title: Paracrine Engineering of Human Explant-Derived Cardiac Stem Cells to Over-Express Stromal-Cell Derived Factor 1α Enhances Myocardial Repair.
abstract: First generation cardiac stem cell products provide indirect cardiac repair but variably produce key cardioprotective cytokines, such as stromal-cell derived factor 1α, which opens the prospect of maximizing up-front paracrine-mediated repair. The mesenchymal subpopulation within explant derived human cardiac stem cells underwent lentiviral mediated gene transfer of stromal-cell derived factor 1α. Unlike previous unsuccessful attempts to increase efficacy by boosting the paracrine signature of cardiac stem cells, cytokine profiling revealed that stromal-cell derived factor 1α over-expression prevented lv-mediated "loss of cytokines" through autocrine stimulation of CXCR4+ cardiac stem cells. Stromal-cell derived factor 1α enhanced angiogenesis and stem cell recruitment while priming cardiac stem cells to readily adopt a cardiac identity. As compared to injection with unmodified cardiac stem cells, transplant of stromal-cell derived factor 1α enhanced cells into immunodeficient mice improved myocardial function and angiogenesis while reducing scarring. Increases in myocardial stromal-cell derived factor 1α content paralleled reductions in myocyte apoptosis but did not influence long-term engraftment or the fate of transplanted cells. Transplantation of stromal-cell derived factor 1α transduced cardiac stem cells increased the generation of new myocytes, recruitment of bone marrow cells, new myocyte/vessel formation and the salvage of reversibly damaged myocardium to enhance cardiac repair after experimental infarction. Stem Cells 2016;34:1826-1835.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada.
authors.forename: Everad L
authors.initials: EL
authors.lastname: Tilokee
authors.affiliation: Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Latham
authors.affiliation: Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada.
authors.forename: Robyn
authors.initials: R
authors.lastname: Jackson
authors.affiliation: Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada.
authors.forename: Audrey E
authors.initials: AE
authors.lastname: Mayfield
authors.affiliation: Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada.
authors.forename: Bin
authors.initials: B
authors.lastname: Ye
authors.affiliation: Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada.
authors.forename: Seth
authors.initials: S
authors.lastname: Mount
authors.affiliation: Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada.
authors.forename: Buu-Khanh
authors.initials: BK
authors.lastname: Lam
authors.affiliation: Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Suuronen
authors.affiliation: Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Ruel
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, K1H8L6, Canada.
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
authors.affiliation: Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, K1Y4W7, Canada.
authors.forename: Darryl R
authors.initials: DR
authors.lastname: Davis
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D054377:Chemokine CXCL12 / Q000378:metabolism*; D006801:Humans; D016086:Lentivirus / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology; D009206:Myocardium / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000378:metabolism; D018919:Neovascularization, Physiologic; D019899:Paracrine Communication; D019718:Receptors, CXCR4; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D023822:Tissue Engineering / Q000379:methods*; D014161:Transduction, Genetic; D014945:Wound Healing
chemical_list: C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4
keywords: Adult stem cells; Cardiac; SDF-1; Tissue-specific stem cells