{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:15:39Z","timestamp":1790352939898,"version":"4.1.0"},"reference-count":20,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T00:00:00Z","timestamp":1616112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01 HL078825 and UM1 HL113530"],"award-info":[{"award-number":["P01 HL078825 and UM1 HL113530"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Using a murine model of chronic ischemic cardiomyopathy caused by an old myocardial infarction (MI), we have previously found that three doses of 1 \u00d7 106 c-kit positive cardiac cells (CPCs) are more effective than a single dose of 1 \u00d7 106 cells. The goal of this study was to determine whether the beneficial effects of three doses of CPCs (1 \u00d7 106 cells each) can be fully replicated by a single combined dose of 3 \u00d7 106 CPCs. Mice underwent a 60-min coronary occlusion; after 90 days of reperfusion, they received three echo-guided intraventricular infusions at 5-week intervals: (1) vehicle \u00d7 3; (2) one combined dose of CPCs (3 \u00d7 106) and vehicle \u00d7 2; or (3) three doses of CPCs (1 \u00d7 106 each). In the combined-dose group, left ventricular ejection fraction (LVEF) improved after the 1st CPC infusion, but not after the 2nd and 3rd (vehicle) infusions. In contrast, in the multiple-dose group, LVEF increased after each CPC infusion; at the final echo, LVEF averaged 35.2 \u00b1 0.6% (p &lt; 0.001 vs. the vehicle group, 27.3 \u00b1 0.2%). At the end of the study, the total cumulative change in EF from pretreatment values was numerically greater in the multiple-dose group (6.6 \u00b1 0.6%) than in the combined-dose group (4.8 \u00b1 0.8%), although the difference was not statistically significant (p = 0.08). Hemodynamic studies showed that several parameters of LV function in the multiple-dose group were numerically greater than in the combined-dose group (p = 0.08 for the difference in LVEF). Compared with vehicle, cardiomyocyte cross-sectional area was reduced only in the multiple-dose group (\u221232.7%, 182.6 \u00b1 15.1 \u00b5m2 vs. 271.5 \u00b1 27.2 \u00b5m2, p &lt; 0.05, in the risk region and \u221228.5%, 148.5 \u00b1 12.1 \u00b5m2 vs. 207.6 \u00b1 20.5 \u00b5m2, p &lt; 0.05, in the noninfarcted region). LV weight\/body weight ratio and LV weight\/tibia length ratios were significantly reduced in both cell treated groups vs. the vehicle group, indicating the attenuation of LV hypertrophy; however, the lung weight\/body weight ratio was significantly reduced only in the multiple-dose group, suggesting decreased pulmonary congestion. Taken together, these results indicate that in mice with chronic ischemic cardiomyopathy, the beneficial effects of three doses of CPCs on LV function and hypertrophy cannot be fully replicated with a single dose, notwithstanding the fact that the total number of cells delivered with one or three doses is the same. Thus, it is the multiplicity of doses, and not the total number of cells, that accounts for the superiority of the repeated-dose paradigm. This study supports the idea that the efficacy of cell therapy in heart failure can be augmented by repeated administrations.<\/jats:p>","DOI":"10.3390\/ijms22063145","type":"journal-article","created":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T11:18:38Z","timestamp":1616152718000},"page":"3145","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Comparison of Repeated Doses of C-kit-Positive Cardiac Cells versus a Single Equivalent Combined Dose in a Murine Model of Chronic Ischemic Cardiomyopathy"],"prefix":"10.3390","volume":"22","author":[{"given":"Qianhong","family":"Li","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0614-9899","authenticated-orcid":false,"given":"Yiru","family":"Guo","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7934-7821","authenticated-orcid":false,"given":"Yibing","family":"Nong","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Tomlin","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Gumpert","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Zhu","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Adeel","family":"Hassan","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Bolli","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1002\/ejhf.1767","article-title":"Time to end the war on cell therapy","volume":"22","author":"Bolli","year":"2020","journal-title":"Eur. 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