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Roncalli J, Roubille F, Meyer N, Pompilio G, Leroux L, Henon P, Trebuchet G, Criquet A, de Kalbermatten M, Saloux E, Manrique A, Marie PY, Bhatt DL, Solomon SD, Montalescot G, Newby DE, Zannad F. Transendocardial injection of expanded autologous CD34+ cells after myocardial infarction: Design of the EXCELLENT trial. ESC Heart Fail 2024. [PMID: 39676512 DOI: 10.1002/ehf2.15124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 09/26/2024] [Accepted: 10/01/2024] [Indexed: 12/17/2024] Open
Abstract
AIMS The extent of irreversible cardiomyocyte necrosis after acute myocardial infarction (AMI) is a major determinant of residual left ventricular (LV) function and clinical outcome. Cell therapy based on CD34+ cells has emerged as an option to help repair the myocardium and to improve outcomes. The dose of CD34+ cells and the route of administration are two important factors that will determine the clinical effectiveness of the approach, provided it is robust and feasible. Here, we describe the rationale and design of the multicentre open-label randomized controlled phase I/IIb trial evaluating the safety and the likelihood of efficacy of transendocardial expanded CD34+ cell administration in patients presenting with AMI and a reduced LV ejection fraction. METHODS Patients with a large AMI and LV ejection fraction <50% are randomized 3:1 to transendocardial expanded CD34+ cell injection plus standard of care or standard of care alone. Patients randomized to intervention are treated with lenograstim for 5 days before 220 ± 10 mL blood cell harvest from which autologous CD34+ cells are purified and expanded for 9 days using an automated good manufacturing practice compliant platform. The primary endpoint is the incidence of major adverse cardiac events over 6 months. The main secondary endpoints are LV end systolic volume index and the viability of the infarcted segments. CONCLUSIONS Autologous CD34+ cell therapy is currently limited by technological constraints. This is the first trial to evaluate the feasibility and potential effect of CD34+ cells after automated expansion and transendocardial administration in patients with large AMI.
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Affiliation(s)
- Jerome Roncalli
- Department of Cardiology, Institute Cardiomet, Centre d'Investigations Cliniques Biotherapies 1436, INSERM I2MC 1297, Toulouse University Hospital, Toulouse, France
| | - François Roubille
- Cardiology Department, Montpellier University Hospital, Montpellier, France
| | - Nicolas Meyer
- GMRC, Pôle de Santé Publique, CHU de Strasbourg, Strasbourg, France
| | - Giulio Pompilio
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, Milan, Italy
- Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, University of Milano, Milan, Italy
| | - Lionel Leroux
- Department of Interventional Cardiology and Intensive Care, Haut-Leveque Hospital, Pessac, France
| | | | | | | | | | - Eric Saloux
- Department of Cardiology, Caen University Hospital, Caen, France
| | - Alain Manrique
- Department of Nuclear Medicine, Normandie Univ, UNICAEN, CHU de Caen Normandie, Caen, France
| | - Pierre-Yves Marie
- Nuclear Medicine & Nancyclotep Experimental Platform, CHRU-Nancy, Université de Lorraine, Nancy, France
| | - Deepak L Bhatt
- Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Scott D Solomon
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | | | - David E Newby
- British Heart Foundation Centre of Research Excellence, The University of Edinburgh, Edinburgh, UK
| | - Faiez Zannad
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques Plurithématique 1433, Centre Hospitalier Régional Universitaire de Nancy, Nancy, France
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2
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Tang X, Wang Z, Wang J, Cui S, Xu R, Wang Y. Functions and regulatory mechanisms of resting hematopoietic stem cells: a promising targeted therapeutic strategy. Stem Cell Res Ther 2023; 14:73. [PMID: 37038215 PMCID: PMC10088186 DOI: 10.1186/s13287-023-03316-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 03/29/2023] [Indexed: 04/12/2023] Open
Abstract
Hematopoietic stem cells (HSCs) are the common and essential precursors of all blood cells, including immune cells, and they are responsible for the lifelong maintenance and damage repair of blood tissue homeostasis. The vast majority (> 95%) of HSCs are in a resting state under physiological conditions and are only activated to play a functional role under stress conditions. This resting state affects their long-term survival and is also closely related to the lifelong maintenance of hematopoietic function; however, abnormal changes may also be an important factor leading to the decline of immune function in the body and the occurrence of diseases in various systems. While the importance of resting HSCs has attracted increasing research attention, our current understanding of this topic remains insufficient, and the direction of clinical targeted treatments is unclear. Here, we describe the functions of HSCs, analyze the regulatory mechanisms that affect their resting state, and discuss the relationship between resting HSCs and different diseases, with a view to providing guidance for the future clinical implementation of related targeted treatments.
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Affiliation(s)
- Xinyu Tang
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhenzhen Wang
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369 Jingshi Road, Lixia District, Jinan, 250014, China
- Institute of Hematology, Shandong University of Traditional Chinese Medicine, Jinan, China
- Shandong Provincial Health Commission Key Laboratory of Hematology of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jingyi Wang
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369 Jingshi Road, Lixia District, Jinan, 250014, China
- Institute of Hematology, Shandong University of Traditional Chinese Medicine, Jinan, China
- Shandong Provincial Health Commission Key Laboratory of Hematology of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Siyuan Cui
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369 Jingshi Road, Lixia District, Jinan, 250014, China
- Institute of Hematology, Shandong University of Traditional Chinese Medicine, Jinan, China
- Shandong Provincial Health Commission Key Laboratory of Hematology of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ruirong Xu
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369 Jingshi Road, Lixia District, Jinan, 250014, China.
- Institute of Hematology, Shandong University of Traditional Chinese Medicine, Jinan, China.
- Shandong Provincial Health Commission Key Laboratory of Hematology of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Yan Wang
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369 Jingshi Road, Lixia District, Jinan, 250014, China.
- Institute of Hematology, Shandong University of Traditional Chinese Medicine, Jinan, China.
- Shandong Provincial Health Commission Key Laboratory of Hematology of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
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Pan Q, Xu X, He W, Wang Y, Xiang Z, Jin X, Tang Q, Zhao T, Ma X. Enrichment of miR-17-5p enhances the protective effects of EPC-EXs on vascular and skeletal muscle injury in a diabetic hind limb ischemia model. Biol Res 2023; 56:16. [PMID: 37005678 PMCID: PMC10067242 DOI: 10.1186/s40659-023-00418-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 02/07/2023] [Indexed: 04/04/2023] Open
Abstract
BACKGROUND/AIMS Diabetes mellitus (DM) is highly susceptible to diabetic hind limb ischemia (DHI). MicroRNA (MiR)-17-5p is downregulated in DM and plays a key role in vascular protection. Endothelial progenitor cell (EPC)-released exosomes (EPC-EXs) contribute to vascular protection and ischemic tissue repair by transferring their contained miRs to target cells. Here, we investigated whether miR-17-5p-enriched EPC-EXs (EPC-EXsmiR-17-5p) had conspicuous effects on protecting vascular and skeletal muscle in DHI in vitro and in vivo. METHODS EPCs transfected with scrambled control or miR-17-5p mimics were used to generate EPC-EXs and EPC-EXsmiR-17-5p. Db/db mice were subjected to hind limb ischemia. After the surgery, EPC-EXs and EPC-EXsmiR-17-5p were injected into the gastrocnemius muscle of the hind limb once every 7 days for 3 weeks. Blood flow, microvessel density, capillary angiogenesis, gastrocnemius muscle weight, structure integrity, and apoptosis in the hind limb were assessed. Vascular endothelial cells (ECs) and myoblast cells (C2C12 cells) were subjected to hypoxia plus high glucose (HG) and cocultured with EPC-EXs and EPC-EXsmiR-17-5p. A bioinformatics assay was used to analyze the potential target gene of miR-17-5p, the levels of SPRED1, PI3K, phosphorylated Akt, cleaved caspase-9 and cleaved caspase-3 were measured, and a PI3K inhibitor (LY294002) was used for pathway analysis. RESULTS In the DHI mouse model, miR-17-5p was markedly decreased in hind limb vessels and muscle tissues, and infusion of EPC-EXsmiR-17-5p was more effective than EPC-EXs in increasing miR-17-5p levels, blood flow, microvessel density, and capillary angiogenesis, as well as in promoting muscle weight, force production and structural integrity while reducing apoptosis in gastrocnemius muscle. In Hypoxia plus HG-injured ECs and C2C12 cells, we found that EPC-EXsmiR-17-5p could deliver their carried miR-17-5p into target ECs and C2C12 cells and subsequently downregulate the target protein SPRED1 while increasing the levels of PI3K and phosphorylated Akt. EPC-EXsmiR-17-5p were more effective than EPC-EXs in decreasing apoptosis and necrosis while increasing viability, migration, and tube formation in Hypoxia plus HG-injured ECs and in decreasing apoptosis while increasing viability and myotube formation in C2C12 cells. These effects of EPC-EXsmiR-17-5p could be abolished by a PI3K inhibitor (LY294002). CONCLUSION Our results suggest that miR-17-5p promotes the beneficial effects of EPC-EXs on DHI by protecting vascular ECs and muscle cell functions.
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Affiliation(s)
- Qunwen Pan
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Xiaobing Xu
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Wen He
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Yan Wang
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
- Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang, China
| | - Zhi Xiang
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Xiaojuan Jin
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Qiong Tang
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Ting Zhao
- Out-Patient Department, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
| | - Xiaotang Ma
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
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4
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Chen Y, Hou S. Application of magnetic nanoparticles in cell therapy. Stem Cell Res Ther 2022; 13:135. [PMID: 35365206 PMCID: PMC8972776 DOI: 10.1186/s13287-022-02808-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/09/2022] [Indexed: 02/08/2023] Open
Abstract
Fe3O4 magnetic nanoparticles (MNPs) are biomedical materials that have been approved by the FDA. To date, MNPs have been developed rapidly in nanomedicine and are of great significance. Stem cells and secretory vesicles can be used for tissue regeneration and repair. In cell therapy, MNPs which interact with external magnetic field are introduced to achieve the purpose of cell directional enrichment, while MRI to monitor cell distribution and drug delivery. This paper reviews the size optimization, response in external magnetic field and biomedical application of MNPs in cell therapy and provides a comprehensive view.
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Affiliation(s)
- Yuling Chen
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin, China. .,Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China.
| | - Shike Hou
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin, China.,Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China
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5
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Matta A, Nader V, Galinier M, Roncalli J. Transplantation of CD34+ cells for myocardial ischemia. World J Transplant 2021; 11:138-146. [PMID: 34046316 PMCID: PMC8131931 DOI: 10.5500/wjt.v11.i5.138] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/01/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
CD34+ cells are multipotent hematopoietic stem cells also known as endothelial progenitor cells and are useful in regenerative medicine. Naturally, these cells are mobilized from the bone marrow into peripheral circulation in response to ischemic tissue injury. CD34+ cells are known for their high proliferative and differentiation capacities that play a crucial role in the repair process of myocardial damage. They have an important paracrine activity in secreting factors to stimulate vasculogenesis, reduce endothelial cells and cardiomyocytes apoptosis, remodel extracellular matrix and activate additional progenitor cells. Once they migrate to the target site, they enhance angiogenesis, neovascularization and tissue regeneration. Several trials have demonstrated the safety and efficacy of CD34+ cell therapy in different settings, such as peripheral limb ischemia, stroke and cardiovascular disease. Herein, we review the potential utility of CD34+ cell transplantation in acute myocardial infarction, refractory angina and ischemic heart failure.
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Affiliation(s)
- Anthony Matta
- Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse, Toulouse 31059, France
- Faculty of Medicine, Holy Spirit University of Kaslik, Kaslik 00000, Lebanon
| | - Vanessa Nader
- Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse, Toulouse 31059, France
- Faculty of Pharmacy, Lebanese University, Beirut 961, Lebanon
| | - Michel Galinier
- Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse, Toulouse 31059, France
| | - Jerome Roncalli
- Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse, Toulouse 31059, France
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6
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Hassanpour M, Aghamohamadzade N, Cheraghi O, Heidarzadeh M, Nouri M. Current status of cardiac regenerative medicine; An update on point of view to cell therapy application. J Cardiovasc Thorac Res 2021; 12:256-268. [PMID: 33510874 PMCID: PMC7828760 DOI: 10.34172/jcvtr.2020.44] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 09/19/2020] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of death globally. Because of the economic and social burden of acute myocardial infarction and its chronic consequences in surviving patients, understanding the pathophysiology of myocardial infarction injury is a major priority for cardiovascular research. MI is defined as cardiomyocytes death caused by an ischemic that resulted from the apoptosis, necrosis, necroptosis, and autophagy. The phases of normal repair following MI including inflammatory, proliferation, and maturation. Normal repair is slow and inefficient generally so that other treatments are required. Because of difficulties, outcomes, and backwashes of traditional therapies including coronary artery bypass grafting, balloon angioplasty, heart transplantation, and artificial heart operations, the novel strategy in the treatment of MI, cell therapy, was newly emerged. In cell therapy, a new population of cells has created that substitute with damaged cells. Different types of stem cell and progenitor cells have been shown to improve cardiac function through various mechanisms, including the formation of new myocytes, endothelial cells, and vascular smooth muscle cells. Bone marrow- and/or adipose tissue-derived mesenchymal stem cells, embryonic stem cells, autologous skeletal myoblasts, induced pluripotent stem cells, endothelial progenitor cells, cardiac progenitor cells and cardiac pericytes considered as a source for cell therapy. In this study, we focused on the point of view of the cell sources.
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Affiliation(s)
- Mehdi Hassanpour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Omid Cheraghi
- Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran
| | | | - Mohammad Nouri
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
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7
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Zhou L, Zhang Y, Wang Y, Zhang M, Sun W, Dai T, Wang A, Wu X, Zhang S, Wang S, Zhou F. A Dual Role of Type I Interferons in Antitumor Immunity. ACTA ACUST UNITED AC 2020; 4:e1900237. [PMID: 33245214 DOI: 10.1002/adbi.201900237] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 02/17/2020] [Accepted: 02/20/2020] [Indexed: 12/12/2022]
Abstract
Type I interferons (IFN-Is) are a family of cytokines that exert direct antiviral effects and regulate innate and adaptive immune responses through direct and indirect mechanisms. It is generally believed that IFN-Is repress tumor development via restricting tumor proliferation and inducing antitumor immune responses. However, recent emerging evidence suggests that IFN-Is play a dual role in antitumor immunity. That is, in the early stage of tumorigenesis, IFN-Is promote the antitumor immune response by enhancing antigen presentation in antigen-presenting cells and activating CD8+ T cells. However, in the late stage of tumor progression, persistent expression of IFN-Is induces the expression of immunosuppressive factors (PD-L1, IDO, and IL-10) on the surface of dendritic cells and other bone marrow cells and inhibits their antitumor immunity. This review outlines these dual functions of IFN-Is in antitumor immunity and elucidates the involved mechanisms, as well as their applications in tumor therapy.
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Affiliation(s)
- Lili Zhou
- Jiangsu Key Laboratory of Infection and Immunity, The Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123, P. R. China
| | - Yuqi Zhang
- Jiangsu Key Laboratory of Infection and Immunity, The Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123, P. R. China
| | - Yongqiang Wang
- Jiangsu Key Laboratory of Infection and Immunity, The Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123, P. R. China
| | - Meirong Zhang
- Jiangsu Key Laboratory of Infection and Immunity, The Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123, P. R. China
| | - Wenhuan Sun
- Jiangsu Key Laboratory of Infection and Immunity, The Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123, P. R. China
| | - Tong Dai
- Jiangsu Key Laboratory of Infection and Immunity, The Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123, P. R. China
| | - Aijun Wang
- Department of Surgery, School of Medicine, UC Davis, Davis, CA, 95817, USA
| | - Xiaojin Wu
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Suping Zhang
- Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Pharmacology, Base for international Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, 518055, China
| | - Shuai Wang
- Jiangsu Key Laboratory of Infection and Immunity, The Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123, P. R. China
| | - Fangfang Zhou
- Jiangsu Key Laboratory of Infection and Immunity, The Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123, P. R. China
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8
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Czabanka M, Petrilli LL, Elvers-Hornung S, Bieback K, Albert Imhof B, Vajkoczy P, Vinci M. Junctional Adhesion Molecule-C Mediates the Recruitment of Embryonic-Endothelial Progenitor Cells to the Perivascular Niche during Tumor Angiogenesis. Int J Mol Sci 2020; 21:ijms21041209. [PMID: 32054130 PMCID: PMC7072851 DOI: 10.3390/ijms21041209] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 02/07/2020] [Indexed: 11/29/2022] Open
Abstract
The homing of Endothelial Progenitor Cells (EPCs) to tumor angiogenic sites has been described as a multistep process, involving adhesion, migration, incorporation and sprouting, for which the underlying molecular and cellular mechanisms are yet to be fully defined. Here, we studied the expression of Junctional Adhesion Molecule-C (JAM-C) by EPCs and its role in EPC homing to tumor angiogenic vessels. For this, we used mouse embryonic-Endothelial Progenitor Cells (e-EPCs), intravital multi-fluorescence microscopy techniques and the dorsal skin-fold chamber model. JAM-C was found to be expressed by e-EPCs and endothelial cells. Blocking JAM-C did not affect adhesion of e-EPCs to endothelial monolayers in vitro but, interestingly, it did reduce their adhesion to tumor endothelium in vivo. The most striking effect of JAM-C blocking was on tube formation on matrigel in vitro and the incorporation and sprouting of e-EPCs to tumor endothelium in vivo. Our results demonstrate that JAM-C mediates e-EPC recruitment to tumor angiogenic sites, i.e., coordinated homing of EPCs to the perivascular niche, where they cluster and interact with tumor blood vessels. This suggests that JAM-C plays a critical role in the process of vascular assembly and may represent a potential therapeutic target to control tumor angiogenesis.
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Affiliation(s)
- Marcus Czabanka
- Department of Neurosurgery, Universitätsmedizin Charitè, 10117 Berlin, Germany;
- Department of Neurosurgery Medical Faculty of the University of Heidelberg, 68167 Mannheim, Germany;
| | - Lucia Lisa Petrilli
- Department of Onco-haematology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital – IRCCS, 00146 Rome, Italy;
| | - Susanne Elvers-Hornung
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Fred Cross Blood Donor Service Baden-Württemberg – Hessen, 68167 Mannheim, Germany (K.B.)
| | - Karen Bieback
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Fred Cross Blood Donor Service Baden-Württemberg – Hessen, 68167 Mannheim, Germany (K.B.)
| | - Beat Albert Imhof
- Department of Pathology and Immunology, Medical Faculty, Centre Medical Universitaire (CMU), University of Geneva, 1206 Geneva, Switzerland;
| | - Peter Vajkoczy
- Department of Neurosurgery, Universitätsmedizin Charitè, 10117 Berlin, Germany;
- Department of Neurosurgery Medical Faculty of the University of Heidelberg, 68167 Mannheim, Germany;
- Correspondence: ; Tel.: +49-30450560-002
| | - Maria Vinci
- Department of Neurosurgery Medical Faculty of the University of Heidelberg, 68167 Mannheim, Germany;
- Department of Onco-haematology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital – IRCCS, 00146 Rome, Italy;
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9
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Sheikh Hosseini M, Parhizkar Roudsari P, Gilany K, Goodarzi P, Payab M, Tayanloo-Beik A, Larijani B, Arjmand B. Cellular Dust as a Novel Hope for Regenerative Cancer Medicine. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1288:139-160. [DOI: 10.1007/5584_2020_537] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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10
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MicroRNA-126 Priming Enhances Functions of Endothelial Progenitor Cells under Physiological and Hypoxic Conditions and Their Therapeutic Efficacy in Cerebral Ischemic Damage. Stem Cells Int 2018; 2018:2912347. [PMID: 29760722 PMCID: PMC5924971 DOI: 10.1155/2018/2912347] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Accepted: 01/09/2018] [Indexed: 02/07/2023] Open
Abstract
Endothelial progenitor cells (EPCs) have shown the potential for treating ischemic stroke (IS), while microRNA-126 (miR-126) is reported to have beneficial effects on endothelial function and angiogenesis. In this study, we investigated the effects of miR-126 overexpression on EPCs and explore the efficacy of miR-126-primed EPCs (EPCmiR-126) in treating IS. The effects of miR-126 overexpression on EPC proliferation, migratory, tube formation capacity, reactive oxygen species (ROS) production, and nitric oxide (NO) generation were determined. In in vivo study, the effects of EPCmiR-126 on the cerebral blood flow (CBF), neurological deficit score (NDS), infarct volume, cerebral microvascular density (cMVD), and angiogenesis were determined. Moreover, the levels of circulating EPCs (cEPCs) and their contained miR-126 were measured. We found (1) miR-126 overexpression promoted the proliferation, migration, and tube formation abilities of EPCs; decreased ROS; and increased NO production of EPCs via activation of PI3K/Akt/eNOS pathway; (2) EPCmiR-126 was more effective than EPCs in attenuating infarct volume and NDS and enhancing cMVD, CBF, and angiogenesis; and (3) infusion of EPCmiR-126 increased the number and the level of miR-126 in cEPCs. Our data indicate that miR-126 overexpression enhanced the function of EPCs in vitro and in vivo.
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11
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Salehi A, Zhang JH, Obenaus A. Response of the cerebral vasculature following traumatic brain injury. J Cereb Blood Flow Metab 2017; 37:2320-2339. [PMID: 28378621 PMCID: PMC5531360 DOI: 10.1177/0271678x17701460] [Citation(s) in RCA: 199] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The critical role of the vasculature and its repair in neurological disease states is beginning to emerge particularly for stroke, dementia, epilepsy, Parkinson's disease, tumors and others. However, little attention has been focused on how the cerebral vasculature responds following traumatic brain injury (TBI). TBI often results in significant injury to the vasculature in the brain with subsequent cerebral hypoperfusion, ischemia, hypoxia, hemorrhage, blood-brain barrier disruption and edema. The sequalae that follow TBI result in neurological dysfunction across a host of physiological and psychological domains. Given the importance of restoring vascular function after injury, emerging research has focused on understanding the vascular response after TBI and the key cellular and molecular components of vascular repair. A more complete understanding of vascular repair mechanisms are needed and could lead to development of new vasculogenic therapies, not only for TBI but potentially vascular-related brain injuries. In this review, we delineate the vascular effects of TBI, its temporal response to injury and putative biomarkers for arterial and venous repair in TBI. We highlight several molecular pathways that may play a significant role in vascular repair after brain injury.
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Affiliation(s)
- Arjang Salehi
- 1 Cell, Molecular and Developmental Biology Program, University of California, Riverside, CA, USA.,2 Department of Pediatrics, Loma Linda University, Loma Linda, CA, USA
| | - John H Zhang
- 3 Department of Physiology and Pharmacology Loma Linda University School of Medicine, CA, USA.,4 Department of Anesthesiology Loma Linda University School of Medicine, CA, USA.,5 Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Andre Obenaus
- 1 Cell, Molecular and Developmental Biology Program, University of California, Riverside, CA, USA.,2 Department of Pediatrics, Loma Linda University, Loma Linda, CA, USA.,6 Department of Pediatrics, University of California, Irvine, Irvine, CA, USA
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12
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Acarbose Accelerates Wound Healing via Akt/eNOS Signaling in db/db Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:7809581. [PMID: 28373902 PMCID: PMC5360971 DOI: 10.1155/2017/7809581] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 01/17/2017] [Accepted: 02/20/2017] [Indexed: 12/21/2022]
Abstract
Refractory wound is a dreaded complication of diabetes and is highly correlated with EPC dysfunction caused by hyperglycemia. Acarbose is a widely used oral glucose-lowering drug exclusively for T2DM. Previous studies have suggested the beneficial effect of acarbose on improving endothelial dysfunction in patients with T2DM. However, no data have been reported on the beneficial efficacy of acarbose in wound healing impairment caused by diabetes. We herein investigated whether acarbose could improve wound healing in T2DM db/db mice and the possible mechanisms involved. Acarbose hastened wound healing and enhanced angiogenesis, accompanied by increased circulating EPC number in db/db mice. In vitro, a reversed BM-EPC dysfunction was observed after the administration of acarbose in db/db mice, as reflected by tube formation assay. In addition, a significantly increased NO production was also witnessed in BM-EPCs from acarbose treated db/db mice, with decreased O2 levels. Akt inhibitor could abolish the beneficial effect of acarbose on high glucose induced EPC dysfunction in vitro, accompanied by reduced eNOS activation. Acarbose displayed potential effect in promoting wound healing and improving angiogenesis in T2DM mice, which was possibly related to the Akt/eNOS signaling pathway.
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13
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Hauser S, Jung F, Pietzsch J. Human Endothelial Cell Models in Biomaterial Research. Trends Biotechnol 2016; 35:265-277. [PMID: 27789063 DOI: 10.1016/j.tibtech.2016.09.007] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Revised: 09/15/2016] [Accepted: 09/28/2016] [Indexed: 01/05/2023]
Abstract
Endothelial cell (EC) models have evolved as important tools in biomaterial research due to ubiquitously occurring interactions between implanted materials and the endothelium. However, screening the available literature has revealed a gap between material scientists and physiologists in terms of their understanding of these biomaterial-endothelium interactions and their relative importance. Consequently, EC models are often applied in nonphysiological experimental setups, or too extensive conclusions are drawn from their results. The question arises whether this might be one reason why, among the many potential biomaterials, only a few have found their way into the clinic. In this review, we provide an overview of established EC models and possible selection criteria to enable researchers to determine the most reliable and relevant EC model to use.
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Affiliation(s)
- Sandra Hauser
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department Radiopharmaceutical and Chemical Biology, Dresden, Germany
| | - Friedrich Jung
- Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany; Helmholtz Virtual Institute 'Multifunctional Biomaterials for Medicine', Teltow, Germany
| | - Jens Pietzsch
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department Radiopharmaceutical and Chemical Biology, Dresden, Germany; Technische Universität Dresden, Department of Chemistry and Food Chemistry, Dresden, Germany.
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14
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Endothelial progenitor cells improve the quality of transplanted hematopoietic stem cells and maintain longer term effects in mice. Ann Hematol 2016; 96:107-114. [DOI: 10.1007/s00277-016-2821-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Accepted: 09/07/2016] [Indexed: 11/25/2022]
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15
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Multilayer Membranes of Glycosaminoglycans and Collagen I Biomaterials Modulate the Function and Microvesicle Release of Endothelial Progenitor Cells. Stem Cells Int 2016; 2016:4796578. [PMID: 27190523 PMCID: PMC4846769 DOI: 10.1155/2016/4796578] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Revised: 03/18/2016] [Accepted: 03/20/2016] [Indexed: 12/20/2022] Open
Abstract
Multilayer composite membrane of biomaterials can increase the function of adipose stem cells or osteoprogenitor cells. Recent evidence indicates endothelial progenitor cells (EPCs) and EPCs released microvesicles (MVs) play important roles in angiogenesis and vascular repair. Here, we investigated the effects of biomaterial multilayer membranes of hyaluronic acid (HA) or chondroitin sulfate (CS) and Collagen I (Col I) on the functions and MVs release of EPCs. Layer-by-layer (LBL) technology was applied to construct the multilayer composite membranes. Four types of the membranes constructed by adsorbing either HA or CS and Col I alternatively with different top layers were studied. The results showed that all four types of multilayer composite membranes could promote EPCs proliferation and migration and inhibit cell senility, apoptosis, and the expression of activated caspase-3. Interestingly, these biomaterials increased the release and the miR-126 level of EPCs-MVs. Moreover, the CS-Col I membrane with CS on the top layer showed the most effects on promoting EPCs proliferation, EPCs-MV release, and miR-126 level in EPCs-MVs. In conclusion, HA/CS and Collagen I composed multilayer composite membranes can promote EPCs functions and release of miR-126 riched EPCs-MVs, which provides a novel strategy for tissue repair treatment.
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16
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Qin Y, He YH, Hou N, Zhang GS, Cai Y, Zhang GP, Xiao Q, He LS, Li SJ, Yi Q, Luo JD. Sonic hedgehog improves ischemia-induced neovascularization by enhancing endothelial progenitor cell function in type 1 diabetes. Mol Cell Endocrinol 2016; 423:30-9. [PMID: 26773732 DOI: 10.1016/j.mce.2016.01.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Revised: 01/06/2016] [Accepted: 01/06/2016] [Indexed: 12/28/2022]
Abstract
The Sonic hedgehog (Shh) pathway is downregulated in type 1 diabetes, and it has been reported that augmentation of this pathway may alleviate diabetic complications. However, the cellular mechanisms underlying these protective effects are poorly understood. Recent studies indicate that impaired function of endothelial progenitor cells (EPCs) may contribute to cardiovascular problems in diabetes. We hypothesized that impaired Shh signaling contribute to endothelial progenitor cell dysfunction and that activating the Shh signaling pathway may rescue EPC function and promote diabetic neovascularization. Adult male C57/B6 mice and streptozotocin (STZ)-induced type 1 diabetic mice were used. Gli1 and Ptc1 protein levels were reduced in EPCs from diabetic mice, indicating inhibition of the Shh signaling pathway. EPC migration, tube formation ability, and mobilization were impaired in diabetic mice compared with non-diabetic controls (p < 0.05 vs control), and all were improved by in vivo administration of the Shh pathway receptor agonist SAG (p < 0.05 vs diabetes). SAG significantly increased capillary density and blood perfusion in the ischemic hindlimbs of diabetic mice (p < 0.05 vs diabetes). The AKT activity was lower in EPCs from diabetic mice than those from non-diabetic controls (p < 0.05 vs control). This decreased AKT activity led to an increased GSK-3β activity and degradation of the Shh pathway transcription factor Gli1/Gli2. SAG significantly increased the activity of AKT in EPCs. Our data clearly demonstrate that an impaired Shh pathway mediated by the AKT/GSK-3β pathway can contribute to EPC dysfunction in diabetes and thus activating the Shh signaling pathway can restore both the number and function of EPCs and increase neovascularization in type 1 diabetic mice.
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Affiliation(s)
- Yuan Qin
- Guangzhou Institute of Venoms, Guangzhou Medical University, Guangzhou 510182, China
| | - Yan-Huan He
- Guangzhou Institute of Venoms, Guangzhou Medical University, Guangzhou 510182, China
| | - Ning Hou
- Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, China
| | - Gen-Shui Zhang
- Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, China
| | - Yi Cai
- Guangzhou Institute of Venoms, Guangzhou Medical University, Guangzhou 510182, China
| | - Gui-Ping Zhang
- Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, China
| | - Qing Xiao
- Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, China
| | - Li-Shan He
- Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, China
| | - Su-Juan Li
- Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, China
| | - Quan Yi
- Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, China
| | - Jian-Dong Luo
- Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, China.
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17
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Functional and Biological Role of Endothelial Precursor Cells in Tumour Progression: A New Potential Therapeutic Target in Haematological Malignancies. Stem Cells Int 2015; 2016:7954580. [PMID: 26788072 PMCID: PMC4691637 DOI: 10.1155/2016/7954580] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2015] [Revised: 06/19/2015] [Accepted: 08/10/2015] [Indexed: 12/11/2022] Open
Abstract
It was believed that vasculogenesis occurred only during embryo life and that postnatal formation of vessels arose from angiogenesis. Recent findings demonstrate the existence of Endothelial Precursor Cells (EPCs), which take partin postnatal vasculogenesis. EPCs are recruited from the bone marrow under the stimulation of growth factors and cytokines and reach the sites of neovascularization in both physiological and pathological conditions such as malignancies where they contribute to the “angiogenic switch” and tumor progression. An implementation of circulating EPCs in the bloodstream of patients with haematological malignancies has been demonstrated. This increase is strictly related to the bone marrow microvessel density and correlated with a poor prognosis. The EPCs characterization is a very complex process and still under investigation. This literature review aims to provide an overview of the functional and biological role of EPCs in haematological malignancies and to investigate their potential as a new cancer therapeutic target.
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18
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Nguyen VT, Nassar D, Batteux F, Raymond K, Tharaux PL, Aractingi S. Delayed Healing of Sickle Cell Ulcers Is due to Impaired Angiogenesis and CXCL12 Secretion in Skin Wounds. J Invest Dermatol 2015; 136:497-506. [PMID: 26967481 DOI: 10.1016/j.jid.2015.11.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 08/14/2015] [Accepted: 10/12/2015] [Indexed: 01/31/2023]
Abstract
Leg ulcers are a major complication of sickle cell disease that occur in 2.5-40% of patients. Leg ulcers are responsible for frequent complications because they are often long-lasting and are highly resistant to therapy. Although their occurrence is associated with hyperhemolysis, the mechanisms underlying sickle cell ulcers remain poorly understood. In this study, we show that skin wound healing is severely altered in old SAD sickle cell mice but is normal in young animals, consistent with reports in humans. Alterations of wound healing were associated with impaired blood and lymphatic angiogenesis in the wound beds and poor endothelial progenitor cell mobilization from the bone marrow. CXCL12 secretion by keratinocytes and inflammatory cells was low in the wounds of SAD mice. Local therapy with endothelial progenitor cells or recombinant CXCL12 injections restored wound angiogenesis and rescued the healing defect together with mobilization of circulating endothelial progenitor cells. To our knowledge, this is a previously unreported study of the cellular and molecular mechanisms of sickle cell ulcers in a murine model that provides promising therapeutic perspectives for clinical trials.
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Affiliation(s)
- Van Tuan Nguyen
- Progenitors and Endothelial Cells During and After Pregnancy Laboratory, INSERM UMR_S 938, Centre de Recherche, St. Antoine, Paris, France; UPMC-Université Paris 6, Paris, France
| | - Dany Nassar
- Progenitors and Endothelial Cells During and After Pregnancy Laboratory, INSERM UMR_S 938, Centre de Recherche, St. Antoine, Paris, France; UPMC-Université Paris 6, Paris, France; Department of Dermatology, American University of Beirut Medical Centre, Beirut, Lebanon; Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Fréderic Batteux
- Faculty of Medicine, Université Paris Descartes-Paris 5, Paris, France
| | - Karine Raymond
- Progenitors and Endothelial Cells During and After Pregnancy Laboratory, INSERM UMR_S 938, Centre de Recherche, St. Antoine, Paris, France
| | | | - Sélim Aractingi
- Progenitors and Endothelial Cells During and After Pregnancy Laboratory, INSERM UMR_S 938, Centre de Recherche, St. Antoine, Paris, France; Faculty of Medicine, Université Paris Descartes-Paris 5, Paris, France; Department of Dermatology, Hôpital Cochin-Tarnier, Paris, France.
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19
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Collet G, Szade K, Nowak W, Klimkiewicz K, El Hafny-Rahbi B, Szczepanek K, Sugiyama D, Weglarczyk K, Foucault-Collet A, Guichard A, Mazan A, Nadim M, Fasani F, Lamerant-Fayel N, Grillon C, Petoud S, Beloeil JC, Jozkowicz A, Dulak J, Kieda C. Endothelial precursor cell-based therapy to target the pathologic angiogenesis and compensate tumor hypoxia. Cancer Lett 2015; 370:345-57. [PMID: 26577811 DOI: 10.1016/j.canlet.2015.11.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 11/04/2015] [Accepted: 11/04/2015] [Indexed: 01/08/2023]
Abstract
Hypoxia-inducing pathologies as cancer develop pathologic and inefficient angiogenesis which rules tumor facilitating microenvironment, a key target for therapy. As such, the putative ability of endothelial precursor cells (EPCs) to specifically home to hypoxic sites of neovascularization prompted to design optimized, site-specific, cell-mediated, drug-/gene-targeting approach. Thus, EPC lines were established from aorta-gonad-mesonephros (AGM) of murine 10.5 dpc and 11.5 dpc embryo when endothelial repertoire is completed. Lines representing early endothelial differentiation steps were selected: MAgEC10.5 and MagEC11.5. Distinct in maturation, they differently express VEGF receptors, VE-cadherin and chemokine/receptors. MAgEC11.5, more differentiated than MAgEC 10.5, displayed faster angiogenesis in vitro, different response to hypoxia and chemokines. Both MAgEC lines cooperated to tube-like formation with mature endothelial cells and invaded tumor spheroids through a vasculogenesis-like process. In vivo, both MAgEC-formed vessels established blood flow. Intravenously injected, both MAgECs invaded Matrigel(TM)-plugs and targeted tumors. Here we show that EPCs (MAgEC11.5) target tumor angiogenesis and allow local overexpression of hypoxia-driven soluble VEGF-receptor2 enabling drastic tumor growth reduction. We propose that such EPCs, able to target tumor angiogenesis, could act as therapeutic gene vehicles to inhibit tumor growth by vessel normalization resulting from tumor hypoxia alleviation.
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Affiliation(s)
- Guillaume Collet
- Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, Kraków 30387, Poland
| | - Krzysztof Szade
- Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, Kraków 30387, Poland
| | - Witold Nowak
- Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, Kraków 30387, Poland
| | - Krzysztof Klimkiewicz
- Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, Kraków 30387, Poland
| | - Bouchra El Hafny-Rahbi
- Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France
| | - Karol Szczepanek
- Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, Kraków 30387, Poland
| | - Daisuke Sugiyama
- Division of Hematopoietic Stem Cells, Kyushu University Faculty of Medical Sciences, Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan
| | - Kazimierz Weglarczyk
- Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France
| | - Alexandra Foucault-Collet
- Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France
| | - Alan Guichard
- Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France
| | - Andrzej Mazan
- Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, Kraków 30387, Poland
| | - Mahdi Nadim
- Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France
| | - Fabienne Fasani
- Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France
| | - Nathalie Lamerant-Fayel
- Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France
| | - Catherine Grillon
- Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France
| | - Stéphane Petoud
- Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France
| | - Jean-Claude Beloeil
- Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France
| | - Alicja Jozkowicz
- Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, Kraków 30387, Poland; Malopolska Biotechnology Centre, Jagiellonian University, Gronostajowa 7A, Kraków 30387, Poland
| | - Jozef Dulak
- Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, Kraków 30387, Poland; Malopolska Biotechnology Centre, Jagiellonian University, Gronostajowa 7A, Kraków 30387, Poland.
| | - Claudine Kieda
- Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, Orléans 45071, France; Malopolska Biotechnology Centre, Jagiellonian University, Gronostajowa 7A, Kraków 30387, Poland.
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20
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Endothelial progenitor cells support tumour growth and metastatisation: implications for the resistance to anti-angiogenic therapy. Tumour Biol 2015; 36:6603-14. [DOI: 10.1007/s13277-015-3823-2] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 07/20/2015] [Indexed: 12/15/2022] Open
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Abstract
Endothelial progenitor cells (EPCs) play a critical role in maintenance of the endothelial integrity and vascular homeostasis, as well as in neovascularization. Dysfunctional EPCs are believed to contribute to the endothelial dysfunction and are closely related to the development of various cardiovascular diseases, such as hypertension, hyperlipidemia, and stroke. However, the underlying mechanisms of EPC dysfunction are complicated and remain largely elusive. Recent studies have demonstrated that reactive oxygen species (ROS) are key factors that involve in modulation of stem and progenitor cell function under various physiologic and pathologic conditions. It has been shown that NADPH oxidase (NOX)-derived ROS are the major sources of ROS in cardiovascular system. Accumulating evidence suggests that NOX-mediated oxidative stress can modulate EPC bioactivities, such as mobilization, migration, and neovascularization, and that inhibition of NOX has been shown to improve EPC functions. This review summarized recent progress in the studies on the correlation between NOX-mediated EPC dysfunction and cardiovascular diseases.
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22
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Stem Cells for Cutaneous Wound Healing. BIOMED RESEARCH INTERNATIONAL 2015; 2015:285869. [PMID: 26137471 PMCID: PMC4468276 DOI: 10.1155/2015/285869] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 03/20/2015] [Indexed: 01/08/2023]
Abstract
Optimum healing of a cutaneous wound involves a well-orchestrated cascade of biological and molecular processes involving cell migration, proliferation, extracellular matrix deposition, and remodelling. When the normal biological process fails for any reason, this healing process can stall resulting in chronic wounds. Wounds are a growing clinical burden on healthcare systems and with an aging population as well as increasing incidences of obesity and diabetes, this problem is set to increase. Cell therapies may be the solution. A range of cell based approaches have begun to cross the rift from bench to bedside and the supporting data suggests that the appropriate administration of stem cells can accelerate wound healing. This review examines the main cell types explored for cutaneous wound healing with a focus on clinical use. The literature overwhelmingly suggests that cell therapies can help to heal cutaneous wounds when used appropriately but we are at risk of clinical use outpacing the evidence. There is a need, now more than ever, for standardised methods of cell characterisation and delivery, as well as randomised clinical trials.
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Herlea-Pana O, Yao L, Heuser-Baker J, Wang Q, Wang Q, Georgescu C, Zou MH, Barlic-Dicen J. Chemokine receptors CXCR2 and CX3CR1 differentially regulate functional responses of bone-marrow endothelial progenitors during atherosclerotic plaque regression. Cardiovasc Res 2015; 106:324-37. [PMID: 25765938 DOI: 10.1093/cvr/cvv111] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 03/07/2015] [Indexed: 01/03/2023] Open
Abstract
AIMS Atherosclerosis manifests itself as arterial plaques, which lead to heart attacks or stroke. Treatments supporting plaque regression are therefore aggressively pursued. Studies conducted in models in which hypercholesterolaemia is reversible, such as the Reversa mouse model we have employed in the current studies, will be instrumental for the development of such interventions. Using this model, we have shown that advanced atherosclerosis regression occurs when lipid lowering is used in combination with bone-marrow endothelial progenitor cell (EPC) treatment. However, it remains unclear how EPCs home to regressing plaques and how they augment atherosclerosis reversal. Here we identify molecules that support functional responses of EPCs during plaque resolution. METHODS AND RESULTS Chemokines CXCL1 and CX3CL1 were detected in the vascular wall of atheroregressing Reversa mice, and their cognate receptors CXCR2 and CX3CR1 were observed on adoptively transferred EPCs in circulation. We tested whether CXCL1-CXCR2 and CX3CL1-CX3CR1 axes regulate functional responses of EPCs during plaque reversal. We show that pharmacological inhibition of CXCR2 or CX3CR1, or genetic inactivation of these two chemokine receptors interfered with EPC-mediated advanced atherosclerosis regression. We also demonstrate that CXCR2 directs EPCs to regressing plaques while CX3CR1 controls a paracrine function(s) of these cells. CONCLUSION CXCR2 and CX3CR1 differentially regulate EPC functional responses during atheroregression. Our study improves understanding of how chemokines and chemokine receptors regulate plaque resolution, which could determine the effectiveness of interventions reducing complications of atherosclerosis.
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Affiliation(s)
- Oana Herlea-Pana
- Cardiovascular Biology, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA
| | - Longbiao Yao
- Cardiovascular Biology, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA
| | - Janet Heuser-Baker
- Cardiovascular Biology, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA
| | - Qiongxin Wang
- Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Qilong Wang
- Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Constantin Georgescu
- Arthritis and Clinical Immunology Programs, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Ming-Hui Zou
- Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Jana Barlic-Dicen
- Cardiovascular Biology, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA
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Plouffe BD, Murthy SK, Lewis LH. Fundamentals and application of magnetic particles in cell isolation and enrichment: a review. REPORTS ON PROGRESS IN PHYSICS. PHYSICAL SOCIETY (GREAT BRITAIN) 2015; 78:016601. [PMID: 25471081 PMCID: PMC4310825 DOI: 10.1088/0034-4885/78/1/016601] [Citation(s) in RCA: 180] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
Magnetic sorting using magnetic beads has become a routine methodology for the separation of key cell populations from biological suspensions. Due to the inherent ability of magnets to provide forces at a distance, magnetic cell manipulation is now a standardized process step in numerous processes in tissue engineering, medicine, and in fundamental biological research. Herein we review the current status of magnetic particles to enable isolation and separation of cells, with a strong focus on the fundamental governing physical phenomena, properties and syntheses of magnetic particles and on current applications of magnet-based cell separation in laboratory and clinical settings. We highlight the contribution of cell separation to biomedical research and medicine and detail modern cell-separation methods (both magnetic and non-magnetic). In addition to a review of the current state-of-the-art in magnet-based cell sorting, we discuss current challenges and available opportunities for further research, development and commercialization of magnetic particle-based cell-separation systems.
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Affiliation(s)
- Brian D Plouffe
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA. The Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, MA 02115, USA
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25
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Ferreras C, Cole CL, Urban K, Jayson GC, Avizienyte E. Segregation of late outgrowth endothelial cells into functional endothelial CD34- and progenitor-like CD34+ cell populations. Angiogenesis 2015; 18:47-68. [PMID: 25269667 DOI: 10.1007/s10456-014-9446-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Accepted: 09/19/2014] [Indexed: 01/16/2023]
Abstract
Late outgrowth endothelial cells (OECs) that originate from peripheral blood mononuclear cells ex vivo have phenotypic and functional properties of mature endothelial cells. Given the potential therapeutic applications of OECs, understanding their biology is crucial. We have identified two distinct OEC populations based on differential expression of the cell surface marker CD34. OEC colonies lacked CD34 expression (CD34-), expressed CD34 in the majority of cells (CD34+), or showed a mixed expression pattern within a colony (CD34+/-). CD34+ and CD34- OECs were negative for hematopoietic cell marker CD45 and expressed the endothelial cell surface markers CD31, CD146, CD105, and VEGFR-2. Functionally CD34- and CD34+ OECs exhibited strikingly distinct behaviors. CD34- OECs, unlike CD34+ OECs, were capable of sprouting, formed tubes, and responded to angiogenic growth factors in vitro. In vivo, CD34- OECs formed endothelial tubes, while CD34+ OECs, despite being unable to form tubes, promoted infiltration of murine vasculature. Global gene expression profiling in CD34- and CD34+ OECs identified functional importance of the MMP-1/PAR-1 pathway in CD34- OECs. MMP-1 stimulated the expression of VEGFR-2, neuropilin-1, neuropilin-2, and CXCR4 and activated ERK1/2, whereas down-regulation of PAR-1 in CD34- OECs resulted in impaired angiogenic responses in vitro and reduced VEGFR-2 levels. In contrast, the CD34+ OEC colonies expressed high levels of the progenitor cell marker ALDH, which was absent in CD34- OECs. In summary, we show that OECs can be classified into functionally mature endothelial cells (CD34- OECs) that depend on the MMP-1/PAR-1 pathway and progenitor-like angiogenesis-promoting cells (CD34+ OECs).
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Affiliation(s)
- Cristina Ferreras
- Institute of Cancer Sciences, Faculty of Medical and Human Sciences, The University of Manchester, Paterson Building, Wilmslow Road, Manchester, M20 4BX, UK
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Wang Y, Chen Q, Zhang Z, Jiang F, Meng X, Yan H. Interleukin-10 overexpression improves the function of endothelial progenitor cells stimulated with TNF-α through the activation of the STAT3 signaling pathway. Int J Mol Med 2014; 35:471-7. [PMID: 25504316 DOI: 10.3892/ijmm.2014.2034] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Accepted: 12/04/2014] [Indexed: 11/06/2022] Open
Abstract
Lentivirus vector-interleukin-10 green fluorescent protein (LV-IL-10-GFP) was transfected into endothelial progenitor cells (EPCs) in the present study. The aim was to detect the function of IL‑10‑modified EPCs and analyze the molecular mechanism. EPCs were cultured and identified by fluorescent labeling with the von Willebrand factor antibody, vascular endothelial growth factor (VEGF) receptor, Ulex europaeus agglutinin-1 and acetylated low‑density lipoprotein. Subsequently, EPCs were transfected with LV-IL-10-GFP and lentivirus vector‑noncontain‑GFP as the control group. Enzyme‑linked immunosorbent assay (ELISA) was used to detect the concentrations of cytokines in the supernatant with or without tumor necrosis factor‑α (TNF‑α). All types of cells were assessed by a tube formation assay, adhesion assay and migration assay induced with or without TNF‑α. Cell cycle was assessed by flow cytometry. Western blot analysis was applied to detect the expression of proteins in the cells. ELISA analysis showed that the levels of TNF‑α and IL‑8 in the supernatant without TNF‑α significantly decreased in EPC‑LV‑IL‑10‑GFP (P<0.05 for all). By contrast, the levels of IL‑10 and VEGF were contrasting in association with these. The concentrations of cytokines in the supernatant with TNF‑α were consistent to the supernatant without TNF‑α. There was no statistically significant difference in the average number of EPCs undergoing migration, adhesion, total length and cell growth among the EPC, EPC‑LV‑IL‑10‑GFP and EPC‑LV‑NC‑GFP groups without TNF‑α. Further study showed that EPC‑LV‑IL‑10‑GFP with TNF‑α significantly enhanced EPC migration, adhesion and promoted tube formation (P<0.05 for all). Western blot analysis revealed that the expression of VEGF, matrix metallopeptidase‑9 and phosphorylated‑signal transducer and activator of transcription 3 (p‑STAT3) significantly increased in the EPC‑LV‑IL‑10‑GFP group. Conversely, STAT‑3 expression decreased in the EPC‑LV‑IL‑10‑GFP group. The present study suggested that overexpression of IL‑10 had no effect on migration, adhesion, tubule formation and cell growth of EPCs without TNF‑α. Furthermore, in EPCs stimulated with TNF‑α, the overexpression of IL‑10 improved EPC function, including migration, adhesion and tubule formation by activating the STAT3 signal pathway.
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Affiliation(s)
- Ying Wang
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Qingzhong Chen
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Zhuhong Zhang
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Feng Jiang
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Xiangda Meng
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Hua Yan
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
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Circulating endothelial progenitor cell: a promising biomarker in clinical oncology. Med Oncol 2014; 32:332. [PMID: 25428376 DOI: 10.1007/s12032-014-0332-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 11/06/2014] [Indexed: 12/11/2022]
Abstract
Human cancers are endowed with sustained vascularization capability, and their growth, invasion, and metastasis are vascularization dependent. Recently, accumulated body of evidence suggests that endothelial progenitor cells (EPCs) can support vasculogenesis and induce angiogenesis through paracrine mechanisms. In addition, numerous clinical studies have revealed the increase in the number of EPCs in the peripheral blood of cancer patients and demonstrated the correlation of circulating EPCs (CEPCs) with the clinical outcomes. This review highlights current enrichment procedures and methods for the detection of CEPCs and different biomarkers to identify CEPCs as well as the functions of EPCs in tumor vascularization. Furthermore, we systematically review available studies on the clinical relevance of CEPCs in cancer patients to explore the potential diagnostic and prognostic values of CEPCs. Although several contrasting results exist, CEPCs can conceivably serve as a promising biomarker for the early diagnosis, prognosis prediction, and treatment response indication in the future. Additionally, further well-designed clinical studies with larger sample size and unique, specific enumeration procedures are warranted to achieve further insight into the clinical implications of CEPCs.
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Roncalli J. An update on primary findings and new designs in biotherapy studies for acute myocardial infarction. Future Cardiol 2014; 10:781-8. [DOI: 10.2217/fca.14.65] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
ABSTRACT Treatment of acute myocardial infarction in the future should focus not only on improving acute treatment, as it has been done over the past decades, but also on secondary prevention of left ventricular dysfunction and/or progression to heart failure by preserving left ventricular shape, avoiding left ventricular remodeling and stimulating cardiac regeneration. Biotherapies with adult stem cells and bone marrow-derived endothelial cell progenitors, combined or not with biomaterials, and new drugs are under investigation and will probably be part of routine clinical practice for patients suffering from myocardial infarction in the near future.
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Zhao X, Yang H, Jiang G, Ni M, Deng Y, Cai J, Li Z, Shen F, Tao X. Simvastatin attenuates radiation-induced tissue damage in mice. JOURNAL OF RADIATION RESEARCH 2014; 55:257-64. [PMID: 24105712 PMCID: PMC3951077 DOI: 10.1093/jrr/rrt115] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Revised: 08/17/2013] [Accepted: 08/21/2013] [Indexed: 05/18/2023]
Abstract
The aim of this study was to investigate the protective effect of simvastatin against radiation-induced tissue injury in mice. Mice were radiated with 4 Gy or 8 Gy after 20 mg/kg/d simvastatin treatment over 2 weeks. Morphological changes were observed in the jejunum and bone marrow, and apoptotic cells were determined in both tissues. Peripheral blood cells were counted, and the superoxide dismutase (SOD) activity and the malondialdehyde (MDA) level in tissues of both thymus and spleen were measured. Compared with the radiation-only group, 20 mg/kg/d simvastatin administration significantly increased the mean villi height and decreased apoptotic cells in jejunum tissue, and stimulated regeneration and reduced apoptotic cells in bone marrow. Peripheral blood cell analysis revealed that simvastatin treatment induced a larger number of red blood cells and increased the hemoglobin level present after 4 Gy of radiation. Interestingly, it was also found that the number of peripheral endothelial progenitor cells was markedly increased following simvastatin administration. Antioxidant determination for tissues displayed that simvastatin therapy increased the SOD activity after both 4 and 8 Gy of radiation, but only decreased the MDA level after 4 Gy. Simvastatin ameliorated radiation-induced tissue damage in mice. The radioprotective effect of simvastatin was possibly related to inhibition of apoptosis and improvement of oxygen-carrying and antioxidant activities.
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Affiliation(s)
- Xinbin Zhao
- Department of Pharmacy, Changzheng Hospital, Second Military Medical University, 415 Feng-Yang Road, Shanghai 200003, China
| | - Hong Yang
- Department of Pharmacy, Changzheng Hospital, Second Military Medical University, 415 Feng-Yang Road, Shanghai 200003, China
| | - Guojun Jiang
- Department of Pharmacy, Xiaoshan Hospital, 728 Yu-Cai-Bei Road, Hangzhou, Zhejiang 311202, China
| | - Min Ni
- Department of Pharmacy, Changzheng Hospital, Second Military Medical University, 415 Feng-Yang Road, Shanghai 200003, China
| | - Yaping Deng
- Department of Pharmacology, School of Pharmacy, Second Military Medical University, 325 Guo-He Road, Shanghai 200433, China
| | - Jian Cai
- Department of Pharmacy, Xiaoshan Hospital, 728 Yu-Cai-Bei Road, Hangzhou, Zhejiang 311202, China
| | - Zhangpeng Li
- Department of Pharmacology, School of Pharmacy, Second Military Medical University, 325 Guo-He Road, Shanghai 200433, China
| | - Fuming Shen
- Department of Pharmacology, School of Pharmacy, Second Military Medical University, 325 Guo-He Road, Shanghai 200433, China
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, 301 Yan-Chang-Zhong Road, Shanghai 200072, China
| | - Xia Tao
- Department of Pharmacy, Changzheng Hospital, Second Military Medical University, 415 Feng-Yang Road, Shanghai 200003, China
- Corresponding author. Tel: +86-21-8188-6182; Fax: +86-21-6549-3951;
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Balaji S, King A, Crombleholme TM, Keswani SG. The Role of Endothelial Progenitor Cells in Postnatal Vasculogenesis: Implications for Therapeutic Neovascularization and Wound Healing. Adv Wound Care (New Rochelle) 2013; 2:283-295. [PMID: 24527350 DOI: 10.1089/wound.2012.0398] [Citation(s) in RCA: 118] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Indexed: 01/16/2023] Open
Abstract
SIGNIFICANCE Postnatal vasculogenesis mediated via endothelial progenitor cells (EPCs) contributes to re-endothelialization and augments neovascularization after ischemia and tissue injury, providing a novel therapeutic application. However, controversy exists with respect to the origin, identification, and contributions of the EPCs to neovascularization, necessitating further study. RECENT ADVANCES Bone marrow (BM) or circulating cells expressing cd133/vascular endothelial growth factor receptor 2 include those with endothelial progenitor capacity. Increasing evidence suggests that there are additional BM-derived (myeloid; mesenchymal cells) and non-BM-derived (peripheral and cord-blood; tissue-resident) cell populations which also give rise to endothelial cells (ECs) and contribute to re-endothelialization and growth factor release after ischemia and tissue injury. Currently, EPCs are being used as diagnostic markers for the assessment of cardiovascular and tumor risk/progression. Techniques aimed at enhancing ex vivo expansion and the therapeutic potential of these cells are being optimized. CRITICAL ISSUES Mobilization and EPC-mediated neovascularization are critically regulated. Stimulatory (growth factors, statins, and exercise) or inhibitory factors (obesity, diabetes, and other cardiovascular diseases) modulate EPC numbers and function. Recruitment and incorporation of EPCs require a coordinated sequence of signaling events, including adhesion, migration (by integrins), and chemoattraction. Finally, EPCs differentiate into ECs and/or secrete angiogenic growth factors. These cells are highly plastic, and depending on the microenvironment and presence of other cells, EPCs transdifferentiate and/or undergo cell fusion and become cells of a different lineage. Therefore, in vitro culture conditions should be optimized to mimic the in vivo milieu to fully characterize the biological function and contribution of EPCs to postnatal vasculogenesis. FUTURE DIRECTIONS Advances in characterization of the EPC biology and enhancement of EPC functions are required. In addition, innovative tissue-engineered carrier matrices that permit embedding of EPCs and provide optimal conditions for EPC survival and endothelial outgrowth will further contribute to EPC-mediated therapeutic applications in wound healing and ischemia repair.
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Affiliation(s)
- Swathi Balaji
- Center for Molecular Fetal Therapy, Division of Pediatric, General, Thoracic, and Fetal Surgery, Cincinnati Children's Hospital and the University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Alice King
- Center for Molecular Fetal Therapy, Division of Pediatric, General, Thoracic, and Fetal Surgery, Cincinnati Children's Hospital and the University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Timothy M. Crombleholme
- Center for Molecular Fetal Therapy, Division of Pediatric, General, Thoracic, and Fetal Surgery, Cincinnati Children's Hospital and the University of Cincinnati College of Medicine, Cincinnati, Ohio
- Center for Children's Surgery, Children's Hospital Colorado and the University of Colorado School of Medicine, Aurora, Colorado
| | - Sundeep G. Keswani
- Center for Molecular Fetal Therapy, Division of Pediatric, General, Thoracic, and Fetal Surgery, Cincinnati Children's Hospital and the University of Cincinnati College of Medicine, Cincinnati, Ohio
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Wood JA, Colletti E, Mead LE, Ingram D, Porada CD, Zanjani ED, Yoder MC, Almeida-Porada G. Distinct contribution of human cord blood-derived endothelial colony forming cells to liver and gut in a fetal sheep model. Hepatology 2012; 56:1086-96. [PMID: 22488442 PMCID: PMC3396735 DOI: 10.1002/hep.25753] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Accepted: 03/23/2012] [Indexed: 12/22/2022]
Abstract
UNLABELLED Although the vasculogenic potential of circulating and cord blood (CB)-derived endothelial colony-forming cells (ECFC) has been demonstrated in vitro and in vivo, little is known about the inherent biologic ability of these cells to home to different organs and contribute to tissue-specific cell populations. Here we used a fetal sheep model of in utero transplantation to investigate and compare the intrinsic ability of human CB-derived ECFC to migrate to the liver and to the intestine, and to define ECFC's intrinsic ability to integrate and contribute to the cytoarchitecture of these same organs. ECFCs were transplanted by an intraperitoneal or intrahepatic route (IH) into fetal sheep at concentrations ranging from 1.1-2.6 × 10(6) cells/fetus. Recipients were evaluated at 85 days posttransplant for donor (human) cells using flow cytometry and confocal microscopy. We found that, regardless of the route of injection, and despite the IH delivery of ECFC, the overall liver engraftment was low, but a significant percentage of cells were located in the perivascular regions and retained the expression of hallmark endothelial makers. By contrast, ECFC migrated preferentially to the intestinal crypt region and contributed significantly to the myofibroblast population. Furthermore, ECFC expressing CD133 and CD117 lodged in areas where endogenous cells expressed those same phenotypes. CONCLUSION ECFC inherently constitute a potential source of cells for the treatment of intestinal diseases, but strategies to increase the numbers of ECFC persisting within the hepatic parenchyma are needed in order to enhance ECFC therapeutic potential for this organ.
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Affiliation(s)
- Joshua A. Wood
- Dept. of Animal Biotechnology, University of Nevada, Reno, USA
| | - Evan Colletti
- Dept. of Animal Biotechnology, University of Nevada, Reno, USA
| | - Laura E. Mead
- Dept. of Pediatrics and Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, USA
| | - David Ingram
- Dept. of Pediatrics and Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, USA
| | | | | | - Mervin C. Yoder
- Dept. of Pediatrics and Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, USA
,Corresponding Authors: Graça Almeida-Porada, M.D., Ph.D., Wake Forest Institute for Regenerative Medicine, 391 Technology Way, Winston-Salem, NC 27157-1083 USA. Phone: (336) 713-1630; FAX: (336) 713-7290 Mervin C. Yoder, M.D. Department of Pediatrics, Herman B Wells Center for Pediatric Research Indiana University School of Medicine, Indianapolis, Ind., USA Phone: (317) 274-4738; FAX: (317) 274-8679
| | - Graça Almeida-Porada
- Dept. of Animal Biotechnology, University of Nevada, Reno, USA
,Corresponding Authors: Graça Almeida-Porada, M.D., Ph.D., Wake Forest Institute for Regenerative Medicine, 391 Technology Way, Winston-Salem, NC 27157-1083 USA. Phone: (336) 713-1630; FAX: (336) 713-7290 Mervin C. Yoder, M.D. Department of Pediatrics, Herman B Wells Center for Pediatric Research Indiana University School of Medicine, Indianapolis, Ind., USA Phone: (317) 274-4738; FAX: (317) 274-8679
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Tissue engineering of bladder using vascular endothelial growth factor gene-modified endothelial progenitor cells. Int J Artif Organs 2012; 34:1137-46. [PMID: 22198599 DOI: 10.5301/ijao.5000069] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/11/2011] [Indexed: 11/20/2022]
Abstract
PURPOSE This study assessed the use of vascular endothelial growth factor (VEGF) gene-modified endothelial progenitor cells (EPCs) seeded onto bladder acellular matrix grafts (BAMGs), to enhance the blood supply in tissue-engineered bladders in a porcine model. METHODS Autologous porcine peripheral EPCs were isolated, cultured, expanded, characterized, and modified with the VEGF gene using an adenovirus vector. The expression of VEGF was examined using reverse transcriptase polymerase chain reaction (RT-PCR) and an enzyme-linked immunosorbent assay (ELISA). VEGF gene modified EPCs were seeded onto BAMG and cultured for 3 days before implantation into pigs for bladder tissue engineering. A partial bladder cystectomy was performed in 12 pigs. The experimental group (6 pigs) received VEGF gene-modified EPC-seeded BAMG. The control group (6 pigs) received BAMG without seeded EPCs. The resulting tissue-engineered bladders were subject to a general and histological analysis. Microvessel density (MVD) was assessed using immunohistochemistry. RESULTS The ex vivo transfection efficiency of EPCs was greater than 60%-70% when concentrated adenovirus was used. The genetically modified cells expressed both VEGF and green fluorescent protein (GFP). Scanning electron microscopy (SEM) and Masson's trichrome staining of cross sections of the cultured cells seeded to BAMG showed cell attachment and proliferation on the surface of the BAMG. Histological examination revealed bladder regeneration in a time-dependent fashion. Significant increases in MVD were observed in the experimental group, in comparison with the control group. CONCLUSIONS VEGF-modified EPCs significantly enhanced neovascularization, compared with BAMG alone. These results indicate that EPCs, combined with VEGF gene therapy, may be a suitable approach for increasing blood supply in the tissue engineering of bladders. Thus, a useful strategy to achieve a tissue-engineered bladder is indicated.
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Bone marrow-derived CMPs and GMPs represent highly functional proangiogenic cells: implications for ischemic cardiovascular disease. Blood 2011; 118:6461-4. [PMID: 21828132 DOI: 10.1182/blood-2011-06-363457] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Clinical studies using bone marrow-derived proangiogenic cells (PACs) have demonstrated modest improvements of function and/or perfusion of ischemic myocardium or skeletal muscle. Because the identities of these PACs and their functional ability to promote neovascularization remain poorly understood, it is possible that a subset of robust PACs exists but is obscured by the heterogeneous nature of this cell population. Herein, we found that common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) preferentially differentiate into PACs compared with megakaryocyte-erythrocyte progenitors, hematopoietic stem cells, and common lymphoid progenitors. In vivo hindlimb ischemia studies and Matrigel plug assays verified the enhanced neovascularization properties uniquely associated with PACs derived from CMPs and GMPs. Taken together, these observations identify CMPs and GMPs as key bone marrow progenitors for optimal PAC function in vitro and in vivo and provide a foundation for novel therapeutic approaches to modulate angiogenesis.
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The promise of EPC-based therapies on vascular dysfunction in diabetes. Eur J Pharmacol 2011; 669:1-6. [PMID: 21839073 DOI: 10.1016/j.ejphar.2011.07.035] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2011] [Revised: 06/29/2011] [Accepted: 07/21/2011] [Indexed: 12/21/2022]
Abstract
Diabetes mellitus is one of the most common metabolic diseases in the world and the vascular dysfunction represents a challenging clinical problem. In diabetes, endothelial cells (ECs), lining the inner wall of blood vessels, do not function properly and contribute to impaired vascular function. Circulating endothelial progenitor cells (EPCs), the precursor of mature EC, actively participate in endothelial repair, by moving to the vascular injury site to form mature EC and new blood vessels. Knowing that the therapeutic interventions can improve only a part of EC dysfunction in diabetes, this review addresses recent findings on the use of EPCs for cell therapy. The strategies proposed in review are based on in vivo and in vitro studies and, thus, their physiological relevance is confirmed. EPC therapy shows great promise for the prevention and cure of diabetes-induced vascular dysfunction.
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Murua A, Orive G, Hernández RM, Pedraz JL. Emerging technologies in the delivery of erythropoietin for therapeutics. Med Res Rev 2011; 31:284-309. [PMID: 19967731 DOI: 10.1002/med.20184] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Deciphering the function of proteins and their roles in signaling pathways is one of the main goals of biomedical research, especially from the perspective of uncovering pathways that may ultimately be exploited for therapeutic benefit. Over the last half century, a greatly expanded understanding of the biology of the glycoprotein hormone erythropoietin (Epo) has emerged from regulator of the circulating erythrocyte mass to a widely used therapeutic agent. Originally viewed as the renal hormone responsible for erythropoiesis, recent in vivo studies in animal models and clinical trials demonstrate that many other tissues locally produce Epo independent of its effects on red blood cell mass. Thus, not only its hematopoietic activity but also the recently discovered nonerythropoietic actions in addition to new drug delivery systems are being thoroughly investigated in order to fulfill the specific Epo release requirements for each therapeutic approach. The present review focuses on updating the information previously provided by similar reviews and recent experimental approaches are presented to describe the advances in Epo drug delivery achieved in the last few years and future perspectives.
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Affiliation(s)
- Ainhoa Murua
- Laboratory of Pharmacy and Pharmaceutical Technology, Networking Biomedical Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, SLFPB-EHU, Faculty of Pharmacy, University of the Basque Country, 01006, Vitoria-Gasteiz, Spain
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Critser PJ, Voytik-Harbin SL, Yoder MC. Isolating and defining cells to engineer human blood vessels. Cell Prolif 2011; 44 Suppl 1:15-21. [PMID: 21481038 DOI: 10.1111/j.1365-2184.2010.00719.x] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
A great deal of attention has been recently focused on understanding the role that bone marrow-derived putative endothelial progenitor cells (EPC) may play in the process of neoangiogenesis. However, recent data indicate that many of the putative EPC populations are comprised of various haematopoietic cell subsets with proangiogenic activity, but these marrow-derived putative EPC fail to display vasculogenic activity. Rather, this property is reserved for a rare population of circulating viable endothelial cells with colony-forming cell (ECFC) ability. Indeed, human ECFC possess clonal proliferative potential, display endothelial and not haematopoietic cell surface antigens, and display in vivo vasculogenic activity when suspended in an extracellular matrix and implanted into immunodeficient mice. Furthermore, human vessels derived became integrated into the murine circulatory system and eventually were remodelled into arterial and venous vessels. Identification of this population now permits determination of optimal type I collagen matrix microenvironment into which the cells should be embedded and delivered to accelerate and even pattern number and size of blood vessels formed, in vivo. Indeed, altering physical properties of ECFC-collagen matrix implants changed numerous parameters of human blood vessel formation, in host mice. These recent discoveries may permit a strategy for patterning vascular beds for eventual tissue and organ regeneration.
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Affiliation(s)
- P J Critser
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, USA
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Thebaud NB, Bareille R, Remy M, Bourget C, Daculsi R, Bordenave L. Human progenitor-derived endothelial cells vs. venous endothelial cells for vascular tissue engineering: an in vitro study. J Tissue Eng Regen Med 2011; 4:473-84. [PMID: 20112278 DOI: 10.1002/term.261] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The isolation of endothelial progenitor cells from human peripheral blood generates a great hope in vascular tissue engineering because of particular benefit when compared with mature endothelial cells. We explored the capability of progenitor-derived endothelial cells (PDECs) to line fibrin and collagen scaffolds in comparison with human saphenous and umbilical cord vein endothelial cells (HSVECs and HUVECs): (a) in a static situation, allowing definition of the optimal cell culture conditions with different media and cell-seeding densities to check cell behaviour; (b) under shear stress conditions (flow chambers or tubular vascular constructs), allowing investigation of cell response and mRNA expression on both substrates by oligonucleotide microarray analysis and quantitative real-time PCR. Well characterized PDECs: (a) could not be expanded adequately with the usual mature ECs culture media; (b) were able to colonize and grow on fibrin glue; (c) exhibited higher resistance to oxidative stress than HSVECs and HUVECs; (d) withstood physiological shear stress when lining both substrates in flow chambers, and their gene expression was regulated; (e) colonized a collagen-impregnated vascular prosthesis and were able to sense mechanical forces. Our results provide an improved qualification of PDECs for vascular tissue engineering.
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Affiliation(s)
- Noélie B Thebaud
- INSERM, U577 Bordeaux, Université Victor Segalen Bordeaux 2, Bordeaux, F-33076 France
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Oshima-Sudo N, Li Q, Hoshino Y, Nakahama KI, Kubota T, Morita I. Optimized method for culturing outgrowth endothelial progenitor cells. Inflamm Regen 2011. [DOI: 10.2492/inflammregen.31.219] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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Marrotte EJ, Chen DD, Hakim JS, Chen AF. Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice. J Clin Invest 2010; 120:4207-19. [PMID: 21060152 DOI: 10.1172/jci36858] [Citation(s) in RCA: 141] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2010] [Accepted: 09/08/2010] [Indexed: 12/15/2022] Open
Abstract
Amputation as a result of impaired wound healing is a serious complication of diabetes. Inadequate angiogenesis contributes to poor wound healing in diabetic patients. Endothelial progenitor cells (EPCs) normally augment angiogenesis and wound repair but are functionally impaired in diabetics. Here we report that decreased expression of manganese superoxide dismutase (MnSOD) in EPCs contributes to impaired would healing in a mouse model of type 2 diabetes. A decreased frequency of circulating EPCs was detected in type 2 diabetic (db/db) mice, and when isolated, these cells exhibited decreased expression and activity of MnSOD. Wound healing and angiogenesis were markedly delayed in diabetic mice compared with normal controls. For cell therapy, topical transplantation of EPCs onto excisional wounds in diabetic mice demonstrated that diabetic EPCs were less effective than normal EPCs at accelerating wound closure. Transplantation of diabetic EPCs after MnSOD gene therapy restored their ability to mediate angiogenesis and wound repair. Conversely, siRNA-mediated knockdown of MnSOD in normal EPCs reduced their activity in diabetic wound healing assays. Increasing the number of transplanted diabetic EPCs also improved the rate of wound closure. Our findings demonstrate that cell therapy using diabetic EPCs after ex vivo MnSOD gene transfer accelerates their ability to heal wounds in a mouse model of type 2 diabetes.
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Affiliation(s)
- Eric J Marrotte
- 1Department of Surgery, Vascular Medicine Institute, McGowan Institute of Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Traini T, Novaes AB, Piattelli A, Papalexiou V, Muglia VA. The relationship between interimplant distances and vascularization of the interimplant bone. Clin Oral Implants Res 2010; 21:822-9. [PMID: 20666796 DOI: 10.1111/j.1600-0501.2010.01926.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Long-term success of the implant restorations is based upon the biology and vasculature of the bone surrounding the implants, especially for the bone between two implants. PURPOSE The aim of this study was to evaluate how loaded implants placed 2 or 3 mm apart influence bone vessel organization. MATERIAL AND METHODS Six mongrel dogs were used for the study. The four mandibular premolars were extracted and 3 months later, four 4.5 x 10 mm implants were placed on each side of the mandible. The implants were placed so that two adjacent implants were 2 mm (group 1) or 3 mm (group 2) distant from each other. After 12 weeks, the implants were loaded with provisional prostheses, then metallic crowns were placed 4 weeks later. Both temporary and metallic restorations were made so that the distance between the contact point and the bone crest was 5 mm. The animals were sacrificed after 8 weeks. The hemi-mandibles were removed and prepared for analysis. The interimplant bone vasculature of the two groups was studied using scanning electron microscopic images fractal analysis. The fractal dimension (D(f)) was calculated using the box-counting method. RESULTS The values of the D(f) for the blood vessels were significantly higher (P<.05) in the specimens of the group 2 (1.969+/-0.169) than the group 1 (1.556+/-0.246). CONCLUSION The presence of more blood vessels in the group 2 is another indication that 3 mm is a preferable distance for contiguous implants than the 2 mm distance.
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Affiliation(s)
- Tonino Traini
- School of Dentistry, University of Chieti-Pescara, Chieti, Italy.
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Wang X, Yan Y, Zhang R. Recent trends and challenges in complex organ manufacturing. TISSUE ENGINEERING PART B-REVIEWS 2010; 16:189-97. [PMID: 19824803 DOI: 10.1089/ten.teb.2009.0576] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Presently, there is a recognized and imperative need for bioartificial organs. The technological advances in transgenosis, tissue engineering, and rapid prototyping have led to the development of spatially complex tissues. An ideal artificial organ should provide nutrient transport system, mechanical stable architecture, and synergetic multicellular organization in one construct. The multinozzle rapid prototyping technique simultaneously assembles vascular systems including hierarchical multicellular structures in an automated and reproducible manner and offers an effective way for treating organ failures. In this article, a brief overview of the recent trends and outstanding challenges in organ manufacturing is provided. From the viewpoint of disciplinary crossing, integration, and development, future directions in the coming years were pointed out.
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Affiliation(s)
- Xiaohong Wang
- Center of Organ Manufacturing & Key Laboratory for Advanced Materials Processing Technology, Ministry of Education, Department of Mechanical Engineering, Tsinghua University, Beijing, 100084, P.R. China
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Abstract
Endothelial cells provide the dynamic lining of blood vessels throughout the body and provide many tissue-specific functions, in addition to providing a nonthrombogenic surface for blood cells and conduit for oxygen and nutrient delivery. As might be expected, some endothelial cells are injured or become senescent and are sloughed into the bloodstream, and most circulating endothelial cells display evidence of undergoing apoptosis or necrosis. However, there are rare viable circulating endothelial cells that display properties consistent with those of a progenitor cell for the endothelial lineage. This article reviews historical and current literature to present some evidence that the endothelial lining of blood vessels may serve as a source for rare endothelial colony-forming cells that display clonal proliferative potential, self-renewal, and in vivo vessel forming ability. The article also discusses the current gaps in our knowledge to prove whether the colony-forming cells are in fact derived from vascular endothelium.
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Affiliation(s)
- Mervin C. Yoder
- From Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Ind
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Atorvastatin increases the number of endothelial progenitor cells after cardiac surgery: a randomized control study. J Cardiovasc Pharmacol 2010; 55:30-8. [PMID: 19834333 DOI: 10.1097/fjc.0b013e3181c37d4d] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Endothelial progenitor cells (EPCs) are a subtype of hematopoietic stem cells, which contribute to the repair of injured endothelium. Treatment with atorvastatin has been shown to increase EPC count in patients with coronary artery disease. Therefore, we investigated whether atorvastatin augments the number of EPCs after cardiopulmonary bypass (CPB) surgery. We conducted a randomized double-blind, placebo-controlled, 2-way crossover trial in 50 patients undergoing elective coronary surgery. Patients received either 3-week treatment with atorvastatin or placebo. EPCs were quantitated by flow cytometric phenotyping on blood samples. Levels of interleukin, IL-6 and IL-8; tumor necrosis factor alpha; SDF-1alpha; granulocyte colony-stimulating factor; and vascular endothelial growth factor were determined at recruitment, preoperatively, post-CPB, and 6, 12, and 24 hours postoperatively. The atorvastatin group showed a significantly higher amount of EPCs both pre- and postoperatively compared with the placebo, with a >4-fold increase compared with the baseline values. CPB induced an increase in all cytokines, but the levels of proinflammatory cytokines were significantly lower in the atorvastatin group (P < 0.05). Statin did not affect levels of SDF-1alpha, granulocyte colony-stimulating factor, and vascular endothelial growth factor. However, no correlation was found between plasma levels of any cytokine and number of EPCs, with the exception of SDF-1alpha. Pretreatment with atorvastatin significantly increases the amount of EPCs after CPB, by a mechanism independent of plasma levels of cytokines and cholesterol.
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Kyrtatos PG, Lehtolainen P, Junemann-Ramirez M, Garcia-Prieto A, Price AN, Martin JF, Gadian DG, Pankhurst QA, Lythgoe MF. Magnetic tagging increases delivery of circulating progenitors in vascular injury. JACC Cardiovasc Interv 2009; 2:794-802. [PMID: 19695550 DOI: 10.1016/j.jcin.2009.05.014] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2009] [Accepted: 05/20/2009] [Indexed: 11/15/2022]
Abstract
OBJECTIVES We sought to magnetically tag endothelial progenitor cells (EPCs) with a clinical agent and target them to a site of arterial injury using a magnetic device positioned outside the body. BACKGROUND Circulating EPCs are involved in physiological processes such as vascular re-endothelialization and post-ischemic neovascularization. However, the success of cell therapies depends on the ability to deliver the cells to the site of injury. METHODS Human EPCs were labeled with iron oxide superparamagnetic nanoparticles. Cell viability and differentiation were tested using flow cytometry. Following finite element modeling computer simulations and flow testing in vitro, angioplasty was performed on rat common carotid arteries to denude the endothelium and EPCs were administered with and without the presence of an external magnetic device for 12 min. RESULTS Computer simulations indicated successful external magnetic cell targeting from a vessel with flow rate similar to a rat common carotid artery; correspondingly there was a 6-fold increase in cell capture in an in vitro flow system. Targeting enhanced cell retention at the site of injury by 5-fold at 24 h after implantation in vivo. CONCLUSIONS Using an externally applied magnetic device, we have been able to enhance EPC localization at a site of common carotid artery injury. This technology could be more widely adapted to localize cells in other organs and may provide a useful tool for the systemic injection of cell therapies.
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Affiliation(s)
- Panagiotis G Kyrtatos
- Centre for Advanced Biomedical Imaging, University College London Department of Medicine and UCL Institute of Child Health, London, United Kingdom
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Plouffe BD, Kniazeva T, Mayer JE, Murthy SK, Sales VL. Development of microfluidics as endothelial progenitor cell capture technology for cardiovascular tissue engineering and diagnostic medicine. FASEB J 2009; 23:3309-14. [PMID: 19487310 DOI: 10.1096/fj.09-130260] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
We have developed a unique microfluidic platform capable of capturing circulating endothelial progenitor cells (EPCs) by understanding surface chemistries and adhesion profiles. The surface of a variable-shear-stress microfluidic device was conjugated with 6 different antibodies [anti-CD34, -CD31, -vascular endothelial growth factor receptor-2 (VEGFR-2), -CD146, -CD45, and -von Willebrand factor (vWF)] designed to match the surface antigens on ovine peripheral blood-derived EPCs. Microfluidic analysis showed a shear-stress-dependent decrease in EPC adhesion on attached surface antigens. EPCs exhibited increased adhesion to antibodies against CD34, VEGFR-2, CD31, and CD146 compared to CD45, consistent with their endothelial cell-specific surface profile, when exposed to a minimum shear stress of 1.47 dyn/cm(2). Bone-marrow-derived mesenchymal stem cells and artery-derived endothelial and smooth muscle cells were used to demonstrate the specificity of the EPC microfluidic device. Coated hematopoietic specific-surface (CD45) and granular vWF antibodies, as well as uncoated bare glass and substrate (1% BSA), were utilized as controls. Microfluidic devices have been developed as an EPC capture platform using immobilized antibodies targeted as EPC surface antigens. This EPC chip may provide a new and effective tool for addressing challenges in cardiovascular disease and tissue engineering.
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Affiliation(s)
- Brian D Plouffe
- Department of Chemical Engineering, Northeastern University, Boston, Massachusetts 02115, USA
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Rouwkema J, Rivron NC, van Blitterswijk CA. Vascularization in tissue engineering. Trends Biotechnol 2008; 26:434-41. [PMID: 18585808 DOI: 10.1016/j.tibtech.2008.04.009] [Citation(s) in RCA: 784] [Impact Index Per Article: 46.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2008] [Revised: 04/14/2008] [Accepted: 04/22/2008] [Indexed: 12/18/2022]
Abstract
Tissue engineering has been an active field of research for several decades now. However, the amount of clinical applications in the field of tissue engineering is still limited. One of the current limitations of tissue engineering is its inability to provide sufficient blood supply in the initial phase after implantation. Insufficient vascularization can lead to improper cell integration or cell death in tissue-engineered constructs. This review will discuss the advantages and limitations of recent strategies aimed at enhancing the vascularization of tissue-engineered constructs. We will illustrate that combining the efforts of different research lines might be necessary to obtain optimal results in the field.
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Affiliation(s)
- Jeroen Rouwkema
- Department of Tissue Regeneration, University of Twente, Drienerlolaan 5, 7522NB Enschede, The Netherlands.
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