{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T03:48:51Z","timestamp":1783050531103,"version":"3.54.6"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T00:00:00Z","timestamp":1635897600000},"content-version":"vor","delay-in-days":1765,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Ministry of Science, ICT & Future Planning","award":["2012M3A9C6049716"],"award-info":[{"award-number":["2012M3A9C6049716"]}]},{"name":"Ministry of Science, ICT & Future Planning","award":["2014M3A9D5A01073598"],"award-info":[{"award-number":["2014M3A9D5A01073598"]}]},{"name":"Ministry of Science, ICT & Future Planning","award":["2016M3A9B6026771"],"award-info":[{"award-number":["2016M3A9B6026771"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) exhibit potency for the regeneration of infarcted hearts. Vascular endothelial growth factor (VEGF) is capable of inducing angiogenesis and can boost stem cell-based therapeutic effects. However, high levels of VEGF can cause abnormal blood vessel growth and hemangiomas. Thus, a controllable system to induce therapeutic levels of VEGF is required for cell therapy. We generated an inducible VEGF-secreting stem cell (VEGF\/hUCB-MSC) that controls the expression of VEGF and tested the therapeutic efficacy in rat myocardial infarction (MI) model to apply functional stem cells to MI. To introduce the inducible VEGF gene cassette into a safe harbor site of the hUCB-MSC chromosome, the transcription activator-like effector nucleases system was used. After confirming the integration of the cassette into the locus, VEGF secretion in physiological concentration from VEGF\/hUCB-MSCs after doxycycline (Dox) induction was proved in conditioned media. VEGF secretion was detected in mice implanted with VEGF\/hUCB-MSCs grown via a cell sheet system. Vessel formation was induced in mice transplanted with Matrigel containing VEGF\/hUCB-MSCs treated with Dox. Moreover, seeding of the VEGF\/hUCB-MSCs onto the cardiac patch significantly improved the left ventricle ejection fraction and fractional shortening in a rat MI model upon VEGF induction. Induced VEGF\/hUCB-MSC patches significantly decreased the MI size and fibrosis and increased muscle thickness, suggesting improved survival of cardiomyocytes and protection from MI damage. These results suggest that our inducible VEGF-secreting stem cell system is an effective therapeutic approach for the treatment of MI.<\/jats:p>","DOI":"10.1002\/sctm.16-0114","type":"journal-article","created":{"date-parts":[[2017,3,10]],"date-time":"2017-03-10T16:12:50Z","timestamp":1489162370000},"page":"1040-1051","source":"Crossref","is-referenced-by-count":47,"title":["Targeted Genome Engineering to Control VEGF Expression in Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells: Potential Implications for the Treatment of Myocardial Infarction"],"prefix":"10.1093","volume":"6","author":[{"given":"Hyun-Min","family":"Cho","sequence":"first","affiliation":[{"name":"a Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pyung-Hwan","family":"Kim","sequence":"additional","affiliation":[{"name":"a Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun-Kyung","family":"Chang","sequence":"additional","affiliation":[{"name":"a Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-ming","family":"Shen","sequence":"additional","affiliation":[{"name":"b Department of Veterinary Pharmacology, College of Veterinary Medicine, Seoul National University, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwaku","family":"Bonsra","sequence":"additional","affiliation":[{"name":"c Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byung-Jae","family":"Kang","sequence":"additional","affiliation":[{"name":"a Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo-Young","family":"Yum","sequence":"additional","affiliation":[{"name":"d Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joo-Hyun","family":"Kim","sequence":"additional","affiliation":[{"name":"a Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So-Yeong","family":"Lee","sequence":"additional","affiliation":[{"name":"b Department of Veterinary Pharmacology, College of Veterinary Medicine, Seoul National University, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-cheol","family":"Choi","sequence":"additional","affiliation":[{"name":"e Department of Veterinary Radiology, College of Veterinary Medicine, Seoul National University, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyongbum (Henry)","family":"Kim","sequence":"additional","affiliation":[{"name":"f Department of Pharmacology, College of Medicine, Yonsei University, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goo","family":"Jang","sequence":"additional","affiliation":[{"name":"d Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Je-Yoel","family":"Cho","sequence":"additional","affiliation":[{"name":"a Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,1,3]]},"reference":[{"key":"2022022809413581800_R1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev-bioeng-071812-152344","article-title":"Heart regeneration with engineered myocardial tissue","volume":"16","author":"Coulombe","year":"2014","journal-title":"Annu Rev Biomed Eng"},{"key":"2022022809413581800_R2","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1056\/NEJMra021498","article-title":"Heart failure","volume":"348","author":"Jessup","year":"2003","journal-title":"N Engl J Med"},{"key":"2022022809413581800_R3","doi-asserted-by":"crossref","first-page":"248","DOI":"10.5966\/sctm.2011-0028","article-title":"Embryonic stem cell-based cardiopatches improve cardiac function in infarcted rats","volume":"1","author":"Vallee","year":"2012","journal-title":"Stem Cells Translational Medicine"},{"key":"2022022809413581800_R4","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1038\/nature06800","article-title":"Stem-cell therapy for cardiac disease","volume":"451","author":"Segers","year":"2008","journal-title":"Nature"},{"key":"2022022809413581800_R5","doi-asserted-by":"crossref","first-page":"3007","DOI":"10.1016\/j.actbio.2014.03.013","article-title":"Umbilical-cord-blood-derived mesenchymal stem cells seeded onto fibronectin-immobilized polycaprolactone nanofiber improve cardiac function","volume":"10","author":"Kang","year":"2014","journal-title":"Acta Biomater"},{"key":"2022022809413581800_R6","doi-asserted-by":"crossref","first-page":"e49447","DOI":"10.1371\/journal.pone.0049447","article-title":"Human umbilical cord blood-derived mesenchymal stem cells promote vascular growth in vivo","volume":"7","author":"Roura","year":"2012","journal-title":"PLoS One"},{"key":"2022022809413581800_R7","doi-asserted-by":"crossref","first-page":"956","DOI":"10.5966\/sctm.2014-0259","article-title":"Postinfarction functional recovery driven by a three-dimensional engineered fibrin patch composed of human umbilical cord blood-derived mesenchymal stem cells","volume":"4","author":"Roura","year":"2015","journal-title":"Stem Cells Translational Medicine"},{"key":"2022022809413581800_R8","doi-asserted-by":"crossref","first-page":"5683","DOI":"10.1016\/j.biomaterials.2012.04.028","article-title":"Combining adult stem cells and polymeric devices for tissue engineering in infarcted myocardium","volume":"33","author":"Karam","year":"2012","journal-title":"Biomaterials"},{"key":"2022022809413581800_R9","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.bbrc.2008.09.004","article-title":"Improving outcome of transplanted mesenchymal stem cells for ischemic heart disease","volume":"376","author":"Shi","year":"2008","journal-title":"Biochem Biophys Res Commun"},{"key":"2022022809413581800_R10","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/nm0603-669","article-title":"The biology of VEGF and its receptors","volume":"9","author":"Ferrara","year":"2003","journal-title":"Nat Med"},{"key":"2022022809413581800_R11","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1161\/01.ATV.0000165696.25680.ce","article-title":"Vascular endothelial growth factor-expressing mesenchymal stem cell transplantation for the treatment of acute myocardial infarction","volume":"25","author":"Matsumoto","year":"2005","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2022022809413581800_R12","doi-asserted-by":"crossref","first-page":"S247","DOI":"10.1161\/CIRCULATIONAHA.108.843680","article-title":"Hepatocyte growth factor or vascular endothelial growth factor gene transfer maximizes mesenchymal stem cell-based myocardial salvage after acute myocardial infarction","volume":"120","author":"Deuse","year":"2009","journal-title":"Circulation"},{"key":"2022022809413581800_R13","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1182\/blood-2002-07-2314","article-title":"Side effects of retroviral gene transfer into hematopoietic stem cells","volume":"101","author":"Baum","year":"2003","journal-title":"Blood"},{"key":"2022022809413581800_R14","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1172\/JCI18420","article-title":"Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis","volume":"113","author":"Ozawa","year":"2004","journal-title":"J Clin Invest"},{"key":"2022022809413581800_R15","doi-asserted-by":"crossref","first-page":"5547","DOI":"10.1073\/pnas.89.12.5547","article-title":"Tight control of gene expression in mammalian cells by tetracycline-responsive promoters","volume":"89","author":"Gossen","year":"1992","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022022809413581800_R16","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.ydbio.2007.01.042","article-title":"Tet-on inducible system combined with in ovo electroporation dissects multiple roles of genes in somitogenesis of chicken embryos","volume":"305","author":"Watanabe","year":"2007","journal-title":"Dev Biol"},{"key":"2022022809413581800_R17","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.tibtech.2013.04.004","article-title":"ZFN, TALEN, and CRISPR\/Cas-based methods for genome engineering","volume":"31","author":"Gaj","year":"2013","journal-title":"Trends Biotechnol"},{"key":"2022022809413581800_R18","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1126\/science.1204094","article-title":"TAL effectors: Customizable proteins for DNA targeting","volume":"333","author":"Bogdanove","year":"2011","journal-title":"Science"},{"key":"2022022809413581800_R19","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nrm3486","article-title":"TALENS: A widely applicable technology for targeted genome editing","volume":"14","author":"Joung","year":"2013","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2022022809413581800_R20","doi-asserted-by":"crossref","first-page":"6762","DOI":"10.1093\/nar\/gku305","article-title":"TALENs facilitate targeted genome editing in human cells with high specificity and low cytotoxicity","volume":"42","author":"Mussolino","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"2022022809413581800_R21","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.3727\/096368910X545086","article-title":"Human umbilical cord blood-derived mesenchymal stem cells protect against neuronal cell death and ameliorate motor deficits in niemann pick type C1 mice","volume":"20","author":"Seo","year":"2011","journal-title":"Cell Transplant"},{"key":"2022022809413581800_R22","doi-asserted-by":"crossref","first-page":"e102426","DOI":"10.1371\/journal.pone.0102426","article-title":"A p38 MAPK-mediated alteration of cox-2\/PGE2 regulates immunomodulatory properties in human mesenchymal stem cell aging","volume":"9","author":"Yu","year":"2014","journal-title":"PLoS One"},{"key":"2022022809413581800_R23","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/nbt.2517","article-title":"A library of TAL effector nucleases spanning the human genome","volume":"31","author":"Kim","year":"2013","journal-title":"Nat Biotechnol"},{"key":"2022022809413581800_R24","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1016\/j.bone.2010.02.013","article-title":"Role of PI3K on the regulation of BMP2-induced beta-catenin activation in human bone marrow stem cells","volume":"46","author":"Lee","year":"2010","journal-title":"Bone"},{"key":"2022022809413581800_R25","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1038\/nprot.2011.356","article-title":"Reproducible subcutaneous transplantation of cell sheets into recipient mice","volume":"6","author":"Obokata","year":"2011","journal-title":"Nat Protoc"},{"key":"2022022809413581800_R26","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1161\/CIRCRESAHA.111.243147","article-title":"Mesenchymal stem cells: Biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease","volume":"109","author":"Williams","year":"2011","journal-title":"Circ Res"},{"key":"2022022809413581800_R27","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1038\/nm912","article-title":"Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts","volume":"9","author":"Mangi","year":"2003","journal-title":"Nat Med"},{"key":"2022022809413581800_R28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jconrel.2014.05.010","article-title":"Injectable multifunctional microgel encapsulating outgrowth endothelial cells and growth factors for enhanced neovascularization","volume":"187","author":"Kim","year":"2014","journal-title":"J Control Release"},{"key":"2022022809413581800_R29","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1161\/01.CIR.0000061911.47710.8A","article-title":"The viva trial: Vascular endothelial growth factor in ischemia for vascular angiogenesis","volume":"107","author":"Henry","year":"2003","journal-title":"Circulation"},{"key":"2022022809413581800_R30","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1002\/stem.291","article-title":"High-throughput flow cytometry purification of transduced progenitors expressing defined levels of vascular endothelial growth factor induces controlled angiogenesis in vivo","volume":"28","author":"Misteli","year":"2010","journal-title":"Stem Cells"},{"key":"2022022809413581800_R31","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1111\/j.1365-2362.2005.01565.x","article-title":"Combined cord blood stem cells and gene therapy enhances angiogenesis and improves cardiac performance in mouse after acute myocardial infarction","volume":"35","author":"Chen","year":"2005","journal-title":"Eur J Clin Invest"},{"key":"2022022809413581800_R32","doi-asserted-by":"crossref","first-page":"2309","DOI":"10.1016\/S0142-9612(03)00110-8","article-title":"Cell sheet engineering for myocardial tissue reconstruction","volume":"24","author":"Shimizu","year":"2003","journal-title":"Biomaterials"},{"key":"2022022809413581800_R33","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/S0735-1097(03)00081-0","article-title":"Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. Histological analysis of cell survival and differentiation","volume":"41","author":"Pagani","year":"2003","journal-title":"J Am Coll Cardiol"},{"key":"2022022809413581800_R34","doi-asserted-by":"crossref","DOI":"10.1161\/01.CIR.0000138191.11580.e3","article-title":"Targeted cell delivery into infarcted rat hearts by retrograde intracoronary infusion: Distribution, dynamics, and influence on cardiac function","volume":"110","author":"Suzuki","year":"2004","journal-title":"Circulation"},{"key":"2022022809413581800_R35","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.jtcvs.2006.01.024","article-title":"Grafted skeletal myoblast sheets attenuate myocardial remodeling in pacing-induced canine heart failure model","volume":"132","author":"Hata","year":"2006","journal-title":"J Thorac Cardiovasc Surg"},{"key":"2022022809413581800_R36","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1534\/genetics.111.131433","article-title":"Genome engineering with zinc-finger nucleases","volume":"188","author":"Carroll","year":"2011","journal-title":"Genetics"},{"key":"2022022809413581800_R37","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1007\/s12033-014-9771-z","article-title":"Applications of TALENs and CRISPR\/Cas9 in human cells and their potentials for gene therapy","volume":"56","author":"Niu","year":"2014","journal-title":"Mol Biotechnol"},{"key":"2022022809413581800_R38","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1007\/s12015-012-9375-6","article-title":"Mesenchymal stem cells for cardiac therapy: Practical challenges and potential mechanisms","volume":"9","author":"Cashman","year":"2013","journal-title":"Stem Cell Rev"},{"key":"2022022809413581800_R39","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1053\/j.semtcvs.2008.04.001","article-title":"Paracrine effects of cell transplantation: Modifying ventricular remodeling in the failing heart","volume":"20","author":"Fedak","year":"2008","journal-title":"Semin Thorac Cardiovasc Surg"},{"key":"2022022809413581800_R40","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/S0022-4804(02)00042-2","article-title":"Vascular endothelial growth factor increases the migration and proliferation of smooth muscle cells through the mediation of growth factors released by endothelial cells","volume":"109","author":"Cucina","year":"2003","journal-title":"J Surg Res"},{"key":"2022022809413581800_R41","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.biomaterials.2012.09.038","article-title":"The effect of controlled expression of vegf by transduced myoblasts in a cardiac patch on vascularization in a mouse model of myocardial infarction","volume":"34","author":"Marsano","year":"2013","journal-title":"Biomaterials"}],"container-title":["Stem Cells Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fsctm.16-0114","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/stcltm\/article-pdf\/6\/3\/1040\/42632731\/stcltm_6_3_1040.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stcltm\/article-pdf\/6\/3\/1040\/42632731\/stcltm_6_3_1040.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T09:56:15Z","timestamp":1646042175000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stcltm\/article\/6\/3\/1040\/6404742"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,1,3]]},"references-count":41,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2017,1,3]]},"published-print":{"date-parts":[[2017,3,1]]}},"URL":"https:\/\/doi.org\/10.1002\/sctm.16-0114","relation":{},"ISSN":["2157-6564","2157-6580"],"issn-type":[{"value":"2157-6564","type":"print"},{"value":"2157-6580","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,3,1]]},"published":{"date-parts":[[2017,1,3]]}}}