{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T20:45:31Z","timestamp":1782333931068,"version":"3.54.5"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2016,4,21]],"date-time":"2016-04-21T00:00:00Z","timestamp":1461196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["#229694"],"award-info":[{"award-number":["#229694"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Canadian Heart and Stroke Foundation","award":["NA-7346"],"award-info":[{"award-number":["NA-7346"]}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"crossref","award":["MC2-121291"],"award-info":[{"award-number":["MC2-121291"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>First generation cardiac stem cell products provide indirect cardiac repair but variably produce key cardioprotective cytokines, such as stromal-cell derived factor 1\u03b1, which opens the prospect of maximizing up-front paracrine-mediated repair. The mesenchymal subpopulation within explant derived human cardiac stem cells underwent lentiviral mediated gene transfer of stromal-cell derived factor 1\u03b1. Unlike previous unsuccessful attempts to increase efficacy by boosting the paracrine signature of cardiac stem cells, cytokine profiling revealed that stromal-cell derived factor 1\u03b1 over-expression prevented lv-mediated \u201closs of cytokines\u201d through autocrine stimulation of CXCR4+ cardiac stem cells. Stromal-cell derived factor 1\u03b1 enhanced angiogenesis and stem cell recruitment while priming cardiac stem cells to readily adopt a cardiac identity. As compared to injection with unmodified cardiac stem cells, transplant of stromal-cell derived factor 1\u03b1 enhanced cells into immunodeficient mice improved myocardial function and angiogenesis while reducing scarring. Increases in myocardial stromal-cell derived factor 1\u03b1 content paralleled reductions in myocyte apoptosis but did not influence long-term engraftment or the fate of transplanted cells. Transplantation of stromal-cell derived factor 1\u03b1 transduced cardiac stem cells increased the generation of new myocytes, recruitment of bone marrow cells, new myocyte\/vessel formation and the salvage of reversibly damaged myocardium to enhance cardiac repair after experimental infarction.<\/jats:p>","DOI":"10.1002\/stem.2373","type":"journal-article","created":{"date-parts":[[2016,4,10]],"date-time":"2016-04-10T12:15:42Z","timestamp":1460290542000},"page":"1826-1835","source":"Crossref","is-referenced-by-count":25,"title":["Paracrine Engineering of Human Explant-Derived Cardiac Stem Cells to Over-Express Stromal-Cell Derived Factor 1\u03b1 Enhances Myocardial Repair"],"prefix":"10.1093","volume":"34","author":[{"given":"Everad L.","family":"Tilokee","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Latham","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robyn","family":"Jackson","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey E.","family":"Mayfield","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Ye","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth","family":"Mount","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Buu-Khanh","family":"Lam","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik J.","family":"Suuronen","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Ruel","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duncan J.","family":"Stewart","sequence":"additional","affiliation":[{"name":"Division of Regenerative Medicine, Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, K1H8L6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darryl R.","family":"Davis","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,4,21]]},"reference":[{"key":"2022010817000133700_stem2373-bib-0001","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1161\/CIRCULATIONAHA.108.784215","article-title":"Long-term trends in the incidence of heart failure after myocardial infarction","volume":"118","author":"Velagaleti","year":"2008","journal-title":"Circulation"},{"key":"2022010817000133700_stem2373-bib-0002","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/S0092-8674(03)00687-1","article-title":"Adult cardiac stem cells are multipotent and support myocardial regeneration","volume":"114","author":"Beltrami","year":"2003","journal-title":"Cell"},{"key":"2022010817000133700_stem2373-bib-0003","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1161\/01.RES.0000147315.71699.51","article-title":"Isolation and expansion of adult cardiac stem cells from human and murine heart","volume":"95","author":"Messina","year":"2004","journal-title":"Circ Res"},{"key":"2022010817000133700_stem2373-bib-0004","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1161\/CIRCULATIONAHA.106.655209","article-title":"Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens","volume":"115","author":"Smith","year":"2007","journal-title":"Circulation"},{"key":"2022010817000133700_stem2373-bib-0005","doi-asserted-by":"crossref","first-page":"e7195","DOI":"10.1371\/journal.pone.0007195","article-title":"Validation of the cardiosphere method to culture cardiac progenitor cells from myocardial tissue","volume":"4","author":"Davis","year":"2009","journal-title":"PLoS One"},{"key":"2022010817000133700_stem2373-bib-0006","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.yjmcc.2010.02.019","article-title":"Isolation and expansion of functionally-competent cardiac progenitor cells directly from heart biopsies","volume":"49","author":"Davis","year":"2010","journal-title":"J Mol Cell Cardiol"},{"key":"2022010817000133700_stem2373-bib-0007","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1002\/stem.413","article-title":"Human cardiospheres are a source of stem cells with cardiomyogenic potential","volume":"28","author":"Davis","year":"2010","journal-title":"Stem Cells"},{"key":"2022010817000133700_stem2373-bib-0008","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1161\/CIRCRESAHA.111.241380","article-title":"Functionally competent cardiac stem cells can be isolated from endomyocardial biopsies of patients with advanced cardiomyopathies","volume":"108","author":"D'Amario","year":"2011","journal-title":"Circ Res"},{"key":"2022010817000133700_stem2373-bib-0009","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1161\/CIRCULATIONAHA.112.000374","article-title":"Human blood and cardiac stem cells synergize to enhance cardiac repair when cotransplanted into ischemic myocardium","volume":"128","author":"Latham","year":"2013","journal-title":"Circulation"},{"key":"2022010817000133700_stem2373-bib-0010","doi-asserted-by":"crossref","first-page":"S70","DOI":"10.1161\/CIRCULATIONAHA.113.007908","article-title":"Hyperglycemia inhibits cardiac stem cell-mediated cardiac repair and angiogenic capacity","volume":"130","author":"Molgat","year":"2014","journal-title":"Circulation"},{"key":"2022010817000133700_stem2373-bib-0011","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/S0140-6736(12)60195-0","article-title":"Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial","volume":"379","author":"Makkar","year":"2012","journal-title":"Lancet"},{"key":"2022010817000133700_stem2373-bib-0012","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1016\/j.jacc.2009.04.097","article-title":"Noninvasive quantification and optimization of acute cell retention by in vivo positron emission tomography after intramyocardial cardiac-derived stem cell delivery","volume":"54","author":"Terrovitis","year":"2009","journal-title":"J Am Coll Cardiol"},{"key":"2022010817000133700_stem2373-bib-0013","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s12265-011-9265-3","article-title":"Constitutive HIF-1alpha expression blunts the beneficial effects of cardiosphere-derived cell therapy in the heart by altering paracrine factor balance","volume":"4","author":"Bonios","year":"2011","journal-title":"J Cardiovasc Transl Res"},{"key":"2022010817000133700_stem2373-bib-0014","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1161\/CIRCRESAHA.109.210682","article-title":"Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice","volume":"106","author":"Chimenti","year":"2010","journal-title":"Circ Res"},{"key":"2022010817000133700_stem2373-bib-0015","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1002\/emmm.201201737","article-title":"Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart","volume":"5","author":"Malliaras","year":"2013","journal-title":"EMBO Mol Med"},{"key":"2022010817000133700_stem2373-bib-0016","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.jchf.2013.08.008","article-title":"Human cardiosphere-derived cells from advanced heart failure patients exhibit augmented functional potency in myocardial repair","volume":"2","author":"Cheng","year":"2014","journal-title":"JACC Heart Fail"},{"key":"2022010817000133700_stem2373-bib-0017","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1002\/emmm.201303626","article-title":"Stimulation of endogenous cardioblasts by exogenous cell therapy after myocardial infarction","volume":"6","author":"Malliaras","year":"2014","journal-title":"EMBO Mol Med"},{"key":"2022010817000133700_stem2373-bib-0018","doi-asserted-by":"crossref","first-page":"14068","DOI":"10.1073\/pnas.0706760104","article-title":"Human cardiac stem cells","volume":"104","author":"Bearzi","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022010817000133700_stem2373-bib-0019","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.biomaterials.2013.09.085","article-title":"The effect of encapsulation of cardiac stem cells within matrix-enriched hydrogel capsules on cell survival, post-ischemic cell retention and cardiac function","volume":"35","author":"Mayfield","year":"2014","journal-title":"Biomaterials"},{"key":"2022010817000133700_stem2373-bib-0020","doi-asserted-by":"crossref","first-page":"e002104","DOI":"10.1161\/JAHA.115.002104","article-title":"Paracrine engineering of human cardiac stem cells with insulin-like growth factor-1 enhances myocardial repair","volume":"4","author":"Jackson","year":"2015","journal-title":"J Am Heart Assoc"},{"issue":"suppl 1","key":"2022010817000133700_stem2373-bib-0021","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.1038\/ncpcardio0771","article-title":"The adult human heart as a source for stem cells: repair strategies with embryonic-like progenitor cells","volume":"4","author":"Ott","year":"2007","journal-title":"Nat Clin Pract Cardiovasc Med"},{"key":"2022010817000133700_stem2373-bib-0022","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1073\/pnas.0808920106","article-title":"c-kit expression identifies cardiovascular precursors in the neonatal heart","volume":"106","author":"Tallini","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022010817000133700_stem2373-bib-0023","doi-asserted-by":"crossref","first-page":"109","DOI":"10.22203\/eCM.v022a09","article-title":"A stromal cell-derived factor-1 releasing matrix enhances the progenitor cell response and blood vessel growth in ischaemic skeletal muscle","volume":"22","author":"Kuraitis","year":"2011","journal-title":"Eur Cell Mater"},{"key":"2022010817000133700_stem2373-bib-0024","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1161\/01.ATV.0000124923.95545.2c","article-title":"Depletion of natural killer cell function decreases atherosclerosis in low-density lipoprotein receptor null mice","volume":"24","author":"Whitman","year":"2004","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2022010817000133700_stem2373-bib-0025","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1007\/s00395-013-0346-0","article-title":"A highly sensitive and accurate method to quantify absolute numbers of c-kit+ cardiac stem cells following transplantation in mice","volume":"108","author":"Hong","year":"2013","journal-title":"Basic Res Cardiol"},{"key":"2022010817000133700_stem2373-bib-0026","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/S0140-6736(03)14232-8","article-title":"Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy","volume":"362","author":"Askari","year":"2003","journal-title":"Lancet"},{"key":"2022010817000133700_stem2373-bib-0027","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1161\/CIRCRESAHA.111.300440","article-title":"An open-label dose escalation study to evaluate the safety of administration of nonviral stromal cell-derived factor-1 plasmid to treat symptomatic ischemic heart failure","volume":"112","author":"Penn","year":"2013","journal-title":"Circ Res"},{"key":"2022010817000133700_stem2373-bib-0028","doi-asserted-by":"crossref","first-page":"e001260","DOI":"10.1161\/JAHA.114.001260","article-title":"Relative roles of CD90 and c-Kit to the regenerative efficacy of cardiosphere-derived cells in humans and in a mouse model of myocardial infarction","volume":"3","author":"Cheng","year":"2014","journal-title":"J Am Heart Assoc"},{"key":"2022010817000133700_stem2373-bib-0029","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.stemcr.2014.03.003","article-title":"THY-1 receptor expression differentiates cardiosphere-derived cells with divergent cardiogenic differentiation potential","volume":"2","author":"Gago-Lopez","year":"2014","journal-title":"Stem Cell Rep"},{"key":"2022010817000133700_stem2373-bib-0030","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature13309","article-title":"c-kit+ cells minimally contribute cardiomyocytes to the heart","volume":"509","author":"van Berlo","year":"2014","journal-title":"Nature"},{"key":"2022010817000133700_stem2373-bib-0031","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1093\/cvr\/cvr014","article-title":"Parathyroid hormone is a DPP-IV inhibitor and increases SDF-1-driven homing of CXCR4(+) stem cells into the ischaemic heart","volume":"90","author":"Huber","year":"2011","journal-title":"Cardiovasc Res"},{"key":"2022010817000133700_stem2373-bib-0032","first-page":"S898","article-title":"Direct intramyocardial injection of autologous cardiosphere-derived cells yields consistent engraftment and improves cardiac function in a porcine model of ischemic cardiomyopathy","volume":"120","author":"Lee","year":"2009","journal-title":"Circulation"},{"key":"2022010817000133700_stem2373-bib-0033","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.stemcr.2014.04.006","article-title":"Exosomes as critical agents of cardiac regeneration triggered by cell therapy","volume":"2","author":"Ibrahim","year":"2014","journal-title":"Stem Cell Rep"},{"key":"2022010817000133700_stem2373-bib-0034","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.phrs.2008.06.007","article-title":"The immune system and cardiac repair","volume":"58","author":"Frangogiannis","year":"2008","journal-title":"Pharmacol Res"},{"key":"2022010817000133700_stem2373-bib-0035","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1182\/blood-2005-02-0468","article-title":"The use of AMD3100 plus G-CSF for autologous hematopoietic progenitor cell mobilization is superior to G-CSF alone","volume":"106","author":"Flomenberg","year":"2005","journal-title":"Blood"},{"key":"2022010817000133700_stem2373-bib-0036","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1161\/CIRCULATIONAHA.107.718718","article-title":"Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction","volume":"116","author":"Segers","year":"2007","journal-title":"Circulation"},{"key":"2022010817000133700_stem2373-bib-0037","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.scr.2011.05.003","article-title":"Dual stem cell therapy after myocardial infarction acts specifically by enhanced homing via the SDF-1\/CXCR4 axis","volume":"7","author":"Theiss","year":"2011","journal-title":"Stem Cell Res"}],"container-title":["Stem Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fstem.2373","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fstem.2373","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/stem.2373","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/stem.2373","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/34\/7\/1826\/42026865\/stmcls_34_7_1826.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/34\/7\/1826\/42026865\/stmcls_34_7_1826.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T02:58:09Z","timestamp":1642561089000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stmcls\/article\/34\/7\/1826-1835\/6408286"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,21]]},"references-count":37,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2016,4,21]]},"published-print":{"date-parts":[[2016,7,1]]}},"URL":"https:\/\/doi.org\/10.1002\/stem.2373","relation":{},"ISSN":["1066-5099","1549-4918"],"issn-type":[{"value":"1066-5099","type":"print"},{"value":"1549-4918","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,7,1]]},"published":{"date-parts":[[2016,4,21]]}}}