title: Preclinical evaluation of the engineered stem cell chemokine stromal cell-derived factor 1α analog in a translational ovine myocardial infarction model.
abstract: BACKGROUND
  After myocardial infarction, there is an inadequate blood supply to the myocardium, and the surrounding borderzone becomes hypocontractile.
  
  
  OBJECTIVE
  To develop a clinically translatable therapy, we hypothesized that in a preclinical ovine model of myocardial infarction, the modified endothelial progenitor stem cell chemokine, engineered stromal cell-derived factor 1α analog (ESA), would induce endothelial progenitor stem cell chemotaxis, limit adverse ventricular remodeling, and preserve borderzone contractility.
  
  
  RESULTS
  Thirty-six adult male Dorset sheep underwent permanent ligation of the left anterior descending coronary artery, inducing an anteroapical infarction, and were randomized to borderzone injection of saline (n=18) or ESA (n=18). Ventricular function, geometry, and regional strain were assessed using cardiac MRI and pressure-volume catheter transduction. Bone marrow was harvested for in vitro analysis, and myocardial biopsies were taken for mRNA, protein, and immunohistochemical analysis. ESA induced greater chemotaxis of endothelial progenitor stem cells compared with saline (P<0.01) and was equivalent to recombinant stromal cell-derived factor 1α (P=0.27). Analysis of mRNA expression and protein levels in ESA-treated animals revealed reduced matrix metalloproteinase 2 in the borderzone (P<0.05), with elevated levels of tissue inhibitor of matrix metalloproteinase 1 and elastin in the infarct (P<0.05), whereas immunohistochemical analysis of borderzone myocardium showed increased capillary and arteriolar density in the ESA group (P<0.01). Animals in the ESA treatment group also had significant reductions in infarct size (P<0.01), increased maximal principle strain in the borderzone (P<0.01), and a steeper slope of the end-systolic pressure-volume relationship (P=0.01).
  
  
  CONCLUSIONS
  The novel, biomolecularly designed peptide ESA induces chemotaxis of endothelial progenitor stem cells, stimulates neovasculogenesis, limits infarct expansion, and preserves contractility in an ovine model of myocardial infarction.
authors.affiliation: From the Division of Cardiovascular Surgery, Department of Surgery (J.W.M., J.E.C., J.R.M., A.T., A.S.F., G.H., W.H., A.B.G., P.A., J.H.G., R.C.G.), Gorman Cardiovascular Research Group, Department of Surgery (J.R.M., J.J.P., J.H.G., R.C.G.), Division of Interventional Cardiology, Department of Medicine (R.L.W.), and Department of Radiology (J.J.P.), University of Pennsylvania School of Medicine, Philadelphia; and Department of Cardiothoracic Surgery, Stanford University School of Medicine, CA (J.W.M., J.E.C., Y.S., J.B.P., B.B.E., Y.J.W.).
authors.forename: John W
authors.initials: JW
authors.lastname: Macarthur
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Cohen
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: McGarvey
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shudo
authors.forename: Jay B
authors.initials: JB
authors.lastname: Patel
authors.forename: Alen
authors.initials: A
authors.lastname: Trubelja
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Fairman
authors.forename: Bryan B
authors.initials: BB
authors.lastname: Edwards
authors.forename: George
authors.initials: G
authors.lastname: Hung
authors.forename: William
authors.initials: W
authors.lastname: Hiesinger
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Goldstone
authors.forename: Pavan
authors.initials: P
authors.lastname: Atluri
authors.forename: Robert L
authors.initials: RL
authors.lastname: Wilensky
authors.forename: James J
authors.initials: JJ
authors.lastname: Pilla
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Gorman
authors.forename: Robert C
authors.initials: RC
authors.lastname: Gorman
authors.forename: Y Joseph
authors.initials: YJ
authors.lastname: Woo
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12 / Q000235:genetics / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D015195:Drug Design; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006439:Hemodynamics / Q000187:drug effects; D021621:Imaging, Three-Dimensional; D008279:Magnetic Resonance Imaging; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008833:Microcirculation / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D015202:Protein Engineering; D034561:Sheep, Domestic; D057170:Translational Research, Biomedical; D018487:Ventricular Dysfunction, Left / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D054377:Chemokine CXCL12
keywords: bioengineering; magnetic resonance imaging; myocardial infarction; translational research