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Jimenez-Trinidad FR, Calvo-Gomez S, Sabaté M, Brugaletta S, Campuzano V, Egea G, Dantas AP. Extracellular Vesicles as Mediators of Endothelial Dysfunction in Cardiovascular Diseases. Int J Mol Sci 2025; 26:1008. [PMID: 39940780 PMCID: PMC11816526 DOI: 10.3390/ijms26031008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/19/2025] [Accepted: 01/22/2025] [Indexed: 02/16/2025] Open
Abstract
This comprehensive review aims to provide a thorough overview of the vital role that extracellular vesicles (EVs) play in endothelial dysfunction, particularly emphasizing how physiological factors-such as sex and aging-along with significant cardiovascular risk factors, influence this process. The review covers studies ranging from the first description of EVs in 1945 to contemporary insights into their biological roles in intercellular signaling and endothelial dysfunction. A comprehensive analysis of peer-reviewed articles and reviews indexed in the PubMed database was conducted to compile the information. Initially, Medical Subject Headings (MeSH) terms included keywords aimed at providing general knowledge about the role of EVs in the regulation of endothelial signaling, such as "extracellular vesicles", "endothelium", and "intercellular signaling". Subsequently, terms related to the pathophysiological implications of EV interactions with endothelial dysfunction and cardiovascular disease were added, including "cardiovascular disease", "sex", "aging", "atherosclerosis", "obesity", and "diabetes". Additionally, the potential applications of EVs in cardiovascular disease were explored using the MeSH terms "extracellular vesicles", "cardiovascular disease", "biomarker", and "therapeutic strategy". The results of this bibliographical review reveal that EVs have the capacity to induce various cellular responses within the cardiovascular system and play a significant role in the complex landscape of endothelial dysfunction and cardiovascular disease. The composition of the EV cargo is subject to modification by pathophysiological conditions such as sex, aging, and cardiovascular risk factors, which result in a complex regulatory influence on endothelial function and neighboring cells when released from a dysfunctional endothelium. Moreover, the data suggest that this field still requires further exploration, as EV biology is continuously evolving, presenting a dynamic and engaging area for research. A deeper understanding of the molecular cargo involved in EV-endothelium interactions could yield valuable biomarkers for monitoring cardiovascular disease progression and facilitate the development of innovative bioengineered therapeutic strategies to enhance patient outcomes.
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Affiliation(s)
- Francisco Rafael Jimenez-Trinidad
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain; (F.R.J.-T.); (V.C.); (G.E.)
- Institut Clínic Cardiovascular (ICCV), Hospital Clínic, 08036 Barcelona, Spain; (M.S.); (S.B.)
- Division of Respiratory, Cardiovascular and Renal Pathobiology and Bioengineering, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Sergi Calvo-Gomez
- Department of Biomedical Sciences, School of Medicine, Universitat Internacional de Catalunya (UIC), 08195 Barcelona, Spain;
| | - Manel Sabaté
- Institut Clínic Cardiovascular (ICCV), Hospital Clínic, 08036 Barcelona, Spain; (M.S.); (S.B.)
- Division of Respiratory, Cardiovascular and Renal Pathobiology and Bioengineering, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Salvatore Brugaletta
- Institut Clínic Cardiovascular (ICCV), Hospital Clínic, 08036 Barcelona, Spain; (M.S.); (S.B.)
- Division of Respiratory, Cardiovascular and Renal Pathobiology and Bioengineering, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Victoria Campuzano
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain; (F.R.J.-T.); (V.C.); (G.E.)
- Rare Diseases Biomedical Research Network Center (CIBERER), Instituto de Salud Carlos III, 28222 Madrid, Spain
| | - Gustavo Egea
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain; (F.R.J.-T.); (V.C.); (G.E.)
- Division of Respiratory, Cardiovascular and Renal Pathobiology and Bioengineering, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center of Medical Genetics, University of Antwerpen, 2659 Edegem, Belgium
| | - Ana Paula Dantas
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain; (F.R.J.-T.); (V.C.); (G.E.)
- Institut Clínic Cardiovascular (ICCV), Hospital Clínic, 08036 Barcelona, Spain; (M.S.); (S.B.)
- Division of Respiratory, Cardiovascular and Renal Pathobiology and Bioengineering, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
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Ali SA, Mahmood Z, Mubarak Z, Asad M, Sarfraz Chaudhri MT, Bilal L, Ashraf T, Khalifa TN, Ashraf T, Saleem F, Masharifa Ahamed F, Tarar S. Assessing the Potential Benefits of Stem Cell Therapy in Cardiac Regeneration for Patients With Ischemic Heart Disease. Cureus 2025; 17:e76770. [PMID: 39897258 PMCID: PMC11786102 DOI: 10.7759/cureus.76770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/01/2025] [Indexed: 02/04/2025] Open
Abstract
Myocardial infarction, commonly known as a heart attack, or ischemic heart disease (IHD), remains one of the most fatal health conditions worldwide due to the limited regenerative capacity of the heart muscle after infarction. Conventional medical treatments primarily focus on symptom control and tissue preservation but fail to address the loss of cardiomyocytes, the cells responsible for heart contraction. This systematic review explores the hypothesis that stem cell therapies can enhance cardiac regeneration by replacing or repairing damaged myocardium, with a focus on mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and embryonic stem cells (ESCs). The review was restricted to literature published between 2015 and 2024, sourced from PubMed, Web of Science, and Google Scholar. This timeframe reflects advances in stem cell research and regenerative therapies. Findings from trials such as Bone Marrow-Derived Mononuclear Cell Therapy in Acute Myocardial Infarction (BAMI) and Cardiopoietic Stem Cell Therapy in Heart Failure (C-CURE) suggest that stem cell therapies may improve left ventricular ejection fraction (LVEF) and reduce infarct size. However, the heterogeneity of trials, small sample sizes, and short follow-up durations limit the generalizability of these results. Long-term benefits, including improved survival rates and reduced hospital readmissions, remain inconclusive. Ethical concerns, particularly the use of ESCs, pose additional challenges, including controversies over embryonic sources and varying regulatory landscapes. Key areas for advancement include optimizing stem cell survival and differentiation, with genetic engineering to enhance tissue repair capabilities considered the most critical for improving clinical outcomes. The integration of regenerative treatments such as extracellular vesicle therapy, derived from stem cells to modulate repair, also shows promise. Imaging techniques, such as MRI and PET, provide real-time monitoring of stem cell effects, offering insights into therapeutic efficacy and safety. Despite promising results from preclinical models and early-phase trials, the full therapeutic potential of stem cell therapy for IHD remains unrealized. Effective treatment protocols, addressing patient-specific factors, ethical considerations, and long-term outcome evaluations, are essential. This review emphasizes the need for ongoing research and clinical development to maximize the potential of stem cell-based approaches in cardiac repair.
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Affiliation(s)
- Syed Ahsan Ali
- Cardiology, Nottingham University Hospitals NHS Trust, Nottingham, GBR
| | - Zahra Mahmood
- Internal Medicine, Akhtar Saeed Medical and Dental College, Lahore, PAK
| | | | - Manahil Asad
- Medicine and Surgery, Foundation University Medical College, Islamabad, PAK
| | | | - Lamiah Bilal
- Medicine and Surgery, Foundation University Medical College, Islamabad, PAK
| | - Tehniat Ashraf
- Internal Medicine, Bhitai Dental & Medical College, Mirpur Khas, PAK
| | | | - Thasneem Ashraf
- General Practice, Cooperative Neethi Healthcare, Thrissur, IND
| | - Falaknaz Saleem
- Internal Medicine, George Eliot Hospital NHS Trust, Nuneaton, GBR
| | | | - Shoaib Tarar
- Internal Medicine, Nishtar Medical University, Multan, PAK
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3
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Figuer A, Alique M, Valera G, Serroukh N, Ceprían N, de Sequera P, Morales E, Carracedo J, Ramírez R, Bodega G. New mechanisms involved in the development of cardiovascular disease in chronic kidney disease. Nefrologia 2023; 43:63-80. [PMID: 37268501 DOI: 10.1016/j.nefroe.2023.05.014] [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: 11/15/2021] [Accepted: 03/02/2022] [Indexed: 06/04/2023] Open
Abstract
Chronic kidney disease (CKD) is a pathology with a high worldwide incidence and an upward trend affecting the elderly. When CKD is very advanced, the use of renal replacement therapies is required to prolong its life (dialysis or kidney transplantation). Although dialysis improves many complications of CKD, the disease does not reverse completely. These patients present an increase in oxidative stress, chronic inflammation and the release of extracellular vesicles (EVs), which cause endothelial damage and the development of different cardiovascular diseases (CVD). CKD patients develop premature diseases associated with advanced age, such as CVD. EVs play an essential role in developing CVD in patients with CKD since their number increases in plasma and their content is modified. The EVs of patients with CKD cause endothelial dysfunction, senescence and vascular calcification. In addition, miRNAs free or transported in EVs together with other components carried in these EVs promote endothelial dysfunction, thrombotic and vascular calcification in CKD, among other effects. This review describes the classic factors and focuses on the role of new mechanisms involved in the development of CVD associated with CKD, emphasizing the role of EVs in the development of cardiovascular pathologies in the context of CKD. Moreover, the review summarized the EVs' role as diagnostic and therapeutic tools, acting on EV release or content to avoid the development of CVD in CKD patients.
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Affiliation(s)
- Andrea Figuer
- Departamento de Biología de Sistemas, Universidad de Alcalá (IRYCIS), Alcalá de Henares (Madrid), Spain
| | - Matilde Alique
- Departamento de Biología de Sistemas, Universidad de Alcalá (IRYCIS), Alcalá de Henares (Madrid), Spain.
| | - Gemma Valera
- Departamento de Biología de Sistemas, Universidad de Alcalá (IRYCIS), Alcalá de Henares (Madrid), Spain
| | - Nadia Serroukh
- Departamento de Genética, Fisiología y Microbiología, Facultad de Ciencias Biológicas, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre (IMAS12), Madrid, Spain
| | - Noemí Ceprían
- Departamento de Genética, Fisiología y Microbiología, Facultad de Ciencias Biológicas, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre (IMAS12), Madrid, Spain
| | - Patricia de Sequera
- Sección de Nefrología, Hospital Universitario Infanta Leonor, Universidad Complutense de Madrid, Madrid, Spain
| | - Enrique Morales
- Sección de Nefrología, Hospital 12 de Octubre, Madrid, Spain
| | - Julia Carracedo
- Departamento de Genética, Fisiología y Microbiología, Facultad de Ciencias Biológicas, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre (IMAS12), Madrid, Spain
| | - Rafael Ramírez
- Departamento de Biología de Sistemas, Universidad de Alcalá (IRYCIS), Alcalá de Henares (Madrid), Spain
| | - Guillermo Bodega
- Departamento de Biomedicina y Biotecnología, Universidad de Alcalá, Alcalá de Henares (Madrid), Spain
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Cheng P, Wang X, Liu Q, Yang T, Qu H, Zhou H. Extracellular vesicles mediate biological information delivery: A double-edged sword in cardiac remodeling after myocardial infarction. Front Pharmacol 2023; 14:1067992. [PMID: 36909157 PMCID: PMC9992194 DOI: 10.3389/fphar.2023.1067992] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 02/13/2023] [Indexed: 02/24/2023] Open
Abstract
Acute myocardial infarction (AMI) is a severe ischemic disease with high morbidity and mortality worldwide. Maladaptive cardiac remodeling is a series of abnormalities in cardiac structure and function that occurs following myocardial infarction (MI). The pathophysiology of this process can be separated into two distinct phases: the initial inflammatory response, and the subsequent longer-term scar revision that includes the regression of inflammation, neovascularization, and fibrotic scar formation. Extracellular vesicles are nano-sized lipid bilayer vesicles released into the extracellular environment by eukaryotic cells, containing bioinformatic transmitters which are essential mediators of intercellular communication. EVs of different cellular origins play an essential role in cardiac remodeling after myocardial infarction. In this review, we first introduce the pathophysiology of post-infarction cardiac remodeling, as well as the biogenesis, classification, delivery, and functions of EVs. Then, we explore the dual role of these small molecule transmitters delivered by EVs in post-infarction cardiac remodeling, including the double-edged sword of pro-and anti-inflammation, and pro-and anti-fibrosis, which is significant for post-infarction cardiac repair. Finally, we discuss the pharmacological and engineered targeting of EVs for promoting heart repair after MI, thus revealing the potential value of targeted modulation of EVs and its use as a drug delivery vehicle in the therapeutic process of post-infarction cardiac remodeling.
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Affiliation(s)
- Peipei Cheng
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Branch of National Clinical Research Center for Chinese Medicine Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xinting Wang
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Branch of National Clinical Research Center for Chinese Medicine Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qian Liu
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Branch of National Clinical Research Center for Chinese Medicine Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Yang
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Branch of National Clinical Research Center for Chinese Medicine Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Huiyan Qu
- Branch of National Clinical Research Center for Chinese Medicine Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Department of Cardiovascular Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hua Zhou
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Branch of National Clinical Research Center for Chinese Medicine Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Department of Cardiovascular Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Alberti G, Russo E, Corrao S, Anzalone R, Kruzliak P, Miceli V, Conaldi PG, Di Gaudio F, La Rocca G. Current Perspectives on Adult Mesenchymal Stromal Cell-Derived Extracellular Vesicles: Biological Features and Clinical Indications. Biomedicines 2022; 10:2822. [PMID: 36359342 PMCID: PMC9687875 DOI: 10.3390/biomedicines10112822] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/19/2022] [Accepted: 10/28/2022] [Indexed: 08/10/2023] Open
Abstract
Extracellular vesicles (EVs) constitute one of the main mechanisms by which cells communicate with the surrounding tissue or at distance. Vesicle secretion is featured by most cell types, and adult mesenchymal stromal cells (MSCs) of different tissue origins have shown the ability to produce them. In recent years, several reports disclosed the molecular composition and suggested clinical indications for EVs derived from adult MSCs. The parental cells were already known for their roles in different disease settings in regulating inflammation, immune modulation, or transdifferentiation to promote cell repopulation. Interestingly, most reports also suggested that part of the properties of parental cells were maintained by isolated EV populations. This review analyzes the recent development in the field of cell-free therapies, focusing on several adult tissues as a source of MSC-derived EVs and the available clinical data from in vivo models.
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Affiliation(s)
- Giusi Alberti
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy
| | - Eleonora Russo
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy
| | - Simona Corrao
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy
| | - Rita Anzalone
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
| | - Peter Kruzliak
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Vitale Miceli
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | - Pier Giulio Conaldi
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | | | - Giampiero La Rocca
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy
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Bahmani L, Ullah M. Different Sourced Extracellular Vesicles and Their Potential Applications in Clinical Treatments. Cells 2022; 11:1989. [PMID: 35805074 PMCID: PMC9265969 DOI: 10.3390/cells11131989] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/19/2022] [Accepted: 06/20/2022] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) include a heterogeneous group of natural cell-derived nanostructures that are increasingly regarded as promising biotherapeutic agents and drug delivery vehicles in human medicine. Desirable intrinsic properties of EVs including the ability to bypass natural membranous barriers and to deliver their unique biomolecular cargo to specific cell populations position them as fiercely competitive alternatives for currently available cell therapies and artificial drug delivery platforms. EVs with distinct characteristics can be released from various cell types into the extracellular environment as a means of transmitting bioactive components and altering the status of the target cell. Despite the existence of a large number of preclinical studies confirming the therapeutic efficacy of different originated EVs for treating several pathological conditions, in this review, we first provide a brief overview of EV biophysical properties with an emphasis on their intrinsic therapeutic benefits over cell-based therapies and synthetic delivery systems. Next, we describe in detail different EVs derived from distinct cell sources, compare their advantages and disadvantages, and recapitulate their therapeutic effects on various human disorders to highlight the progress made in harnessing EVs for clinical applications. Finally, knowledge gaps and concrete hurdles that currently hinder the clinical translation of EV therapies are debated with a futuristic perspective.
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Affiliation(s)
- Leila Bahmani
- Institute for Immunity and Transplantation, Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Palo Alto, CA 94304, USA;
- Molecular Medicine Department of Medicine, Stanford University, Palo Alto, CA 94304, USA
| | - Mujib Ullah
- Institute for Immunity and Transplantation, Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Palo Alto, CA 94304, USA;
- Molecular Medicine Department of Medicine, Stanford University, Palo Alto, CA 94304, USA
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7
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Extracellular vesicles derived from human bone marrow mesenchymal stem cells protect rats against acute myocardial infarction-induced heart failure. Cell Tissue Res 2022; 389:23-40. [PMID: 35524813 DOI: 10.1007/s00441-022-03612-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 03/09/2022] [Indexed: 02/06/2023]
Abstract
Extracellular vesicles (EVs) derived from human bone marrow mesenchymal stem cells (BMSCs) are suggested to promote angiogenesis in a rat model of acute myocardial infarction (AMI). This study aimed to explore the underlying mechanism of BMSCs-EVs in AMI-induced heart failure (HF). BMSCs were isolated and verified, and EVs were purified and identified. After establishment of AMI-induced HF models, rats were treated with BMSCs-EVs and/or overexpressing (ov)/knocking down (kd) bone morphogenetic protein 2 (BMP2). Cardiac function, myocardial histopathological changes, angiogenesis, and vascular regeneration density were measured. Levels of pro-angiogenesis factors and cardiomyocyte apoptosis were detected. The viability and angiogenesis of hypoxic human umbilical vein endothelial cells (HUVECs) were measured. After BMSCs-EV treatment, the cardiac function of HF rats was improved, myocardial fibrosis and inflammatory cell infiltration were decreased, angiogenesis was increased, and cardiomyocyte apoptosis was inhibited. BMP2 was significantly upregulated in the myocardium. Ov-BMP2-BMSCs-EVs alleviated myocardial fibrosis and inflammatory cell infiltration, and promoted angiogenesis of HF rats, and improved the activity and angiogenesis of hypoxic HUVECs, while kd-BMP2-BMSCs-EVs showed limited protection against AMI-induced HF. BMSCs-EVs deliver BMP2 to promote angiogenesis and improve cardiac function of HF rats.
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8
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Figuer A, Alique M, Valera G, Serroukh N, Ceprían N, de Sequera P, Morales E, Carracedo J, Ramírez R, Bodega G. Nuevos mecanismos implicados en el desarrollo de la enfermedad cardiovascular en la enfermedad renal crónica. Nefrologia 2022. [DOI: 10.1016/j.nefro.2022.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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Vilahur G, Nguyen PH, Badimon L. Impact of Diabetes Mellitus on the Potential of Autologous Stem Cells and Stem Cell-Derived Microvesicles to Repair the Ischemic Heart. Cardiovasc Drugs Ther 2021; 36:933-949. [PMID: 34251593 DOI: 10.1007/s10557-021-07208-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/25/2021] [Indexed: 10/20/2022]
Abstract
Ischemic heart disease remains the leading cause of morbidity and mortality worldwide. Despite the advances in medical management and catheter-based therapy, mortality remains high, as does the risk of developing heart failure. Regenerative therapies have been widely used as an alternative option to repair the damaged heart mainly because of their paracrine-related beneficial effects. Although cell-based therapy has been demonstrated as feasible and safe, randomized controlled trials and meta-analyses show little consistent benefit from treatments with adult-derived stem cells. Mounting evidence from our group and others supports that cardiovascular risk factors and comorbidities impair stem cell potential thus hampering their autologous use. This review aims to better understand the influence of diabetes on stem cell potential. For this purpose, we will first discuss the most recent advances in the mechanistic understanding of the effects of diabetes on stem cell phenotype, function, and molecular fingerprint to further elaborate on diabetes-induced alterations in stem cell extracellular vesicle profile. Although we acknowledge that multiple sources of stem or progenitor cells are used for regenerative purposes, we will focus on bone marrow hematopoietic stem/progenitor cells, mesenchymal stem cells residing in the bone marrow, and adipose tissue and briefly discuss endothelial colony-forming cells.
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Affiliation(s)
- Gemma Vilahur
- Cardiovascular-Program ICCC, IR-Hospital Santa Creu I Sant Pau, IIB Sant Pau, C/Sant Antoni Mª Claret 167, 08025, Barcelona, Spain.,Ciber CV - ISCIII, Madrid, Spain
| | - Phuong Hue Nguyen
- Cardiovascular-Program ICCC, IR-Hospital Santa Creu I Sant Pau, IIB Sant Pau, C/Sant Antoni Mª Claret 167, 08025, Barcelona, Spain
| | - Lina Badimon
- Cardiovascular-Program ICCC, IR-Hospital Santa Creu I Sant Pau, IIB Sant Pau, C/Sant Antoni Mª Claret 167, 08025, Barcelona, Spain. .,Ciber CV - ISCIII, Madrid, Spain. .,Cardiovascular Research Chair UAB, Barcelona, Spain.
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Abstract
The role of stem cells in augmenting reparative processes in the heart after ischemic injury has been successfully demonstrated in small and large animal models. However, the outcomes of cell therapy in clinical trials have been somewhat variable, with overall effects of autologous stem cell therapies demonstrating a modest improvement in cardiac structure and function. How stem cells repair the heart after cardiac injury is still not well understood. Most recent studies suggest that adult derived stem cells act primarily through paracrine signaling to exert beneficial effects, including modulation of immune response, stimulation of new blood vessel formation, or by inducing mature myocytes to transiently reenter the cell cycle, rather than robust direct differentiation of the transplanted cells into myocytes. In addition, data from multiple laboratory results confirmed clearance of stem cells themselves within a few days still leading to functional benefits further confirming the role of paracrine signaling in augmenting cardiac reparative processes rather than direct differentiation of cells. These findings rapidly evolved the field of extracellular vesicles specifically microvesicles (MVs) as they are active hubs of autocrine, paracrine, and endocrine signaling targeting different biological processes. The beneficial effects seen after stem cell transplantation could be linked to the cardioprotective factors packaged in the MVs secreted from stem cells. Therefore, stem cell MVs provide a new avenue for the treatment of cardiovascular disease through a multitude of mechanisms including cellular communication within the stem cell niches, delivery of genetic information, regulation of the immune system in the heart, and stimulation of angiogenesis which will be discussed in this review.
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Chinnici CM, Russelli G, Bulati M, Miceli V, Gallo A, Busà R, Tinnirello R, Conaldi PG, Iannolo G. Mesenchymal stromal cell secretome in liver failure: Perspectives on COVID-19 infection treatment. World J Gastroenterol 2021; 27:1905-1919. [PMID: 34007129 PMCID: PMC8108038 DOI: 10.3748/wjg.v27.i17.1905] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/05/2021] [Accepted: 04/05/2021] [Indexed: 02/06/2023] Open
Abstract
Due to their immunomodulatory potential and release of trophic factors that promote healing, mesenchymal stromal cells (MSCs) are considered important players in tissue homeostasis and regeneration. MSCs have been widely used in clinical trials to treat multiple conditions associated with inflammation and tissue damage. Recent evidence suggests that most of the MSC therapeutic effects are derived from their secretome, including the extracellular vesicles, representing a promising approach in regenerative medicine application to treat organ failure as a result of inflammation/fibrosis. The recent outbreak of respiratory syndrome coronavirus, caused by the newly identified agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has forced scientists worldwide to use all available instruments to fight the infection, including the inflammatory cascade caused by this pandemic disease. The use of MSCs is a valid approach to combat organ inflammation in different compartments. In addition to the lungs, which are considered the main inflammatory target for this virus, other organs are compromised by the infection. In particular, the liver is involved in the inflammatory response to SARS-CoV-2 infection, which causes organ failure, leading to death in coronavirus disease 2019 (COVID-19) patients. We herein summarize the current implications derived from the use of MSCs and their soluble derivatives in COVID-19 treatment, and emphasize the potential of MSC-based therapy in this clinical setting.
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Affiliation(s)
- Cinzia Maria Chinnici
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
- Department of Regenerative Medicine, Fondazione Ri.MED, Palermo 90127, Italy
| | - Giovanna Russelli
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Matteo Bulati
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Vitale Miceli
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Alessia Gallo
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Rosalia Busà
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Rosaria Tinnirello
- Neuroscience Unit, CNR Institute of Biomedicine and Molecular Immunology, Palermo 90146, Italy
| | - Pier Giulio Conaldi
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Gioacchin Iannolo
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
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Saheera S, Jani VP, Witwer KW, Kutty S. Extracellular vesicle interplay in cardiovascular pathophysiology. Am J Physiol Heart Circ Physiol 2021; 320:H1749-H1761. [PMID: 33666501 PMCID: PMC8163654 DOI: 10.1152/ajpheart.00925.2020] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 02/27/2021] [Indexed: 02/06/2023]
Abstract
Extracellular vesicles (EVs) are nanosized lipid bilayer-delimited particles released from cells that mediate intercellular communications and play a pivotal role in various physiological and pathological processes. Subtypes of EVs may include plasma membrane ectosomes or microvesicles and endosomal origin exosomes, although functional distinctions remain unclear. EVs carry cargo proteins, nucleic acids (RNA and DNA), lipids, and metabolites. By presenting or transferring this cargo to recipient cells, EVs can trigger cellular responses. We summarize contemporary understanding of EV biogenesis, composition, and function, with an emphasis on the role of EVs in the cardiovascular system. In addition, we outline the functional relevance of EVs in cardiovascular pathophysiology, further highlighting their potential for diagnostic and therapeutic applications.
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Affiliation(s)
- Sherin Saheera
- Department of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Vivek P Jani
- Helen B. Taussig Heart Center, The Johns Hopkins Hospital and School of Medicine, Baltimore, Maryland
| | - Kenneth W Witwer
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Shelby Kutty
- Helen B. Taussig Heart Center, The Johns Hopkins Hospital and School of Medicine, Baltimore, Maryland
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Therapeutic Applications of Stem Cells and Extracellular Vesicles in Emergency Care: Futuristic Perspectives. Stem Cell Rev Rep 2021; 17:390-410. [PMID: 32839921 PMCID: PMC7444453 DOI: 10.1007/s12015-020-10029-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Regenerative medicine (RM) is an interdisciplinary field that aims to repair, replace or regenerate damaged or missing tissue or organs to function as close as possible to its physiological architecture and functions. Stem cells, which are undifferentiated cells retaining self-renewal potential, excessive proliferation and differentiation capacity into offspring or daughter cells that form different lineage cells of an organism, are considered as an important part of the RM approaches. They have been widely investigated in preclinical and clinical studies for therapeutic purposes. Extracellular vesicles (EVs) are the vital mediators that regulate the therapeutic effects of stem cells. Besides, they carry various types of cargo between cells which make them a significant contributor of intercellular communication. Given their role in physiological and pathological conditions in living cells, EVs are considered as a new therapeutic alternative solution for a variety of diseases in which there is a high unmet clinical need. This review aims to summarize and identify therapeutic potential of stem cells and EVs in diseases requiring acute emergency care such as trauma, heart diseases, stroke, acute respiratory distress syndrome and burn injury. Diseases that affect militaries or societies including acute radiation syndrome, sepsis and viral pandemics such as novel coronavirus disease 2019 are also discussed. Additionally, featuring and problematic issues that hamper clinical translation of stem cells and EVs are debated in a comparative manner with a futuristic perspective. Graphical Abstract.
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Riaud M, Martinez MC, Montero-Menei CN. Scaffolds and Extracellular Vesicles as a Promising Approach for Cardiac Regeneration after Myocardial Infarction. Pharmaceutics 2020; 12:E1195. [PMID: 33317141 PMCID: PMC7763019 DOI: 10.3390/pharmaceutics12121195] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/03/2020] [Accepted: 12/04/2020] [Indexed: 12/14/2022] Open
Abstract
Clinical studies have demonstrated the regenerative potential of stem cells for cardiac repair over the past decades, but their widespread use is limited by the poor tissue integration and survival obtained. Natural or synthetic hydrogels or microcarriers, used as cell carriers, contribute to resolving, in part, the problems encountered by providing mechanical support for the cells allowing cell retention, survival and tissue integration. Moreover, hydrogels alone also possess mechanical protective properties for the ischemic heart. The combined effect of growth factors with cells and an appropriate scaffold allow a therapeutic effect on myocardial repair. Despite this, the effects obtained with cell therapy remain limited and seem to be equivalent to the effects obtained with extracellular vesicles, key actors in intercellular communication. Extracellular vesicles have cardioprotective effects which, when combined proangiogenic properties with antiapoptotic and anti-inflammatory actions, make it possible to act on all the damages caused by ischemia. The evolution of biomaterial engineering allows us to envisage their association with new major players in cardiac therapy, extracellular vesicles, in order to limit undesirable effects and to envisage a transfer to the clinic. This new therapeutic approach could be associated with the release of growth factors to potentialized the beneficial effect obtained.
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Affiliation(s)
- Melody Riaud
- SOPAM, U1063, INSERM, UNIV Angers, SFR ICAT, F-49800 Angers, France;
- CRCINA, UMR 1232, INSERM, Université de Nantes, Université d’Angers, F-49933 Angers, France
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15
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Kulkarni P, Rawtani D, Kumar M, Lahoti SR. Cardiovascular drug delivery: A review on the recent advancements in nanocarrier based drug delivery with a brief emphasis on the novel use of magnetoliposomes and extracellular vesicles and ongoing clinical trial research. J Drug Deliv Sci Technol 2020. [DOI: 10.1016/j.jddst.2020.102029] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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16
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Duddu S, Chakrabarti R, Ghosh A, Shukla PC. Hematopoietic Stem Cell Transcription Factors in Cardiovascular Pathology. Front Genet 2020; 11:588602. [PMID: 33193725 PMCID: PMC7596349 DOI: 10.3389/fgene.2020.588602] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 09/21/2020] [Indexed: 12/14/2022] Open
Abstract
Transcription factors as multifaceted modulators of gene expression that play a central role in cell proliferation, differentiation, lineage commitment, and disease progression. They interact among themselves and create complex spatiotemporal gene regulatory networks that modulate hematopoiesis, cardiogenesis, and conditional differentiation of hematopoietic stem cells into cells of cardiovascular lineage. Additionally, bone marrow-derived stem cells potentially contribute to the cardiovascular cell population and have shown potential as a therapeutic approach to treat cardiovascular diseases. However, the underlying regulatory mechanisms are currently debatable. This review focuses on some key transcription factors and associated epigenetic modifications that modulate the maintenance and differentiation of hematopoietic stem cells and cardiac progenitor cells. In addition to this, we aim to summarize different potential clinical therapeutic approaches in cardiac regeneration therapy and recent discoveries in stem cell-based transplantation.
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Affiliation(s)
| | | | | | - Praphulla Chandra Shukla
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
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17
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Carracedo J, Alique M, Vida C, Bodega G, Ceprián N, Morales E, Praga M, de Sequera P, Ramírez R. Mechanisms of Cardiovascular Disorders in Patients With Chronic Kidney Disease: A Process Related to Accelerated Senescence. Front Cell Dev Biol 2020; 8:185. [PMID: 32266265 PMCID: PMC7099607 DOI: 10.3389/fcell.2020.00185] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 03/05/2020] [Indexed: 01/08/2023] Open
Abstract
Cardiovascular diseases (CVDs), especially those involving a systemic inflammatory process such as atherosclerosis, remain the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). CKD is a systemic condition affecting approximately 10% of the general population. The prevalence of CKD has increased over the past decades because of the aging of the population worldwide. Indeed, CVDs in patients with CKD constitute a premature form of CVD observed in the general population. Multiple studies indicate that patients with renal disease undergo accelerated aging, which precipitates the appearance of pathologies, including CVDs, usually associated with advanced age. In this review, we discuss several aspects that characterize CKD-associated CVDs, such as etiopathogenic elements that CKD patients share with the general population, changes in the cellular balance of reactive oxygen species (ROS), and the associated process of cellular senescence. Uremia-associated aging is linked with numerous changes at the cellular and molecular level. These changes are similar to those observed in the normal process of physiologic aging. We also discuss new perspectives in the study of CKD-associated CVDs and epigenetic alterations in intercellular signaling, mediated by microRNAs and/or extracellular vesicles (EVs), which promote vascular damage and subsequent development of CVD. Understanding the processes and factors involved in accelerated senescence and other abnormal intercellular signaling will identify new therapeutic targets and lead to improved methods of diagnosis and monitoring for patients with CKD-associated CVDs.
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Affiliation(s)
- Julia Carracedo
- Departamento de Genética, Fisiología y Microbiología, Universidad Complutense/Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
| | - Matilde Alique
- Departamento Biología de Sistemas, Facultad de Medicina y Ciencias de la Salud (IRYCIS), Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
| | - Carmen Vida
- Departamento Biología de Sistemas, Facultad de Medicina y Ciencias de la Salud (IRYCIS), Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
| | - Guillermo Bodega
- Departamento de Biomedicina y Biotecnología, Facultad de Biología, Química y Ciencias Ambientales, Universidad de Alcalá, Alcalá de Henares, Spain
| | - Noemí Ceprián
- Departamento de Genética, Fisiología y Microbiología, Universidad Complutense/Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
| | - Enrique Morales
- Departamento de Nefrología, Hospital Universitario 12 de Octubre/Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.,Departamento de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Manuel Praga
- Departamento de Nefrología, Hospital Universitario 12 de Octubre/Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.,Departamento de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Patricia de Sequera
- Departamento de Medicina, Universidad Complutense de Madrid, Madrid, Spain.,Sección de Nefrología, Hospital Universitario Infanta Leonor, Madrid, Spain
| | - Rafael Ramírez
- Departamento Biología de Sistemas, Facultad de Medicina y Ciencias de la Salud (IRYCIS), Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
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Extracellular Vesicles in Cardiovascular Diseases: Alternative Biomarker Sources, Therapeutic Agents, and Drug Delivery Carriers. Int J Mol Sci 2019; 20:ijms20133272. [PMID: 31277271 PMCID: PMC6650854 DOI: 10.3390/ijms20133272] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 06/27/2019] [Accepted: 07/01/2019] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases (CVD) represent the leading cause of morbidity and mortality globally. The emerging role of extracellular vesicles (EVs) in intercellular communication has stimulated renewed interest in exploring the potential application of EVs as tools for diagnosis, prognosis, and therapy in CVD. The ubiquitous nature of EVs in biological fluids presents a technological advantage compared to current diagnostic tools by virtue of their notable stability. EV contents, such as proteins and microRNAs, represent specific signatures of cellular activation or injury. This feature positions EVs as an alternative source of biomarkers. Furthermore, their intrinsic activity and immunomodulatory properties offer EVs unique opportunities to act as therapeutic agents per se or to serve as drug delivery carriers by acting as miniaturized vehicles incorporating bioactive molecules. In this article, we aim to review the recent advances and applications of EV-based biomarkers and therapeutics. In addition, the potential of EVs as a drug delivery and theranostic platform for CVD will also be discussed.
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Sánchez-Alonso S, Alcaraz-Serna A, Sánchez-Madrid F, Alfranca A. Extracellular Vesicle-Mediated Immune Regulation of Tissue Remodeling and Angiogenesis After Myocardial Infarction. Front Immunol 2018; 9:2799. [PMID: 30555478 PMCID: PMC6281951 DOI: 10.3389/fimmu.2018.02799] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Accepted: 11/13/2018] [Indexed: 12/20/2022] Open
Abstract
Myocardial ischemia-related disorders constitute a major health problem, being a leading cause of death in the world. Upon ischemia, tissue remodeling processes come into play, comprising a series of inter-dependent stages, including inflammation, cell proliferation and repair. Neovessel formation during late phases of remodeling provides oxygen supply, together with cellular and soluble components necessary for an efficient myocardial reconstruction. Immune system plays a central role in processes aimed at repairing ischemic myocardium, mainly in inflammatory and angiogenesis phases. In addition to cellular components and soluble mediators as chemokines and cytokines, the immune system acts in a paracrine fashion through small extracellular vesicles (EVs) release. These vesicular structures participate in multiple biological processes, and transmit information through bioactive cargoes from one cell to another. Cell therapy has been employed in an attempt to improve the outcome of these patients, through the promotion of tissue regeneration and angiogenesis. However, clinical trials have shown variable results, which put into question the actual applicability of cell-based therapies. Paracrine factors secreted by engrafted cells partially mediate tissue repair, and this knowledge has led to the hypothesis that small EVs may become a useful tool for cell-free myocardial infarction therapy. Current small EVs engineering strategies allow delivery of specific content to selected cell types, thus revealing the singular properties of these vesicles for myocardial ischemia treatment.
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Affiliation(s)
- Santiago Sánchez-Alonso
- Immunology Service, Hospital de la Princesa, Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, Madrid, Spain
| | - Ana Alcaraz-Serna
- Immunology Service, Hospital de la Princesa, Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, Madrid, Spain
| | - Francisco Sánchez-Madrid
- Immunology Service, Hospital de la Princesa, Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, Madrid, Spain.,Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.,CIBER Cardiovascular, Madrid, Spain
| | - Arantzazu Alfranca
- Immunology Service, Hospital de la Princesa, Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, Madrid, Spain.,CIBER Cardiovascular, Madrid, Spain
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