Sustained release of endothelial progenitor cell-derived extracellular vesicles from shear-thinning hydrogels improves angiogenesis and promotes function after myocardial infarction

被引：181

作者：

Chen, Carol W. ^{[1
]}

Wang, Leo L. ^{[2
]}

Zaman, Samir ^{[1
]}

Gordon, Jon ^{[1
]}

Arisi, Maria F. ^{[1
]}

Venkataraman, Chantel M. ^{[1
]}

Chung, Jennifer J. ^{[1
]}

Hung, George ^{[1
]}

Gaffey, Ann C. ^{[1
]}

Spruce, Lynn A. ^{[3
]}

Fazelinia, Hossein ^{[3
]}

Gorman, Robert C. ^{[1
]}

Seeholzer, Steven H. ^{[3
]}

Burdick, Jason A. ^{[2
]}

Atluri, Pavan ^{[1
]}

机构：

[1] Univ Penn, Dept Surg, Div Cardiovasc Surg, Silverstein 6,3400 Spruce St, Philadelphia, PA 19104 USA

[2] Univ Penn, Dept Bioengn, 240 Skirkanich,210 S 33rd St, Philadelphia, PA 19104 USA

[3] Childrens Hosp Philadelphia, Prot & Prote Core Facil, Res Inst, 3615 Civ Ctr Blvd, Philadelphia, PA 19104 USA

来源：

CARDIOVASCULAR RESEARCH | 2018年 / 114卷 / 07期

基金：

美国国家卫生研究院;

关键词：

Endothelial progenitor cells; Extracellular vesicles; Exosomes; Hydrogel; Angiogenesis; MESENCHYMAL STEM-CELLS; ISCHEMIC-MYOCARDIUM; IN-VIVO; TUMOR MICROENVIRONMENT; IMPAIRED ANGIOGENESIS; EXOSOMES; MICE; THERAPY; NEOVASCULARIZATION; DYSFUNCTION;

D O I：

10.1093/cvr/cvy067

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Aims Previous studies have demonstrated improved cardiac function following myocardial infarction (MI) after administration of endothelial progenitor cells (EPCs) into ischaemic myocardium. A growing body of literature supports paracrine effectors, including extracellular vesicles (EVs), as the main mediators of the therapeutic benefits of EPCs. The direct use of paracrine factors is an attractive strategy that harnesses the effects of cell therapy without concerns of cell engraftment or viability. We aim to reproduce the beneficial effects of EPC treatment through delivery of EPC-derived EVs within a shear-thinning gel (STG) for precise localization and sustained delivery. Methods and results EVs were harvested from EPCs isolated from adult male Rattus norvegicus (Wistar) rats and characterized by electron microscopy, nanoparticle tracking analysis (NTA), and mass spectrometry. EVs were incorporated into the STG and injected at the border zone in rat models of MI. Haemodynamic function, angiogenesis, and myocardial remodelling were analyzed in five groups: phosphate buffered saline (PBS) control, STG control, EVs in PBS, EVs in STG, and EPCs in STG. Electron microscopy and NTA of EVs showed uniform particles of 50-200 nm. EV content analysis revealed several key angiogenic mediators. EV uptake by endothelial cells was confirmed and followed by robust therapeutic angiogenesis. In vivo animal experiments demonstrated that delivery of EVs within the STG resulted in increased peri-infarct vascular proliferation, preservation of ventricular geometry, and improved haemodynamic function post-MI. Conclusions EPC-derived EVs delivered into ischaemic myocardium via an injectable hydrogel enhanced peri-infarct angiogenesis and myocardial haemodynamics in a rat model of MI. The STG greatly increased therapeutic efficiency and efficacy of EV-mediated myocardial preservation.

引用

页码：1029 / 1040

页数：12

共 46 条

[1]

Tissue-engineered, hydrogel-based endothelial progenitor cell therapy robustly revascularizes ischemic myocardium and preserves ventricular function [J].

Atluri, Pavan ;

Miller, Jordan S. ;

Emery, Robert J. ;

Hung, George ;

Trubelja, Alen ;

Cohen, Jeffrey E. ;

Lloyd, Kelsey ;

Han, Jason ;

Gaffey, Ann C. ;

MacArthur, John W. ;

Chen, Christopher S. ;

Woo, Y. Joseph .

JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY, 2014, 148 (03) :1090-1097

[2]

Integrins in angiogenesis and lymphangiogenesis [J].

Avraamides, Christie J. ;

Garmy-Susini, Barbara ;

Varner, Judith A. .

NATURE REVIEWS CANCER, 2008, 8 (08) :604-617

[3]

Microvesicle-mediated Wnt/β-Catenin Signaling Promotes Interspecies Mammary Stem/Progenitor Cell Growth [J].

Bussche, Leen ;

Rauner, Gat ;

Antonyak, Marc ;

Syracuse, Bethany ;

McDowell, Melissa ;

Brown, Anthony M. C. ;

Cerione, Richard A. ;

Van de Walle, Gerlinde R. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2016, 291 (47) :24390-24405

[4]

Integrin αvβ3 acting as membrane receptor for thyroid hormones mediates angiogenesis in malignant T cells [J].

Cayrol, Florencia ;

Diaz Flaque, Maria Celeste ;

Fernando, Tharu ;

Yang, Shao Ning ;

Andrea Sterle, Helena ;

Bolontrade, Marcela ;

Amoros, Mariana ;

Isse, Blanca ;

Norberto Farias, Ricardo ;

Ahn, Haelee ;

Tian, Ye F. ;

Tabbo, Fabrizio ;

Singh, Ankur ;

Inghirami, Giorgio ;

Cerchietti, Leandro ;

Alicia Cremaschi, Graciela .

BLOOD, 2015, 125 (05) :841-851

[5]

Bone marrow-derived CD13+ cells sustain tumor progression A potential non-malignant target for anticancer therapy [J].

Dondossola, Eleonora ;

Corti, Angelo ;

Sidman, Richard L. ;

Arap, Wadih ;

Pasqualini, Renata .

ONCOIMMUNOLOGY, 2014, 3 (01)

[6]

Extracellular vesicles: biology and emerging therapeutic opportunities [J].

EL Andaloussi, Samir ;

Maeger, Imre ;

Breakefield, Xandra O. ;

Wood, Matthew J. A. .

NATURE REVIEWS DRUG DISCOVERY, 2013, 12 (05) :348-358

[7]

Injectable shear-thinning hydrogels used to deliver endothelial progenitor cells, enhance cell engraftment, and improve ischemic myocardium [J].

Gaffey, Ann C. ;

Chen, Minna H. ;

Venkataraman, Chantel M. ;

Trubelja, Alen ;

Rodell, Christopher B. ;

Dinh, Patrick V. ;

Hung, George ;

MacArthur, John W. ;

Soopan, Renganaden V. ;

Burdick, Jason A. ;

Atluri, Pavan .

JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY, 2015, 150 (05) :1268-1276

[8]

Impaired angiogenesis in glutathione peroxidase-1-deficient mice is associated with endothelial progenitor cell dysfunction [J].

Galasso, G ;

Schiekofer, S ;

Sato, K ;

Shibata, R ;

Handy, DE ;

Ouchi, N ;

Leopold, JA ;

Loscalzo, J ;

Walsh, K .

CIRCULATION RESEARCH, 2006, 98 (02) :254-261

[9]

Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells [J].

Gnecchi, M ;

He, HM ;

Liang, OD ;

Melo, LG ;

Morello, F ;

Mu, H ;

Noiseux, N ;

Zhang, LN ;

Pratt, RE ;

Ingwall, JS ;

Dzau, VJ .

NATURE MEDICINE, 2005, 11 (04) :367-368

[10]

Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment [J].

Guzman-Rojas, Liliana ;

Rangel, Roberto ;

Salameh, Ahmad ;

Edwards, Julianna K. ;

Dondossola, Eleonora ;

Kim, Yun-Gon ;

Saghatelian, Alan ;

Giordano, Ricardo J. ;

Kolonin, Mikhail G. ;

Staquicini, Fernanda I. ;

Koivunen, Erkki ;

Sidman, Richard L. ;

Arap, Wadih ;

Pasqualini, Renata .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012, 109 (05) :1637-1642

← 1 2 3 4 5 →