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An early boost of intracardiac regenerative key mechanisms and angiogenetic niche signaling in cardiac mesenchymal stem cells (MSCs) could improve myocardial infarction (MI) healing. Epicardial erythropoietin (EPO, 300U kg\u22121) was compared with intraperitoneal and intramyocardial EPO treatments after acute MI in rats (n=156). Real-time PCR and confocal microscopy revealed epicardial EPO treatment enhanced intracardiac regenerative key indicators (SDF-1, CXCR-4, CD34, Bcl-2, Cyclin D1, Cdc2, MMP2), induced TGF-\u03b2\/WNT signaling in intramyocardial MSC niches through direct activation of AKT, upregulations of upstream signals FOS and Fzd7 and augmented intracardiac mesenchymal proliferation 24 hours after MI. Cardiac catheterization and tissues showed superior cardiac functions, beneficial remodeling and capillary density 6 weeks after MI. Concomitant fluorescence-activated cell sorting, co-cultures with neonatal cardiomyocytes, angiogenesis assays, ELISA, western-blotting and RAMAN spectroscopy illustrated EPO could promote tissue origin-specific cardiomyogenic differentiation and enhance paracrine angiogenetic activity in cardiac CD45\u2212CD44+DDR2+ MSCs. Epicardial EPO delivery might be the optimal route for efficient up-regulation of regenerative key signals after acute MI. Early EPO-mediated stimulation of mesenchymal proliferation, synergistic angiogenesis with cardiac MSCs and direct induction of TGF-\u03b2\/WNT signaling in intramyocardial cardiac MSCs might have initiated an accelerated healing process which enhanced cardiac recovery.<\/jats:p>","DOI":"10.1242\/dmm.033282","type":"journal-article","created":{"date-parts":[[2018,5,10]],"date-time":"2018-05-10T12:25:11Z","timestamp":1525955111000},"source":"Crossref","is-referenced-by-count":15,"title":["Intramyocardial angiogenetic stem cells and epicardial erythropoietin save the acute ischemic heart"],"prefix":"10.1242","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1736-2521","authenticated-orcid":false,"given":"Christian","family":"Klopsch","sequence":"first","affiliation":[{"name":"Reference and Translation Center for Cardiac Stem Cell Therapy, Rostock University Medical Center, 18055 Rostock, Germany."},{"name":"Department of Cardiac Surgery, Heart Center Rostock, University of Rostock, 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