title: Stem cell factor gene transfer improves cardiac function after myocardial infarction in swine.
abstract: BACKGROUND
  Stem cell factor (SCF), a ligand of the c-kit receptor, is a critical cytokine, which contributes to cell migration, proliferation, and survival. It has been shown that SCF expression increases after myocardial infarction (MI) and may be involved in cardiac repair. The aim of this study was to determine whether gene transfer of membrane-bound human SCF improves cardiac function in a large animal model of MI.
  
  
  RESULTS
  A transmural MI was created by implanting an embolic coil in the left anterior descending artery in Yorkshire pigs. One week after the MI, the pigs received direct intramyocardial injections of either a recombinant adenovirus encoding for SCF (Ad.SCF, n=9) or β-gal (Ad.β-gal, n=6) into the infarct border area. At 3 months post-MI, ejection fraction increased by 12% relative to baseline after Ad.SCF therapy, whereas it decreased by 4.2% (P=0.004) in pigs treated with Ad.β-gal. Preload-recruitable stroke work was significantly higher in pigs after SCF treatment (Ad.SCF, 55.5±11.6 mm Hg versus Ad.β-gal, 31.6±12.6 mm Hg, P=0.005), indicating enhanced cardiac function. Histological analyses confirmed the recruitment of c-kit(+) cells as well as a reduced degree of apoptosis 1 week after Ad.SCF injection. In addition, increased capillary density compared with pigs treated with Ad.β-gal was found at 3 months and suggests an angiogenic role of SCF.
  
  
  CONCLUSIONS
  Local overexpression of SCF post-MI induces the recruitment of c-kit(+) cells at the infarct border area acutely. In the chronic stages, SCF gene transfer was associated with improved cardiac function in a preclinical model of ischemic cardiomyopathy.
authors.affiliation: From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., K.F., J.A., E.Y.-G., D.J., C.K., L.T., L.F., L.L., K.D.C., R.J.H.); Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)-Epidemiology, Atherothrombosis and Imaging Department, Madrid, Spain (J.A.); David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge (A.A.E., D.G.A.); and Celladon Corporation, San Diego, CA (K.Z.). kiyotake.ishikawa@mssm.edu.
authors.forename: Kiyotake
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., K.F., J.A., E.Y.-G., D.J., C.K., L.T., L.F., L.L., K.D.C., R.J.H.); Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)-Epidemiology, Atherothrombosis and Imaging Department, Madrid, Spain (J.A.); David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge (A.A.E., D.G.A.); and Celladon Corporation, San Diego, CA (K.Z.).
authors.forename: Kenneth
authors.initials: K
authors.lastname: Fish
authors.affiliation: From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., K.F., J.A., E.Y.-G., D.J., C.K., L.T., L.F., L.L., K.D.C., R.J.H.); Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)-Epidemiology, Atherothrombosis and Imaging Department, Madrid, Spain (J.A.); David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge (A.A.E., D.G.A.); and Celladon Corporation, San Diego, CA (K.Z.).
authors.forename: Jaume
authors.initials: J
authors.lastname: Aguero
authors.affiliation: From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., K.F., J.A., E.Y.-G., D.J., C.K., L.T., L.F., L.L., K.D.C., R.J.H.); Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)-Epidemiology, Atherothrombosis and Imaging Department, Madrid, Spain (J.A.); David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge (A.A.E., D.G.A.); and Celladon Corporation, San Diego, CA (K.Z.).
authors.forename: Elisa
authors.initials: E
authors.lastname: Yaniz-Galende
authors.affiliation: From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., K.F., J.A., E.Y.-G., D.J., C.K., L.T., L.F., L.L., K.D.C., R.J.H.); Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)-Epidemiology, Atherothrombosis and Imaging Department, Madrid, Spain (J.A.); David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge (A.A.E., D.G.A.); and Celladon Corporation, San Diego, CA (K.Z.).
authors.forename: Dongtak
authors.initials: D
authors.lastname: Jeong
authors.affiliation: From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., K.F., J.A., E.Y.-G., D.J., C.K., L.T., L.F., L.L., K.D.C., R.J.H.); Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)-Epidemiology, Atherothrombosis and Imaging Department, Madrid, Spain (J.A.); David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge (A.A.E., D.G.A.); and Celladon Corporation, San Diego, CA (K.Z.).
authors.forename: Changwon
authors.initials: C
authors.lastname: Kho
authors.affiliation: From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., K.F., J.A., E.Y.-G., D.J., C.K., L.T., L.F., L.L., K.D.C., R.J.H.); Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)-Epidemiology, Atherothrombosis and Imaging Department, Madrid, Spain (J.A.); David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge (A.A.E., D.G.A.); and Celladon Corporation, San Diego, CA (K.Z.).
authors.forename: Lisa
authors.initials: L
authors.lastname: Tilemann
authors.affiliation: From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., K.F., J.A., E.Y.-G., D.J., C.K., L.T., L.F., L.L., K.D.C., R.J.H.); Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)-Epidemiology, Atherothrombosis and Imaging Department, Madrid, Spain (J.A.); David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge (A.A.E., D.G.A.); and Celladon Corporation, San Diego, CA (K.Z.).
authors.forename: Lauren
authors.initials: L
authors.lastname: Fish
authors.affiliation: From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., K.F., J.A., E.Y.-G., D.J., C.K., L.T., L.F., L.L., K.D.C., R.J.H.); Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)-Epidemiology, Atherothrombosis and Imaging Department, Madrid, Spain (J.A.); David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge (A.A.E., D.G.A.); and Celladon Corporation, San Diego, CA (K.Z.).
authors.forename: Lifan
authors.initials: L
authors.lastname: Liang
authors.affiliation: From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., K.F., J.A., E.Y.-G., D.J., C.K., L.T., L.F., L.L., K.D.C., R.J.H.); Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)-Epidemiology, Atherothrombosis and Imaging Department, Madrid, Spain (J.A.); David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge (A.A.E., D.G.A.); and Celladon Corporation, San Diego, CA (K.Z.).
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Eltoukhy
authors.affiliation: From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., K.F., J.A., E.Y.-G., D.J., C.K., L.T., L.F., L.L., K.D.C., R.J.H.); Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)-Epidemiology, Atherothrombosis and Imaging Department, Madrid, Spain (J.A.); David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge (A.A.E., D.G.A.); and Celladon Corporation, San Diego, CA (K.Z.).
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
authors.affiliation: From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., K.F., J.A., E.Y.-G., D.J., C.K., L.T., L.F., L.L., K.D.C., R.J.H.); Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)-Epidemiology, Atherothrombosis and Imaging Department, Madrid, Spain (J.A.); David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge (A.A.E., D.G.A.); and Celladon Corporation, San Diego, CA (K.Z.).
authors.forename: Krisztina
authors.initials: K
authors.lastname: Zsebo
authors.affiliation: From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., K.F., J.A., E.Y.-G., D.J., C.K., L.T., L.F., L.L., K.D.C., R.J.H.); Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)-Epidemiology, Atherothrombosis and Imaging Department, Madrid, Spain (J.A.); David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge (A.A.E., D.G.A.); and Celladon Corporation, San Diego, CA (K.Z.).
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Costa
authors.affiliation: From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., K.F., J.A., E.Y.-G., D.J., C.K., L.T., L.F., L.L., K.D.C., R.J.H.); Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)-Epidemiology, Atherothrombosis and Imaging Department, Madrid, Spain (J.A.); David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge (A.A.E., D.G.A.); and Celladon Corporation, San Diego, CA (K.Z.).
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019089:Stem Cell Factor / Q000378:metabolism*; D013318:Stroke Volume; D013552:Swine; D016277:Ventricular Function, Left / Q000502:physiology*
chemical_list: D019089:Stem Cell Factor
keywords: angiogenesis; gene therapy; myocardial infarction; paracrine factor