Journal
CYTOTHERAPY
Volume 16, Issue 4, Pages 460-470Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.jcyt.2013.07.016
Keywords
cardiac magnetic resonance; hypoxic conditioning; mesenchymal stromal cells; multiple intervention; myocardial infarction; optimization; prospective isolation; repair; timing
Categories
Funding
- International Postgraduate Research Scholarship at the University of Adelaide, Australia
- National Health and Medical Research Council of Australia
- Royal Australasian College of Physicians
- National Health and Medical Research Council
- Australian National Heart Foundation
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Background aims. Traditionally, stem cell therapy for myocardial infarction (MI) has been administered as a single treatment in the acute or subacute period after MI. These time intervals coincide with marked differences in the post-infarct myocardial environment, raising the prospect that repeat cell dosing could provide incremental benefit beyond a solitary intervention. This prospect was evaluated with the use of mesenchymal stromal cells (MSCs). Methods. Three groups of rats were studied. Single-therapy and dual-therapy groups received allogeneic, prospectively isolated MSCs (1 x 10(6) cells) by trans-epicardial injection immediately after MI, with additional dosing 1 week later in the dual-therapy cohort. Control animals received cryopreservant solution only. Left ventricular (LV) dimensions and ejection fraction (EF) were assessed by cardiac magnetic resonance immediately before MI and at 1, 2, and 4 weeks after MI. Results. Immediate MSC treatment attenuated. early myocardial damage with EF of 35.3 +/- 3.1% (dual group, n = 12) and 35.2 +/- 2.2% (single group, n = 15) at 1 week after MI compared with 22.1 +/- 1.9% in controls (n = 17, P < 0.01). In animals receiving a second dose of MSCs, EF increased to 40.7 +/- 3.1% by week 4, which was significantly higher than in the single-therapy group (EF 35.9 +/- 1.8%, P < 0.05). Dual MSC treatment was also associated with greater myocardial mass and arteriolar density, with trends toward reduced myocardial fibrosis. These incremental benefits were especially observed in remote (non-infarct) segments of LV myocardium. Conclusions. Repeated stem cell intervention in both the acute and the sub-acute period after MI provides additional improvement in ventricular function beyond solitary cell dosing, largely owing to beneficial changes remote to the area of infarction.
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