuki Niki
- Department of Cellular Physiological Chemistry, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Risa Kawatsura
- Department of Cellular Physiological Chemistry, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Hiroyuki Harada
- Department of Oral and Maxillofacial Surgery, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Ken-Ichi Nakahama
- Department of Cellular Physiological Chemistry, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
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Lee Y, Im E. Regulation of miRNAs by Natural Antioxidants in Cardiovascular Diseases: Focus on SIRT1 and eNOS. Antioxidants (Basel) 2021; 10:antiox10030377. [PMID: 33802566 PMCID: PMC8000568 DOI: 10.3390/antiox10030377] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/22/2021] [Accepted: 02/26/2021] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular diseases (CVDs) are the most common cause of morbidity and mortality worldwide. The potential benefits of natural antioxidants derived from supplemental nutrients against CVDs are well known. Remarkably, natural antioxidants exert cardioprotective effects by reducing oxidative stress, increasing vasodilation, and normalizing endothelial dysfunction. Recently, considerable evidence has highlighted an important role played by the synergistic interaction between endothelial nitric oxide synthase (eNOS) and sirtuin 1 (SIRT1) in the maintenance of endothelial function. To provide a new perspective on the role of natural antioxidants against CVDs, we focused on microRNAs (miRNAs), which are important posttranscriptional modulators in human diseases. Several miRNAs are regulated via the consumption of natural antioxidants and are related to the regulation of oxidative stress by targeting eNOS and/or SIRT1. In this review, we have discussed the specific molecular regulation of eNOS/SIRT1-related endothelial dysfunction and its contribution to CVD pathologies; furthermore, we selected nine different miRNAs that target the expression of eNOS and SIRT1 in CVDs. Additionally, we have summarized the alteration of miRNA expression and regulation of activities of miRNA through natural antioxidant consumption.
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Affiliation(s)
| | - Eunok Im
- Correspondence: ; Tel.: +82-51-510-2812; Fax: +82-51-513-6754
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Liu Y, Wang M, Liang Y, Wang C, Naruse K, Takahashi K. Treatment of Oxidative Stress with Exosomes in Myocardial Ischemia. Int J Mol Sci 2021; 22:ijms22041729. [PMID: 33572188 PMCID: PMC7915208 DOI: 10.3390/ijms22041729] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/02/2021] [Accepted: 02/04/2021] [Indexed: 02/06/2023] Open
Abstract
A thrombus in a coronary artery causes ischemia, which eventually leads to myocardial infarction (MI) if not removed. However, removal generates reactive oxygen species (ROS), which causes ischemia–reperfusion (I/R) injury that damages the tissue and exacerbates the resulting MI. The mechanism of I/R injury is currently extensively understood. However, supplementation of exogenous antioxidants is ineffective against oxidative stress (OS). Enhancing the ability of endogenous antioxidants may be a more effective way to treat OS, and exosomes may play a role as targeted carriers. Exosomes are nanosized vesicles wrapped in biofilms which contain various complex RNAs and proteins. They are important intermediate carriers of intercellular communication and material exchange. In recent years, diagnosis and treatment with exosomes in cardiovascular diseases have gained considerable attention. Herein, we review the new findings of exosomes in the regulation of OS in coronary heart disease, discuss the possibility of exosomes as carriers for the targeted regulation of endogenous ROS generation, and compare the advantages of exosome therapy with those of stem-cell therapy. Finally, we explore several miRNAs found in exosomes against OS.
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Kh S, Haider KH. Stem Cells: A Renewable Source of Pancreatic β-Cells and Future for Diabetes Treatment. Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Aramini B, Masciale V, Haider KH. Defining lung cancer stem cells exosomal payload of miRNAs in clinical perspective. World J Stem Cells 2020; 12:406-421. [PMID: 32742559 PMCID: PMC7360993 DOI: 10.4252/wjsc.v12.i6.406] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 04/29/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023] Open
Abstract
Since the first publication regarding the existence of stem cells in cancer [cancer stem cells (CSCs)] in 1994, many studies have been published providing in-depth information about their biology and function. This research has paved the way in terms of appreciating the role of CSCs in tumour aggressiveness, progression, recurrence and resistance to cancer therapy. Targeting CSCs for cancer therapy has still not progressed to a sufficient degree, particularly in terms of exploring the mechanism of dynamic interconversion between CSCs and non-CSCs. Besides the CSC scenario, the problem of cancer dissemination has been analyzed in-depth with the identification and isolation of microRNAs (miRs), which are now considered to be compelling molecular markers in the diagnosis and prognosis of tumours in general and specifically in patients with non-small cell lung cancer. Paracrine release of miRs via “exosomes” (small membrane vesicles (30-100 nm), the derivation of which lies in the luminal membranes of multi-vesicular bodies) released by fusion with the cell membrane is gaining popularity. Whether exosomes play a significant role in maintaining a dynamic equilibrium state between CSCs and non-CSCs and their mechanism of activity is as yet unknown. Future studies on CSC-related exosomes will provide new perspectives for precision-targeted treatment strategies.
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Affiliation(s)
- Beatrice Aramini
- Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena 41124, Italy
| | - Valentina Masciale
- Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena 41124, Italy
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MiRNA-Mediated Mechanisms of Cardiac Protection in Ischemic and Remote Ischemic Preconditioning-A Qualitative Systematic Review. Shock 2020; 51:44-51. [PMID: 29642230 DOI: 10.1097/shk.0000000000001156] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Ischemic preconditioning (IPC) and remote ischemic preconditioning (RIPC) protect myocardial tissue against subsequent ischemia and reperfusion injury (IRI) and have a high potential to improve patient outcome. The mediators and mechanisms of protection through IPC and RIPC remain largely unknown, but micro-RNAs (miRNAs) are promising candidates. METHODS Systematic review of Medline and Embase databases for biomedical scientific literature. RESULTS A total of 26 relevant publications (21 full-text original articles and 5 conference abstracts) were identified, 8 describing cell culture experiments, 14 animal experiments, and 4 randomized clinical trials in humans. Most commonly reported miRNAs with differential expression between preconditioned and control groups include miR-1, miR-21, and miR-144. Experimental designs and procedures differ widely, thereby limiting the potential to compare results between studies. Two of the four RCTs did not find any differentially expressed miRNAs. CONCLUSIONS Results from RCTs should feed back into basic research and focused studies confirming or rejecting hypotheses generated by these RCTs are needed.
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Haider KH, Aramini B. Mircrining the injured heart with stem cell-derived exosomes: an emerging strategy of cell-free therapy. Stem Cell Res Ther 2020; 11:23. [PMID: 31918755 PMCID: PMC6953131 DOI: 10.1186/s13287-019-1548-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 12/18/2019] [Accepted: 12/29/2019] [Indexed: 02/06/2023] Open
Abstract
Bone marrow-derived mesenchymal stem cells (MSCs) have successfully progressed to phase III clinical trials successive to an intensive in vitro and pre-clinical assessment in experimental animal models of ischemic myocardial injury. With scanty evidence regarding their cardiogenic differentiation in the recipient patients' hearts post-engraftment, paracrine secretion of bioactive molecules is being accepted as the most probable underlying mechanism to interpret the beneficial effects of cell therapy. Secretion of small non-coding microRNA (miR) constitutes an integral part of the paracrine activity of stem cells, and there is emerging interest in miRs' delivery to the heart as part of cell-free therapy to exploit their integral role in various cellular processes. MSCs also release membrane vesicles of diverse sizes loaded with a wide array of miRs as part of their paracrine secretions primarily for intercellular communication and to shuttle genetic material. Exosomes can also be loaded with miRs of interest for delivery to the organs of interest including the heart, and hence, exosome-based cell-free therapy is being assessed for cell-free therapy as an alternative to cell-based therapy. This review of literature provides an update on cell-free therapy with primary focus on exosomes derived from BM-derived MSCs for myocardial repair.
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Affiliation(s)
- Khawaja Husnain Haider
- Sulaiman Alrajhi University, Al-Qaseem, Kingdom of Saudi Arabia
- Department of Basic Sciences, Sulaiman Alrajhi University, PO Box 777, Al Bukairiyah, 51941 Kingdom of Saudi Arabia
| | - Beatrice Aramini
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
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Šustr F, Stárek Z, Souček M, Novák J. Non-coding RNAs and Cardiac Arrhythmias. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1229:287-300. [PMID: 32285419 DOI: 10.1007/978-981-15-1671-9_17] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/26/2023]
Abstract
Cardiac arrhythmias represent wide and heterogenic group of disturbances in the cardiac rhythm. Pathophysiology of individual arrhythmias is highly complex and dysfunction in ion channels/currents involved in generation or spreading of action potential is usually documented. Non-coding RNAs (ncRNAs) represent highly variable group of molecules regulating the heart expression program, including regulation of the expression of individual ion channels and intercellular connection proteins, e.g. connexins.Within this chapter, we will describe basic electrophysiological properties of the myocardium. We will focus on action potential generation and spreading in pacemaker and non-pacemaker cells, including description of individual ion channels (natrium, potassium and calcium) and their ncRNA-mediated regulation. Most of the studies have so far focused on microRNAs, thus, their regulatory function will be described into greater detail. Clinical consequences of altered ncRNA regulatory function will also be described together with potential future directions of the research in the field.
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Affiliation(s)
- Filip Šustr
- Second Department of Internal Medicine of St. Anne's University Hospital in Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Zdeněk Stárek
- First Department of Internal Medicine and Cardioangiology of St. Anne's University Hospital in Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Miroslav Souček
- Second Department of Internal Medicine of St. Anne's University Hospital in Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Jan Novák
- Second Department of Internal Medicine of St. Anne's University Hospital in Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
- CEITEC - Central European Institute for Technology, Masaryk University, Brno, Czech Republic.
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17
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Zaccagnini G, Maimone B, Fuschi P, Longo M, Da Silva D, Carrara M, Voellenkle C, Perani L, Esposito A, Gaetano C, Martelli F. Hypoxia-Induced miR-210 Is Necessary for Vascular Regeneration upon Acute Limb Ischemia. Int J Mol Sci 2019; 21:ijms21010129. [PMID: 31878120 PMCID: PMC6981725 DOI: 10.3390/ijms21010129] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 12/18/2019] [Accepted: 12/20/2019] [Indexed: 01/24/2023] Open
Abstract
Critical limb ischemia is the most serious form of peripheral artery disease, characterized by severe functional consequences, difficult clinical management and reduced life expectancy. The goal of this study was to investigate the miR-210 role in the neo-angiogenic response after acute limb ischemia. Complementary approaches were used in a mouse model of hindlimb ischemia: miR-210 loss-of-function was obtained by administration of LNA-oligonucleotides anti-miR-210; for miR-210 gain-of-function, a doxycycline-inducible miR-210 transgenic mouse was used. We tested miR-210 ability to stimulate vascular regeneration following ischemia. We found that miR-210 was necessary and sufficient to stimulate blood perfusion recovery, as well as arteriolar and capillary density increase, in the ischemic muscle. To clarify the molecular events underpinning miR-210 pro-angiogenic action, the transcriptomic changes in ischemic muscles upon miR-210 blocking were analyzed. We found that miR-210 impacted the transcriptome significantly, regulating pathways and functions linked to vascular regeneration. In agreement with a pro-angiogenic role, miR-210 also improved cardiac function and left ventricular remodeling after myocardial infarction. Moreover, miR-210 blocking decreased capillary density in a Matrigel plug assay, indicating that miR-210 is necessary for angiogenesis independently of ischemia. Collectively, these data indicate that miR-210 plays a pivotal role in promoting vascular regeneration.
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Affiliation(s)
- Germana Zaccagnini
- Laboratory of Molecular Cardiology, IRCCS Policlinico San Donato, 20097 San Donato Milanese, 20097 Milan, Italy; (B.M.); (P.F.); (M.L.); (D.D.S.); (M.C.)
- Correspondence: (G.Z.); (F.M.); Tel.: +39-02-2643-7737 (G.Z.); +39-02-2643-7762 or +39-02-5277-4533 (F.M.)
| | - Biagina Maimone
- Laboratory of Molecular Cardiology, IRCCS Policlinico San Donato, 20097 San Donato Milanese, 20097 Milan, Italy; (B.M.); (P.F.); (M.L.); (D.D.S.); (M.C.)
| | - Paola Fuschi
- Laboratory of Molecular Cardiology, IRCCS Policlinico San Donato, 20097 San Donato Milanese, 20097 Milan, Italy; (B.M.); (P.F.); (M.L.); (D.D.S.); (M.C.)
| | - Marialucia Longo
- Laboratory of Molecular Cardiology, IRCCS Policlinico San Donato, 20097 San Donato Milanese, 20097 Milan, Italy; (B.M.); (P.F.); (M.L.); (D.D.S.); (M.C.)
| | - Daniel Da Silva
- Laboratory of Molecular Cardiology, IRCCS Policlinico San Donato, 20097 San Donato Milanese, 20097 Milan, Italy; (B.M.); (P.F.); (M.L.); (D.D.S.); (M.C.)
| | - Matteo Carrara
- Laboratory of Molecular Cardiology, IRCCS Policlinico San Donato, 20097 San Donato Milanese, 20097 Milan, Italy; (B.M.); (P.F.); (M.L.); (D.D.S.); (M.C.)
| | - Christine Voellenkle
- Laboratory of Molecular Cardiology, IRCCS Policlinico San Donato, 20097 San Donato Milanese, 20097 Milan, Italy; (B.M.); (P.F.); (M.L.); (D.D.S.); (M.C.)
| | - Laura Perani
- Preclinical Imaging Facility, Experimental Imaging Center, San Raffaele Scientific Institute, 20132 Milan, Italy; (L.P.); (A.E.)
| | - Antonio Esposito
- Preclinical Imaging Facility, Experimental Imaging Center, San Raffaele Scientific Institute, 20132 Milan, Italy; (L.P.); (A.E.)
- Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Carlo Gaetano
- Laboratorio di Epigenetica, Istituti Clinici Scientifici Maugeri, via Maugeri 4, 27100 Pavia, Italy;
| | - Fabio Martelli
- Laboratory of Molecular Cardiology, IRCCS Policlinico San Donato, 20097 San Donato Milanese, 20097 Milan, Italy; (B.M.); (P.F.); (M.L.); (D.D.S.); (M.C.)
- Correspondence: (G.Z.); (F.M.); Tel.: +39-02-2643-7737 (G.Z.); +39-02-2643-7762 or +39-02-5277-4533 (F.M.)
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18
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Qiu Q, Shen T, Wang Q, Yu X, Jia N, He Q. Cardiac shock wave therapy protects cardiomyocytes from hypoxia‑induced injury by modulating miR‑210. Mol Med Rep 2019; 21:631-640. [PMID: 31974607 PMCID: PMC6947887 DOI: 10.3892/mmr.2019.10892] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Accepted: 10/17/2019] [Indexed: 01/05/2023] Open
Abstract
Cardiac shock wave therapy (SWT) has been described as a novel therapeutic strategy that is able to alleviate myocardial ischemic injury. microRNA (miRNA/miR)‑210 plays a cytoprotective role in cardiomyocytes in response to hypoxia by regulating cell apoptosis. The aim of the present study was to investigate whether cardiac SWT could protect cardiomyocytes from hypoxia‑induced injury by regulating miR‑210 expression. The murine adult cardiomyocyte cell line HL‑1 was incubated for 5 h in hypoxic conditions, followed by reoxygenation for 12 h and treatment with SWT immediately following hypoxia in the present study. The cell viability was determined using an MTS assay. Western blot analyses were performed in order to detect cell signaling changes. Reactive oxygen species production was detected using dihydroethidium staining, and malondialdehyde levels were measured using the thiobarbituric acid method. miRNA and mRNA expression levels were confirmed via reverse transcription‑quantitative PCR. Apoptosis was evaluated by means of flow cytometry. HL‑1 cells were then transfected with miR‑210 mimics or inhibitors in order to alter miR‑210 expression levels, and the effects on HL‑1 cells were determined. Hypoxia led to elevated oxidative stress, enhanced cell apoptosis and upregulated miR‑210 expression levels in HL‑1 cells, while SWT could alleviate hypoxia‑induced cell injury and further promote miR‑210 expression. miR‑210 overexpression decreased apoptosis and oxidative stress during hypoxic stress in HL‑1 cells, whereas inhibition of miR‑210 increased cell apoptosis and promoted oxidative stress. Furthermore, miR‑210 inhibition could reverse the effects of SWT on HL‑1 cells. Finally, the mRNA analysis revealed that SWT significantly attenuated apoptosis‑inducing factor mitochondrion‑associated 3 and caspase 8 associated protein 2 mRNA expression levels in cardiomyocytes exposed to hypoxia, which were two targets of miR‑210. SWT could exert cardioprotective effects against hypoxia‑induced cardiac injury by modulating miR‑210.
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Affiliation(s)
- Quan Qiu
- Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing Hospital, Beijing 100730, P.R. China
| | - Tao Shen
- The MOH Key Laboratory of Geriatrics, National Center of Gerontology, Beijing Hospital, Beijing 100730, P.R. China
| | - Que Wang
- The MOH Key Laboratory of Geriatrics, National Center of Gerontology, Beijing Hospital, Beijing 100730, P.R. China
| | - Xiaoxue Yu
- The MOH Key Laboratory of Geriatrics, National Center of Gerontology, Beijing Hospital, Beijing 100730, P.R. China
| | - Na Jia
- Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing Hospital, Beijing 100730, P.R. China
| | - Qing He
- Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing Hospital, Beijing 100730, P.R. China
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19
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Effect of Hypoxia-Induced MicroRNA-210 Expression on Cardiovascular Disease and the Underlying Mechanism. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:4727283. [PMID: 31249644 PMCID: PMC6556335 DOI: 10.1155/2019/4727283] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Revised: 04/08/2019] [Accepted: 05/06/2019] [Indexed: 12/20/2022]
Abstract
Cardiovascular diseases have high morbidity and mortality rates worldwide, and their treatment and prevention are challenging. MicroRNAs are a series of noncoding RNAs with highly conserved sequences and regulate gene expression by inhibiting mRNA transcription or degrading targeting proteins. MicroRNA-210 is significantly upregulated during hypoxia and plays a protective role by inhibiting apoptosis and regulating cell proliferation, differentiation, migration, mitochondrial metabolism, and angiogenesis in hypoxic cells. MicroRNA-210 expression is altered in cardiovascular diseases such as atherosclerosis, acute myocardial infarction, preeclampsia, aortic stenosis, and heart failure, and overexpression of microRNA-210 in some of these diseases exerts protective effects on target organs. Furthermore, chronically upregulated miR-210 potentially plays a marked pathogenic role in specific situations. This review primarily focuses on the upstream pathways, downstream targets, clinical progress in cardiovascular disease, and potential applications of microRNA-210.
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20
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Marofi F, Vahedi G, hasanzadeh A, Salarinasab S, Arzhanga P, Khademi B, Farshdousti Hagh M. Mesenchymal stem cells as the game‐changing tools in the treatment of various organs disorders: Mirage or reality? J Cell Physiol 2018; 234:1268-1288. [DOI: 10.1002/jcp.27152] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 07/05/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Faroogh Marofi
- Department of Hematology Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran
| | - Ghasem Vahedi
- Faculty of Veterinary Medicine, University of Tehran Tehran Iran
| | - Ali hasanzadeh
- Department of Hematology Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran
| | - Sadegh Salarinasab
- Department of Biochemistry and Clinical Laboratories Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Pishva Arzhanga
- Department of Biochemistry and Diet Therapy Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences Tabriz Iran
| | - Bahareh Khademi
- Department of Medical Genetic Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran
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21
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Besnier M, Gasparino S, Vono R, Sangalli E, Facoetti A, Bollati V, Cantone L, Zaccagnini G, Maimone B, Fuschi P, Da Silva D, Schiavulli M, Aday S, Caputo M, Madeddu P, Emanueli C, Martelli F, Spinetti G. miR-210 Enhances the Therapeutic Potential of Bone-Marrow-Derived Circulating Proangiogenic Cells in the Setting of Limb Ischemia. Mol Ther 2018; 26:1694-1705. [PMID: 29908843 DOI: 10.1016/j.ymthe.2018.06.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 06/05/2018] [Accepted: 06/05/2018] [Indexed: 12/28/2022] Open
Abstract
Therapies based on circulating proangiogenic cells (PACs) have shown promise in ischemic disease models but require further optimization to reach the bedside. Ischemia-associated hypoxia robustly increases microRNA-210 (miR-210) expression in several cell types, including endothelial cells (ECs). In ECs, miR-210 represses EphrinA3 (EFNA3), inducing proangiogenic responses. This study provides new mechanistic evidences for a role of miR-210 in PACs. PACs were obtained from either adult peripheral blood or cord blood. miR-210 expression was modulated with either an inhibitory complementary oligonucleotide (anti-miR-210) or a miRNA mimic (pre-miR-210). Scramble and absence of transfection served as controls. As expected, hypoxia increased miR-210 in PACs. In vivo, migration toward and adhesion to the ischemic endothelium facilitate the proangiogenic actions of transplanted PACs. In vitro, PAC migration toward SDF-1α/CXCL12 was impaired by anti-miR-210 and enhanced by pre-miR-210. Moreover, pre-miR-210 increased PAC adhesion to ECs and supported angiogenic responses in co-cultured ECs. These responses were not associated with changes in extracellular miR-210 and were abrogated by lentivirus-mediated EFNA3 overexpression. Finally, ex-vivo pre-miR-210 transfection predisposed PACs to induce post-ischemic therapeutic neovascularization and blood flow recovery in an immunodeficient mouse limb ischemia model. In conclusion, miR-210 modulates PAC functions and improves their therapeutic potential in limb ischemia.
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Affiliation(s)
- Marie Besnier
- Bristol Heart Institute, School of Clinical Science, University of Bristol, Bristol, UK
| | - Stefano Gasparino
- Laboratory of Cardiovascular Research, IRCCS MultiMedica, Milan, Italy
| | - Rosa Vono
- Laboratory of Cardiovascular Research, IRCCS MultiMedica, Milan, Italy
| | - Elena Sangalli
- Laboratory of Cardiovascular Research, IRCCS MultiMedica, Milan, Italy
| | - Amanda Facoetti
- Laboratory of Cardiovascular Research, IRCCS MultiMedica, Milan, Italy
| | - Valentina Bollati
- EPIGET Lab, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Laura Cantone
- EPIGET Lab, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Germana Zaccagnini
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato, Italy
| | - Biagina Maimone
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato, Italy
| | - Paola Fuschi
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato, Italy
| | - Daniel Da Silva
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato, Italy
| | - Michele Schiavulli
- AORN Santobono Pausilipon, Transfusion Medicine and Bone Marrow Transplantation Unit-Regional Reference Center for Coagulation Disorders, Napoli, Italy
| | - Sezin Aday
- Bristol Heart Institute, School of Clinical Science, University of Bristol, Bristol, UK
| | - Massimo Caputo
- Bristol Heart Institute, School of Clinical Science, University of Bristol, Bristol, UK
| | - Paolo Madeddu
- Bristol Heart Institute, School of Clinical Science, University of Bristol, Bristol, UK
| | - Costanza Emanueli
- Bristol Heart Institute, School of Clinical Science, University of Bristol, Bristol, UK; National Heart and Lung Institute, Imperial College London, London, UK
| | - Fabio Martelli
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato, Italy.
| | - Gaia Spinetti
- Laboratory of Cardiovascular Research, IRCCS MultiMedica, Milan, Italy.
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22
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Li G, Morris-Blanco KC, Lopez MS, Yang T, Zhao H, Vemuganti R, Luo Y. Impact of microRNAs on ischemic stroke: From pre- to post-disease. Prog Neurobiol 2018; 163-164:59-78. [PMID: 28842356 PMCID: PMC11884751 DOI: 10.1016/j.pneurobio.2017.08.002] [Citation(s) in RCA: 128] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 06/12/2017] [Accepted: 08/16/2017] [Indexed: 12/21/2022]
Abstract
Stroke is the number one cause of neurological dysfunction in adults and has a heavy socioeconomic burden worldwide. The etiological origins of ischemic stroke and resulting pathological processes are mediated by a multifaceted cascade of molecular mechanisms that are in part modulated by posttranscriptional activity. Accumulating evidence has revealed a role for microRNAs (miRNAs) as essential mediators of posttranscriptional gene silencing in both the physiology of brain development and pathology of ischemic stroke. In this review, we compile miRNAs that have been reported to regulate various stroke risk factors and pre-disease mechanisms, including hypertension, atherosclerosis, and diabetes, followed by an in-depth analysis of miRNAs in ischemic stroke pathogenesis, such as excitotoxicity, oxidative stress, inflammation, apoptosis, angiogenesis and neurogenesis. Since promoting or suppressing expression of miRNAs by specific pharmaceutical and non-pharmaceutical therapies may be beneficial to post-stroke recovery, we also highlight the potential therapeutic value of miRNAs in clinical settings.
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Affiliation(s)
- Guangwen Li
- Cerebrovascular Diseases Research Institute and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing 10053, China
| | | | - Mary S Lopez
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA; Cellular and Molecular Pathology Graduate Program, University of Wisconsin, Madison, WI, USA
| | - Tuo Yang
- Department of Neurology, University of Pittsburgh School of Medicine, PA, USA
| | - Haiping Zhao
- Cerebrovascular Diseases Research Institute and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing 10053, China
| | - Raghu Vemuganti
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA; Cellular and Molecular Pathology Graduate Program, University of Wisconsin, Madison, WI, USA; William S. Middleton VA Hospital, Madison, WI, USA.
| | - Yumin Luo
- Cerebrovascular Diseases Research Institute and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing 10053, China; Beijing Institute for Brain Disorders and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing 10053, China.
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23
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Bruter AV, Kandarakov OF, Belyavsky AV. Persistence of plasmid-mediated expression of transgenes in human mesenchymal stem cells depends primarily on CpG levels of both vector and transgene. J Gene Med 2018; 20:e3009. [DOI: 10.1002/jgm.3009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Revised: 01/20/2018] [Accepted: 01/20/2018] [Indexed: 01/25/2023] Open
Affiliation(s)
- Alexandra V. Bruter
- Russian Academy of Sciences; Engelhardt Institute of Molecular Biology; Moscow Russia
| | - Oleg F. Kandarakov
- Russian Academy of Sciences; Engelhardt Institute of Molecular Biology; Moscow Russia
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24
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Farías JG, Molina VM, Carrasco RA, Zepeda AB, Figueroa E, Letelier P, Castillo RL. Antioxidant Therapeutic Strategies for Cardiovascular Conditions Associated with Oxidative Stress. Nutrients 2017; 9:nu9090966. [PMID: 28862654 PMCID: PMC5622726 DOI: 10.3390/nu9090966] [Citation(s) in RCA: 124] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Revised: 08/17/2017] [Accepted: 08/18/2017] [Indexed: 12/14/2022] Open
Abstract
Oxidative stress (OS) refers to the imbalance between the generation of reactive oxygen species (ROS) and the ability to scavenge these ROS by endogenous antioxidant systems, where ROS overwhelms the antioxidant capacity. Excessive presence of ROS results in irreversible damage to cell membranes, DNA, and other cellular structures by oxidizing lipids, proteins, and nucleic acids. Oxidative stress plays a crucial role in the pathogenesis of cardiovascular diseases related to hypoxia, cardiotoxicity and ischemia-reperfusion. Here, we describe the participation of OS in the pathophysiology of cardiovascular conditions such as myocardial infarction, anthracycline cardiotoxicity and congenital heart disease. This review focuses on the different clinical events where redox factors and OS are related to cardiovascular pathophysiology, giving to support for novel pharmacological therapies such as omega 3 fatty acids, non-selective betablockers and microRNAs.
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Affiliation(s)
- Jorge G Farías
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4780000, Chile.
| | - Víctor M Molina
- Unidad de Cuidados Intensivos, Hospital de Niños Roberto del Río, Santiago 7500922, Chile.
- Unidad de Cuidados Intensivos Pediátricos, Hospital Clínico Pontificia Universidad Católica de Chile, Santiago 7500922, Chile.
| | - Rodrigo A Carrasco
- Laboratorio de Investigación Biomédica, Departamento de Medicina Interna, Hospital del Salvador, Santiago 7500922, Chile.
- Departamento de Cardiología, Clínica Alemana, Santiago 7500922, Chile.
| | - Andrea B Zepeda
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4780000, Chile.
| | - Elías Figueroa
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4780000, Chile.
- Núcleo de Investigación en Producción Alimentaria, BIOACUI, Escuela de Acuicultura, Universidad Católica de Temuco, Temuco 4780000, Chile.
| | - Pablo Letelier
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4780000, Chile.
- School of Health Sciences, Universidad Católica de Temuco, Temuco 4780000, Chile.
| | - Rodrigo L Castillo
- Laboratorio de Investigación Biomédica, Departamento de Medicina Interna, Hospital del Salvador, Santiago 7500922, Chile.
- Programa de Fisiopatología Oriente, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 7500922, Chile.
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25
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Zaccagnini G, Maimone B, Fuschi P, Maselli D, Spinetti G, Gaetano C, Martelli F. Overexpression of miR-210 and its significance in ischemic tissue damage. Sci Rep 2017; 7:9563. [PMID: 28842599 PMCID: PMC5573334 DOI: 10.1038/s41598-017-09763-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 07/28/2017] [Indexed: 02/07/2023] Open
Abstract
Hypoxia-induced miR-210 displays a pro-survival, cytoprotective and pro-angiogenic role in several in vitro systems. In vivo, we previously found that miR-210 inhibition increases ischemic damage. Here we describe the generation of a versatile transgenic mouse model allowing the evaluation of miR-210 therapeutic potential in ischemic cardiovascular diseases. We generated a Tet-On miR-210 transgenic mouse strain (TG-210) by targeted transgenesis in the ROSA26 locus. To functionally validate miR-210 transgenic mice, hindlimb ischemia was induced by femoral artery dissection. Blood perfusion was evaluated by power Doppler while tissue damage and inflammation were assessed by histological evaluation. We found that miR-210 levels were rapidly increased in TG-210 mice upon doxycycline administration. miR-210 overexpression was maintained over time and remained within physiological levels in multiple tissues. When hindlimb ischemia was induced, miR-210 overexpression protected from both muscular and vascular ischemic damage, decreased inflammatory cells density and allowed to maintain a better calf perfusion. In conclusion, we generated and functionally validated a miR-210 transgenic mouse model. Albeit validated in the context of a specific cardiovascular ischemic disease, miR-210 transgenic mice may also represent a useful model to assess the function of miR-210 in other physio-pathological conditions.
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Affiliation(s)
- G Zaccagnini
- Laboratory of Molecular Cardiology, Policlinico San Donato-IRCCS, 20097 San Donato Milanese, Milan, Italy
| | - B Maimone
- Laboratory of Molecular Cardiology, Policlinico San Donato-IRCCS, 20097 San Donato Milanese, Milan, Italy
| | - P Fuschi
- Laboratory of Molecular Cardiology, Policlinico San Donato-IRCCS, 20097 San Donato Milanese, Milan, Italy
| | - D Maselli
- Laboratory of Cardiovascular Research, MultiMedica-IRCCS, 20138, Milan, Italy
| | - G Spinetti
- Laboratory of Cardiovascular Research, MultiMedica-IRCCS, 20138, Milan, Italy
| | - C Gaetano
- Division of Cardiovascular Epigenetics, Department of Cardiology, Internal Medicine Clinic III, Goethe University, Frankfurt am Main, Germany
| | - F Martelli
- Laboratory of Molecular Cardiology, Policlinico San Donato-IRCCS, 20097 San Donato Milanese, Milan, Italy.
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26
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Ziaee SM, Tabeshmehr P, Haider KH, Farrokhi M, Shariat A, Amiri A, Hosseini SM. Optimization of time for neural stem cells transplantation for brain stroke in rats. Stem Cell Investig 2017; 4:29. [PMID: 28529944 DOI: 10.21037/sci.2017.03.10] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2016] [Accepted: 03/14/2017] [Indexed: 12/20/2022]
Abstract
BACKGROUND Despite encouraging data in terms of neurological outcome, stem cell based therapy for ischemic stroke in experimental models and human patients is still hampered by multiple as yet un-optimized variables, i.e., time of intervention, that significantly influence the prognosis. The aim of the present study was to delineate the optimum time for neural stem cells (NSCs) transplantation after ischemic stroke. METHODS The NSCs were isolated from 14 days embryo rat ganglion eminence and were cultured in NSA medium (neurobasal medium, 2% B27, 1% N2, bFGF 10 ng/mL, EGF 20 ng/mL and 1% pen/strep). The cells were characterized for tri-lineage differentiation by immunocytochemistry for tubulin-III, Olig2 and GFAP expression for neurons, oligodendrocytes and astrocyte respectively. The NSCs at passage 3 were injected intraventricularly in a rodent model of middle-cerebral artery occlusion (MCAO) on stipulated time points of 1 & 12 h, and 1, 3, 5 and 7 days after ischemic stroke. The animals were euthanized on day 28 after their respective treatment. RESULTS dUTP nick end labeling (TUNEL) assay and Caspase assay showed significantly reduced number of apoptotic cells on day 3 treated animals as compared to the other treatment groups of animals. The neurological outcome showed that the group which received NSCs 3 days after brain ischemia had the best neurological performance. CONCLUSIONS The optimum time for NSCs transplantation was day 3 after ischemic stroke in terms of attenuation of ischemic zone expansion and better preserved neurological performance.
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Affiliation(s)
- Seyyed Mohyeddin Ziaee
- Student Research Committee, Medical Faculty, Shiraz University of Medical Sciences, Shiraz, Iran.,Stem Cell Laboratory, Department of Anatomy, Medical Faculty, Shiraz University of Medical Sciences, Shiraz, Iran.,Cell & Molecular Medicine Student Research Group, Medical Faculty, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Parisa Tabeshmehr
- Cell & Molecular Medicine Student Research Group, Medical Faculty, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Majidreza Farrokhi
- Shiraz Neuroscience Research Center, Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran.,Neurosurgery Department, Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abdolhamid Shariat
- Shiraz Neuroscience Research Center, Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran.,Clinical Neurology Research Center, Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Atena Amiri
- Shiraz Neuroscience Research Center, Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Mojtaba Hosseini
- Student Research Committee, Medical Faculty, Shiraz University of Medical Sciences, Shiraz, Iran.,Stem Cell Laboratory, Department of Anatomy, Medical Faculty, Shiraz University of Medical Sciences, Shiraz, Iran.,Cell & Molecular Medicine Student Research Group, Medical Faculty, Shiraz University of Medical Sciences, Shiraz, Iran
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27
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Protection of Human Umbilical Vein Endothelial Cells against Oxidative Stress by MicroRNA-210. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:3565613. [PMID: 28367268 PMCID: PMC5359453 DOI: 10.1155/2017/3565613] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 01/12/2017] [Accepted: 02/09/2017] [Indexed: 01/09/2023]
Abstract
Oxidative stress induces endothelial cell apoptosis and promotes atherosclerosis development. MicroRNA-210 (miR-210) is linked with apoptosis in different cell types. This study aimed to investigate the role of miR-210 in human umbilical vein endothelial cells (HUVECs) under oxidative stress and to determine the underlying mechanism. HUVECs were treated with different concentrations of hydrogen peroxide (H2O2), and cell viability was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and ATP assay. To evaluate the role of miR-210 in H2O2-mediated apoptosis, gain-and-loss-of-function approaches were used, and the effects on apoptosis and reactive oxygen species (ROS) level were assayed using flow cytometry. Moreover, miR-210 expression was detected by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and expression of the following apoptosis-related genes was assessed by qRT-PCR and Western blot at the RNA and protein level, respectively: caspase-8-associated protein 2 (CASP8AP2), caspase-8, and caspase-3. The results showed that H2O2 induced apoptosis in HUVECs in a dose-dependent manner and increased miR-210 expression. Overexpression of miR-210 inhibited apoptosis and reduced ROS level in HUVECs treated with H2O2. Furthermore, miR-210 downregulated CASP8AP2 and related downstream caspases at protein level. Thus, under oxidative stress, miR-210 has a prosurvival and antiapoptotic effect on HUVECs by reducing ROS generation and downregulating the CASP8AP2 pathway.
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28
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Busch A, Eken SM, Maegdefessel L. Prospective and therapeutic screening value of non-coding RNA as biomarkers in cardiovascular disease. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:236. [PMID: 27429962 DOI: 10.21037/atm.2016.06.06] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Non-coding RNA (ncRNA) is a class of genetic, epigenetic and translational regulators, containing short and long transcripts with intriguing abilities for use as biomarkers due to their superordinate role in disease development. In the past five years many of these have been investigated in cardiovascular diseases (CVD), mainly myocardial infarction (MI) and heart failure. To extend this view, we summarize the existing data about ncRNA as biomarker in the whole entity of CVDs by literature-based review and comparison of the identified candidates. The myomirs miRNA-1, -133a/b, -208a, -499 with well-defined cellular functions have proven equal to classic protein biomarkers for disease detection in MI. Other microRNAs (miRNAs) were reproducibly found to correlate with disease, disease severity and outcome in heart failure, stroke, coronary artery disease (CAD) and aortic aneurysm. An additional utilization has been discovered for therapeutic monitoring. The function of long non-coding transcripts is only about to be unraveled, yet shows great potential for outcome prediction. ncRNA biomarkers have a distinct role if no alternative test is available or has is performing poorly. With increasing mechanistic understanding, circulating miRNA and long non-coding transcripts will provide useful disease information with high predictive power.
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Affiliation(s)
- Albert Busch
- Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institute, Center for Molecular Medicine, Stockholm, Sweden
| | - Suzanne M Eken
- Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institute, Center for Molecular Medicine, Stockholm, Sweden
| | - Lars Maegdefessel
- Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institute, Center for Molecular Medicine, Stockholm, Sweden
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29
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Nollet E, Hoymans VY, Van Craenenbroeck AH, Vrints CJ, Van Craenenbroeck EM. Improving stem cell therapy in cardiovascular diseases: the potential role of microRNA. Am J Physiol Heart Circ Physiol 2016; 311:H207-18. [PMID: 27208159 DOI: 10.1152/ajpheart.00239.2016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 05/11/2016] [Indexed: 11/22/2022]
Abstract
The initial promising prospect of autologous bone marrow-derived stem cell therapy in the setting of cardiovascular diseases has been overshadowed by functional shortcomings of the stem cell product. As powerful epigenetic regulators of (stem) cell function, microRNAs are valuable targets for novel therapeutic strategies. Indeed, modulation of specific miRNA expression could contribute to improved therapeutic efficacy of stem cell therapy. First, this review elaborates on the functional relevance of miRNA dysregulation in bone marrow-derived progenitor cells in different cardiovascular diseases. Next, we provide a comprehensive overview of the current evidence on the effect of specific miRNA modulation in several types of progenitor cells on cardiac and/or vascular regeneration. By elaborating on the cardioprotective regulation of progenitor cells on cardiac miRNAs, more insight in the underlying mechanisms of stem cell therapy is provided. Finally, some considerations are made regarding the potential of circulating miRNAs as regulators of the miRNA signature of progenitor cells in cardiovascular diseases.
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Affiliation(s)
- Evelien Nollet
- Laboratory of Cellular and Molecular Cardiology, Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium; Cardiovascular Diseases, Department of Translational Pathophysiological Research, University of Antwerp, Antwerp, Belgium
| | - Vicky Y Hoymans
- Laboratory of Cellular and Molecular Cardiology, Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium; Cardiovascular Diseases, Department of Translational Pathophysiological Research, University of Antwerp, Antwerp, Belgium
| | - Amaryllis H Van Craenenbroeck
- Cardiovascular Diseases, Department of Translational Pathophysiological Research, University of Antwerp, Antwerp, Belgium; Department of Nephrology, Antwerp University Hospital, Antwerp, Belgium; Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium; and
| | - Christiaan J Vrints
- Laboratory of Cellular and Molecular Cardiology, Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium; Cardiovascular Diseases, Department of Translational Pathophysiological Research, University of Antwerp, Antwerp, Belgium; Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
| | - Emeline M Van Craenenbroeck
- Laboratory of Cellular and Molecular Cardiology, Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium; Cardiovascular Diseases, Department of Translational Pathophysiological Research, University of Antwerp, Antwerp, Belgium; Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
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30
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Lemcke H, Steinhoff G, David R. Gap junctional shuttling of miRNA — A novel pathway of intercellular gene regulation and its prospects in clinical application. Cell Signal 2015; 27:2506-14. [DOI: 10.1016/j.cellsig.2015.09.012] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 09/03/2015] [Accepted: 09/07/2015] [Indexed: 01/05/2023]
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31
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Vinken M. Regulation of connexin signaling by the epigenetic machinery. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2015; 1859:262-8. [PMID: 26566120 DOI: 10.1016/j.bbagrm.2015.11.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Revised: 11/03/2015] [Accepted: 11/06/2015] [Indexed: 12/31/2022]
Abstract
Connexins and their channels are involved in the control of all aspects of the cellular life cycle, ranging from cell growth to cell death, by mediating extracellular, intercellular and intracellular communication. These multifaceted aspects of connexin-related cellular signaling obviously require strict regulation. While connexin channel activity is mainly directed by posttranslational modifications, connexin expression as such is managed by classical cis/trans mechanisms. Over the past few years, it has become clear that connexin production is equally dictated by epigenetic actions. This paper provides an overview of the role of major determinants of the epigenome, including DNA methylation, histone acetylation and microRNA species, in connexin expression.
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Affiliation(s)
- Mathieu Vinken
- Vrije Universiteit Brussel, Department of In Vitro Toxicology and Dermato-Cosmetology, Building G, Room G226, Laarbeeklaan 103, B-1090 Brussels, Belgium.
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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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Bader AM, Klose K, Bieback K, Korinth D, Schneider M, Seifert M, Choi YH, Kurtz A, Falk V, Stamm C. Hypoxic Preconditioning Increases Survival and Pro-Angiogenic Capacity of Human Cord Blood Mesenchymal Stromal Cells In Vitro. PLoS One 2015; 10:e0138477. [PMID: 26380983 PMCID: PMC4575058 DOI: 10.1371/journal.pone.0138477] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Hypoxic preconditioning was shown to improve the therapeutic efficacy of bone marrow-derived multipotent mesenchymal stromal cells (MSCs) upon transplantation in ischemic tissue. Given the interest in clinical applications of umbilical cord blood-derived MSCs, we developed a specific hypoxic preconditioning protocol and investigated its anti-apoptotic and pro-angiogenic effects on cord blood MSCs undergoing simulated ischemia in vitro by subjecting them to hypoxia and nutrient deprivation with or without preceding hypoxic preconditioning. Cell number, metabolic activity, surface marker expression, chromosomal stability, apoptosis (caspases-3/7 activity) and necrosis were determined, and phosphorylation, mRNA expression and protein secretion of selected apoptosis and angiogenesis-regulating factors were quantified. Then, human umbilical vein endothelial cells (HUVEC) were subjected to simulated ischemia in co-culture with hypoxically preconditioned or naïve cord blood MSCs, and HUVEC proliferation was measured. Migration, proliferation and nitric oxide production of HUVECs were determined in presence of cord blood MSC-conditioned medium. Cord blood MSCs proved least sensitive to simulated ischemia when they were preconditioned for 24 h, while their basic behavior, immunophenotype and karyotype in culture remained unchanged. Here, “post-ischemic” cell number and metabolic activity were enhanced and caspase-3/7 activity and lactate dehydrogenase release were reduced as compared to non-preconditioned cells. Phosphorylation of AKT and BAD, mRNA expression of BCL-XL, BAG1 and VEGF, and VEGF protein secretion were higher in preconditioned cells. Hypoxically preconditioned cord blood MSCs enhanced HUVEC proliferation and migration, while nitric oxide production remained unchanged. We conclude that hypoxic preconditioning protects cord blood MSCs by activation of anti-apoptotic signaling mechanisms and enhances their angiogenic potential. Hence, hypoxic preconditioning might be a translationally relevant strategy to increase the tolerance of cord blood MSCs to ischemia and improve their therapeutic efficacy in clinical applications.
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Affiliation(s)
- Andreas Matthäus Bader
- Berlin-Brandenburg Center for Regenerative Therapies, Charité—Universitätsmedizin Berlin, Berlin, Germany
- Deutsches Herzzentrum Berlin, Berlin, Germany
| | - Kristin Klose
- Berlin-Brandenburg Center for Regenerative Therapies, Charité—Universitätsmedizin Berlin, Berlin, Germany
| | - Karen Bieback
- Institute of Transfusion Medicine and Immunology, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
| | | | - Maria Schneider
- Berlin-Brandenburg Center for Regenerative Therapies, Charité—Universitätsmedizin Berlin, Berlin, Germany
| | - Martina Seifert
- Berlin-Brandenburg Center for Regenerative Therapies, Charité—Universitätsmedizin Berlin, Berlin, Germany
| | | | - Andreas Kurtz
- Berlin-Brandenburg Center for Regenerative Therapies, Charité—Universitätsmedizin Berlin, Berlin, Germany
| | | | - Christof Stamm
- Berlin-Brandenburg Center for Regenerative Therapies, Charité—Universitätsmedizin Berlin, Berlin, Germany
- Deutsches Herzzentrum Berlin, Berlin, Germany
- * E-mail:
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34
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Nowakowski A, Walczak P, Janowski M, Lukomska B. Genetic Engineering of Mesenchymal Stem Cells for Regenerative Medicine. Stem Cells Dev 2015; 24:2219-42. [PMID: 26140302 DOI: 10.1089/scd.2015.0062] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs), which can be obtained from various organs and easily propagated in vitro, are one of the most extensively used types of stem cells and have been shown to be efficacious in a broad set of diseases. The unique and highly desirable properties of MSCs include high migratory capacities toward injured areas, immunomodulatory features, and the natural ability to differentiate into connective tissue phenotypes. These phenotypes include bone and cartilage, and these properties predispose MSCs to be therapeutically useful. In addition, MSCs elicit their therapeutic effects by paracrine actions, in which the metabolism of target tissues is modulated. Genetic engineering methods can greatly amplify these properties and broaden the therapeutic capabilities of MSCs, including transdifferentiation toward diverse cell lineages. However, cell engineering can also affect safety and increase the cost of therapy based on MSCs; thus, the advantages and disadvantages of these procedures should be discussed. In this review, the latest applications of genetic engineering methods for MSCs with regenerative medicine purposes are presented.
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Affiliation(s)
- Adam Nowakowski
- 1 NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences , Warsaw, Poland
| | - Piotr Walczak
- 2 Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland.,3 Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland.,4 Department of Radiology, Faculty of Medical Sciences, University of Warmia and Mazury , Olsztyn, Poland
| | - Miroslaw Janowski
- 1 NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences , Warsaw, Poland .,2 Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland.,3 Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland
| | - Barbara Lukomska
- 1 NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences , Warsaw, Poland
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35
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The role of microRNAs in coronary artery disease: From pathophysiology to diagnosis and treatment. Atherosclerosis 2015; 241:624-33. [PMID: 26117399 DOI: 10.1016/j.atherosclerosis.2015.06.037] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Revised: 05/31/2015] [Accepted: 06/17/2015] [Indexed: 01/08/2023]
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36
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Boštjančič E, Glavač D. miRNome in myocardial infarction: Future directions and perspective. World J Cardiol 2014; 6:939-958. [PMID: 25276296 PMCID: PMC4176804 DOI: 10.4330/wjc.v6.i9.939] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Revised: 03/28/2014] [Accepted: 06/27/2014] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs), which are small and non-coding RNAs, are genome encoded from viruses to humans. They contribute to various developmental, physiological and pathological processes in living organisms. A huge amount of research results revealed that miRNAs regulate these processes also in the heart. miRNAs may have cell-type-specific or tissue-specific expression patterns or may be expressed ubiquitously. Primary studies of miRNA involvement in hypertrophy, heart failure and myocardial infarction analyzed miRNAs that are enriched in or specific for cardiomyocytes; however, growing evidence suggest that other miRNAs, not cardiac or muscle-specific, play a significant role in cardiovascular disease. Abnormal miRNA regulation has been shown to be involved in cardiac diseases, suggesting that miRNAs might affect cardiac structure and function. In this review, we focus on miRNAs that have been found to contribute to the pathogenesis of myocardial infarction (MI) and the response post-MI and characterized as diagnostic, prognostic and therapeutic targets. The majority of these studies were performed using mouse and rat models of MI, with a focus on the identification of basic cellular and molecular pathways involved in MI and in the response post-MI. Much research has also been performed on animal and human plasma samples from MI individuals to identify miRNAs that are possible prognostic and/or diagnostic targets of MI and other MI-related diseases. A large proportion of research is focused on miRNAs as promising therapeutic targets and biomarkers of drug responses and/or stem cell treatment approaches. However, only a few studies have described miRNA expression in human heart tissue following MI.
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37
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Greco S, Gaetano C, Martelli F. HypoxamiR regulation and function in ischemic cardiovascular diseases. Antioxid Redox Signal 2014; 21:1202-19. [PMID: 24053126 PMCID: PMC4142792 DOI: 10.1089/ars.2013.5403] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
SIGNIFICANCE MicroRNAs (miRNAs) are deregulated and play a causal role in numerous cardiovascular diseases, including myocardial infarction, coronary artery disease, hypertension, heart failure, stroke, peripheral artery disease, kidney ischemia-reperfusion. RECENT ADVANCES One crucial component of ischemic cardiovascular diseases is represented by hypoxia. Indeed, hypoxia is a powerful stimulus regulating the expression of a specific subset of miRNAs, named hypoxia-induced miRNAs (hypoxamiR). These miRNAs are fundamental regulators of the cell responses to decreased oxygen tension. Certain hypoxamiRs seem to have a particularly pervasive role, such as miR-210 that is virtually induced in all ischemic diseases tested so far. However, its specific function may change according to the physiopathological context. CRITICAL ISSUES The discovery of HypoxamiR dates back 6 years. Thus, despite a rapid growth in knowledge and attention, a deeper insight of the molecular mechanisms underpinning hypoxamiR regulation and function is needed. FUTURE DIRECTIONS An extended understanding of the function of hypoxamiR in gene regulatory networks associated with cardiovascular diseases will allow the identification of novel molecular mechanisms of disease and indicate the development of innovative therapeutic approaches.
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Affiliation(s)
- Simona Greco
- 1 Molecular Cardiology Laboratory , IRCCS-Policlinico San Donato, Milan, Italy
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38
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miRNA Expression in Mesenchymal Stem Cells. CURRENT PATHOBIOLOGY REPORTS 2014. [DOI: 10.1007/s40139-014-0045-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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39
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Sala V, Bergerone S, Gatti S, Gallo S, Ponzetto A, Ponzetto C, Crepaldi T. MicroRNAs in myocardial ischemia: identifying new targets and tools for treating heart disease. New frontiers for miR-medicine. Cell Mol Life Sci 2014; 71:1439-52. [PMID: 24218009 PMCID: PMC11113160 DOI: 10.1007/s00018-013-1504-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Revised: 10/17/2013] [Accepted: 10/18/2013] [Indexed: 01/16/2023]
Abstract
MicroRNAs (miRNAs) are natural, single-stranded, small RNA molecules which subtly control gene expression. Several studies indicate that specific miRNAs can regulate heart function both in development and disease. Despite prevention programs and new therapeutic agents, cardiovascular disease remains the main cause of death in developed countries. The elevated number of heart failure episodes is mostly due to myocardial infarction (MI). An increasing number of studies have been carried out reporting changes in miRNAs gene expression and exploring their role in MI and heart failure. In this review, we furnish a critical analysis of where the frontier of knowledge has arrived in the fields of basic and translational research on miRNAs in cardiac ischemia. We first summarize the basal information on miRNA biology and regulation, especially concentrating on the feedback loops which control cardiac-enriched miRNAs. A focus on the role of miRNAs in the pathogenesis of myocardial ischemia and in the attenuation of injury is presented. Particular attention is given to cardiomyocyte death (apoptosis and necrosis), fibrosis, neovascularization, and heart failure. Then, we address the potential of miR-diagnosis (miRNAs as disease biomarkers) and miR-drugs (miRNAs as therapeutic targets) for cardiac ischemia and heart failure. Finally, we evaluate the use of miRNAs in the emerging field of regenerative medicine.
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Affiliation(s)
- V. Sala
- Department of Oncology, University of Turin, Turin, Italy
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - S. Bergerone
- Azienda Ospedaliera Città della Salute e della Scienza di Torino, Turin, Italy
| | - S. Gatti
- Department of Oncology, University of Turin, Turin, Italy
| | - S. Gallo
- Department of Oncology, University of Turin, Turin, Italy
| | - A. Ponzetto
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - C. Ponzetto
- Department of Oncology, University of Turin, Turin, Italy
| | - T. Crepaldi
- Department of Oncology, University of Turin, Turin, Italy
- Institute of Anatomy, Corso Massimo d’Azeglio 52, 10126 Turin, Italy
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40
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The road ahead: working towards effective clinical translation of myocardial gene therapies. Ther Deliv 2014; 5:39-51. [PMID: 24341816 DOI: 10.4155/tde.13.134] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
During the last two decades the fields of molecular and cellular cardiology, and more recently molecular cardiac surgery, have developed rapidly. The concept of delivering cDNA encoding a therapeutic gene to cardiomyocytes using a vector system with substantial cardiac tropism, allowing for long-term expression of a therapeutic protein, has moved from hypothesis to bench to clinical application. However, the clinical results to date are still disappointing. The ideal gene transfer method should be explored in clinically relevant animal models of heart disease to evaluate the relative roles of specific molecular pathways in disease pathogenesis, helping to validate the potential targets for therapeutic intervention. Successful clinical cardiovascular gene therapy also requires the use of nonimmunogenic cardiotropic vectors capable of expressing the requisite amount of therapeutic protein in vivo and in situ. Depending on the desired application either regional or global myocardial gene delivery is required. Cardiac-specific delivery techniques incorporating mapping technologies for regional delivery and highly efficient methodologies for global delivery should improve the precision and specificity of gene transfer to the areas of interest and minimize collateral organ gene expression.
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41
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Zhang Y, Liang X, Lian Q, Tse HF. Perspective and challenges of mesenchymal stem cells for cardiovascular regeneration. Expert Rev Cardiovasc Ther 2013; 11:505-17. [PMID: 23570363 DOI: 10.1586/erc.13.5] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Mesenchymal stem cells (MSCs) exhibit multipotent differentiation potential and can be derived from embryonic, neonatal and adult differentiation stage III tissue sources. While increasing preclinical studies and clinical trials have indicated that MSC-based therapy is a promising strategy for cardiovascular regeneration, there are major challenges to overcome before this stem-cell technology can be widely applied in clinical settings. In this review, the following important issues will be addressed. First, optimal sources of MSC derivation suitable for myocardial repair are not determined. Second, assessments for preclinical and clinical studies of MSCs require more scientific data analysis. Third, mechanisms of MSC-based therapy for cardiovascular regeneration have not been fully understood yet. Finally, the potential benefit-risk ratio of MSC therapy needs to be evaluated systematically. Additionally, future development of MSC therapy will be discussed.
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Affiliation(s)
- Yuelin Zhang
- Cardiology Division, Department of Medicine, University of Hong Kong, Hong Kong
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42
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Krenz M, Baines C, Kalogeris T, Korthuis R. Cell Survival Programs and Ischemia/Reperfusion: Hormesis, Preconditioning, and Cardioprotection. ACTA ACUST UNITED AC 2013. [DOI: 10.4199/c00090ed1v01y201309isp044] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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43
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Igura K, Okada M, Kim HW, Ashraf M. Identification of small juvenile stem cells in aged bone marrow and their therapeutic potential for repair of the ischemic heart. Am J Physiol Heart Circ Physiol 2013; 305:H1354-62. [PMID: 23997098 DOI: 10.1152/ajpheart.00379.2013] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Stem cell-mediated cardiac regeneration is impaired with age. In this study, we identified a novel subpopulation of small juvenile stem cells (SJSCs) isolated from aged bone marrow-derived stem cells (BMSCs) with high proliferation and differentiation potential. SJSCs expressed mesenchymal stem cell markers, CD29(+)/CD44(+)/CD59(+)/CD90(+), but were negative for CD45(-)/CD117(-) as examined by flow cytometry analysis. SJSCs showed higher proliferation, colony formation, and differentiation abilities compared with BMSCs. We also observed that SJSCs significantly expressed cardiac lineage markers (Gata-4 and myocyte-specific enhancer factor 2C) and pluripotency markers (octamer-binding transcription factor 4, sex-determining region Y box 2, stage-specific embryonic antigen 1, and Nanog) as well as antiaging factors such as telomerase reverse transcriptase and sirtuin 1. Interestingly, SJSCs either from young or aged animals showed significantly longer telomere length as well as lower senescence-associated β-galactosidase expression, suggesting that SJSCs possess antiaging properties, whereas aged BMSCs have limited potential for proliferation and differentiation. Furthermore, transplantation of aged SJSCs into the infarcted rat heart significantly reduced the infarction size and improved left ventricular function, whereas transplantation of aged BMSCs was less effective. Moreover, neovascularization as well as cardiomyogenic differentiation in the peri-infarcted area were significantly increased in the SJSC-transplanted group compared with the BMSC-transplated group, as evaluated by immunohistochemical analysis. Taken together, these findings demonstrate that SJSCs possess characteristics of antiaging, pluripotency, and high proliferation and differentiation rates, and, therefore, these cells offer great therapeutic potential for repair of the injured myocardium.
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Affiliation(s)
- Koichi Igura
- Department of Pathology and Lab of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio
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Muscari C, Giordano E, Bonafè F, Govoni M, Pasini A, Guarnieri C. Priming adult stem cells by hypoxic pretreatments for applications in regenerative medicine. J Biomed Sci 2013; 20:63. [PMID: 23985033 PMCID: PMC3765890 DOI: 10.1186/1423-0127-20-63] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 08/24/2013] [Indexed: 12/16/2022] Open
Abstract
The efficiency of regenerative medicine can be ameliorated by improving the biological performances of stem cells before their transplantation. Several ex-vivo protocols of non-damaging cell hypoxia have been demonstrated to significantly increase survival, proliferation and post-engraftment differentiation potential of stem cells. The best results for priming cultured stem cells against a following, otherwise lethal, ischemic stress have been obtained with brief intermittent episodes of hypoxia, or anoxia, and reoxygenation in accordance with the extraordinary protection afforded by the conventional maneuver of ischemic preconditioning in severely ischemic organs. These protocols of hypoxic preconditioning can be rather easily reproduced in a laboratory; however, more suitable pharmacological interventions inducing stem cell responses similar to those activated in hypoxia are considered among the most promising solutions for future applications in cell therapy. Here we want to offer an up-to-date review of the molecular mechanisms translating hypoxia into beneficial events for regenerative medicine. To this aim the involvement of epigenetic modifications, microRNAs, and oxidative stress, mainly activated by hypoxia inducible factors, will be discussed. Stem cell adaptation to their natural hypoxic microenvironments (niche) in healthy and neoplastic tissues will be also considered.
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Affiliation(s)
- Claudio Muscari
- Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.
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Affiliation(s)
- Friedrich C Luft
- Experimental and Clinical Research Center, Charité Medical Faculty and Max-Delbrück Center for Molecular Medicine, Lindenbergerweg 80, 13125 Berlin, Germany.
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Sen CK, Roy S. OxymiRs in cutaneous development, wound repair and regeneration. Semin Cell Dev Biol 2012; 23:971-80. [PMID: 23063665 PMCID: PMC3762568 DOI: 10.1016/j.semcdb.2012.09.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2012] [Accepted: 09/27/2012] [Indexed: 01/08/2023]
Abstract
The state of tissue oxygenation is widely recognized as a major microenvironmental cue that is known to regulate the expression of coding genes. Recent works have extended that knowledge to demonstrate that the state of tissue oxygenation may potently regulate the expression of microRNAs (miRs). Collectively, such miRs that are implicated in defining biological outcomes in response to a change in the state of tissue oxygenation may be referred to as oxymiRs. Broadly, oxymiRs may be categorized into three groups: (A) the existence (expression and/or turnover) of which is directly influenced by changes in the state of tissue oxygenation; (B) the existence of which is indirectly (e.g. oxygen-sensitive proteins, metabolites, pH, etc.) influenced by changes in the state of tissue oxygenation; and (C) those that modify biological outcomes to changes in the state of tissue oxygenation by targeting oxygen sensing pathways. This work represents the first review of how oxymiRs may regulate development, repair and regeneration. Currently known oxymiRs may affect the functioning of a large number of coding genes which have hitherto fore never been linked to oxygen sensing. Many of such target genes have been validated and that number is steadily growing. Taken together, our understanding of oxymiRs has vastly expanded the implications of changes in the state of tissue oxygenation. This emerging paradigm has major implications in untangling the complexities underlying diseases associated with ischemia and related hypoxic insult such as chronic wounds.
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Affiliation(s)
- Chandan K Sen
- Center for Regenerative Medicine and Cell-Based Therapies, Comprehensive Wound Center and Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, OH 43210, USA.
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