title: Human vasculogenic cells form functional blood vessels and mitigate adverse remodeling after ischemia reperfusion injury in rats.
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 × 10(6) 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.
authors.affiliation: Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.
authors.forename: Kyu-Tae
authors.initials: KT
authors.lastname: Kang
authors.forename: Matthew
authors.initials: M
authors.lastname: Coggins
authors.forename: Chunyang
authors.initials: C
authors.lastname: Xiao
authors.forename: Anthony
authors.initials: A
authors.lastname: Rosenzweig
authors.forename: Joyce
authors.initials: J
authors.lastname: Bischoff
mesh_terms: D000328:Adult; D000818:Animals; D036101:Cord Blood Stem Cell Transplantation; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005240:Feasibility Studies; D017930:Genes, Reporter; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006439:Hemodynamics; D064593:Heterografts; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D055806:Microvessels / Q000648:ultrastructure; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051381:Rats; D011923:Rats, Nude; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000517:prevention & control*; D020257:Ventricular Remodeling