title: Synergistic Effects of Combined Cell Therapy for Chronic Ischemic Cardiomyopathy.
abstract: BACKGROUND
  Both bone marrow-derived mesenchymal stem cells (MSCs) and c-kit(+) cardiac stem cells (CSCs) improve left ventricular remodeling in porcine models and clinical trials. Using xenogeneic (human) cells in immunosuppressed animals with acute ischemic heart disease, we previously showed that these 2 cell types act synergistically.
  
  
  OBJECTIVE
  To more accurately model clinical applications for heart failure, this study tested whether the combination of autologous MSCs and CSCs produce greater improvement in cardiac performance than MSCs alone in a nonimmunosuppressed porcine model of chronic ischemic cardiomyopathy.
  
  
  METHODS
  Three months after ischemia/reperfusion injury, Göttingen swine received transendocardial injections with MSCs alone (n = 6) or in combination with cardiac-derived CSCs (n = 8), or placebo (vehicle; n = 6). Cardiac functional and anatomic parameters were assessed using cardiac magnetic resonance at baseline and before and after therapy.
  
  
  RESULTS
  Both groups of cell-treated animals exhibited significantly reduced scar size (MSCs -44.1 ± 6.8%; CSC/MSC -37.2 ± 5.4%; placebo -12.9 ± 4.2%; p < 0.0001), increased viable tissue, and improved wall motion relative to placebo 3 months post-injection. Ejection fraction (EF) improved (MSCs 2.9 ± 1.6 EF units; CSC/MSC 6.9 ± 2.8 EF units; placebo 2.5 ± 1.6 EF units; p = 0.0009), as did stroke volume, cardiac output, and diastolic strain only in the combination-treated animals, which also exhibited increased cardiomyocyte mitotic activity.
  
  
  CONCLUSIONS
  These findings illustrate that interactions between MSCs and CSCs enhance cardiac performance more than MSCs alone, establish the safety of autologous cell combination strategies, and support the development of second-generation cell therapeutic products.
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Vasileios
authors.initials: V
authors.lastname: Karantalis
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Viky Y
authors.initials: VY
authors.lastname: Suncion-Loescher
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Luiza
authors.initials: L
authors.lastname: Bagno
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Samuel
authors.initials: S
authors.lastname: Golpanian
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Ariel
authors.initials: A
authors.lastname: Wolf
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sanina
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Courtney
authors.initials: C
authors.lastname: Premer
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Kanelidis
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Frederic
authors.initials: F
authors.lastname: McCall
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Wayne
authors.initials: W
authors.lastname: Balkan
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Jose
authors.initials: J
authors.lastname: Rodriguez
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Marcos
authors.initials: M
authors.lastname: Rosado
authors.affiliation: Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Azorides
authors.initials: A
authors.lastname: Morales
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Hatzistergos
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Makoto
authors.initials: M
authors.lastname: Natsumeda
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Irene
authors.initials: I
authors.lastname: Margitich
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Ivonne Hernandez
authors.initials: IH
authors.lastname: Schulman
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Samirah A
authors.initials: SA
authors.lastname: Gomes
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Muzammil
authors.initials: M
authors.lastname: Mushtaq
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Darcy L
authors.initials: DL
authors.lastname: DiFede
authors.affiliation: Department of Radiology, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Joel E
authors.initials: JE
authors.lastname: Fishman
authors.affiliation: Department of Radiology, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Pradip
authors.initials: P
authors.lastname: Pattany
authors.affiliation: Cardiovascular Medicine, Jackson South Community Hospital, Miami, Florida.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Zambrano
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Alan W
authors.initials: AW
authors.lastname: Heldman
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida. Electronic address: jhare@med.miami.edu.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology / Q000628:therapy; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D006801:Humans; D019028:Magnetic Resonance Imaging, Cine / Q000379:methods; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D032386:Myoblasts, Cardiac / Q000637:transplantation*; D015428:Myocardial Reperfusion Injury / Q000150:complications*; D013318:Stroke Volume; D013552:Swine; D016042:Transplantation, Heterotopic / Q000379:methods; D016896:Treatment Outcome; D020257:Ventricular Remodeling
keywords: cardiac; combination therapy; heart failure; mesenchymal stem cell