Abstract
Cell-based therapies to restore heart function after infarction have been tested in pre-clinical models and clinical trials with mixed results, and will likely require both contractile cells and a vascular network to support them. We and others have shown that human endothelial colony forming cells (ECFC) combined with mesenchymal progenitor cells (MPC) can be used to “bio-engineer” functional human blood vessels. Here we investigated whether ECFC + MPC form functional vessels in ischemic myocardium and whether this affects cardiac function or remodeling. Myocardial ischemia/reperfusion injury (IRI) was induced in 12-week-old immunodeficient rats by ligation of the left anterior descending coronary artery. After 40 min, myocardium was reperfused and ECFC + MPC (2 × 106 cells, 2:3 ratio) or PBS was injected. Luciferase assays after injection of luciferase-labeled ECFC + MPC showed that 1,500 ECFC were present at day 14. Human ECFC-lined perfused vessels were directly visualized by femoral vein injection of a fluorescently-tagged human-specific lectin in hearts injected with ECFC + MPC but not PBS alone. While infarct size at day 1 was no different, LV dimensions and heart weight to tibia length ratios were lower in cell-treated hearts compared with PBS at 4 months, suggesting post-infarction remodeling was ameliorated by local cell injection. Fractional shortening, LV wall motion score, and fibrotic area were not different between groups at 4 months. However, pressure–volume loops demonstrated improved cardiac function and reduced volumes in cell-treated animals. These data suggest that myocardial delivery of ECFC + MPC at reperfusion may provide a therapeutic strategy to mitigate LV remodeling and cardiac dysfunction after IRI.
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Acknowledgments
Supported by HL09262 (JB, TR) and K08-HL098569 (MC). We thank Dr. David Zurokowski, Boston Children’s Hospital, for advice on the statistical analyses. We thank Thomas Neufeld for the excellent technical assistance on fibrosis analysis.
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The authors have no conflicts of interest to disclose.
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Kyu-Tae Kang and Matthew Coggins contributed equally to this study.
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Kang, KT., Coggins, M., Xiao, C. et al. Human vasculogenic cells form functional blood vessels and mitigate adverse remodeling after ischemia reperfusion injury in rats. Angiogenesis 16, 773–784 (2013). https://doi.org/10.1007/s10456-013-9354-9
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DOI: https://doi.org/10.1007/s10456-013-9354-9