title: Pim1 Kinase Overexpression Enhances ckit+Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine.
abstract: BACKGROUND
  Pim1 kinase plays an important role in cell division, survival, and commitment of precursor cells towards a myocardial lineage, and overexpression of Pim1 in ckit+cardiac stem cells (CSCs) enhances their cardioreparative properties.
  
  
  OBJECTIVE
  The authors sought to validate the effect of Pim1-modified CSCs in a translationally relevant large animal preclinical model of myocardial infarction (MI).
  
  
  METHODS
  Human cardiac stem cells (hCSCs, n = 10), hckit+CSCs overexpressing Pim1 (Pim1+; n = 9), or placebo (n = 10) were delivered by intramyocardial injection to immunosuppressed Yorkshire swine (n = 29) 2 weeks after MI. Cardiac magnetic resonance and pressure volume loops were obtained before and after cell administration.
  
  
  RESULTS
  Whereas both hCSCs reduced MI size compared to placebo, Pim1+cells produced a ∼3-fold greater decrease in scar mass at 8 weeks post-injection compared to hCSCs (-29.2 ± 2.7% vs. -8.4 ± 0.7%; p < 0.003). Pim1+hCSCs also produced a 2-fold increase of viable mass compared to hCSCs at 8 weeks (113.7 ± 7.2% vs. 65.6 ± 6.8%; p <0.003), and a greater increase in regional contractility in both infarct and border zones (both p < 0.05). Both CSC types significantly increased ejection fraction at 4 weeks but this was only sustained in the Pim1+group at 8 weeks compared to placebo. Both hCSC and Pim1+hCSC treatment reduced afterload (p = 0.02 and p = 0.004, respectively). Mechanoenergetic recoupling was significantly greater in the Pim1+hCSC group (p = 0.005).
  
  
  CONCLUSIONS
  Pim1 overexpression enhanced the effect of intramyocardial delivery of CSCs to infarcted porcine hearts. These findings provide a rationale for genetic modification of stem cells and consequent translation to clinical trials.
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Shathiyah
authors.initials: S
authors.lastname: Kulandavelu
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: Julia
authors.initials: J
authors.lastname: Fritsch
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Konstantinos E
authors.initials: KE
authors.lastname: Hatzistergos
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: Loescher
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: 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: Justin
authors.initials: J
authors.lastname: Grenet
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Adam
authors.initials: A
authors.lastname: Williams
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Aaron
authors.initials: A
authors.lastname: Kupin
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Aaron
authors.initials: A
authors.lastname: Rosenfeld
authors.affiliation: Biology Department and Integrated Regenerative Research Institute, San Diego State University, San Diego, California.
authors.forename: Sadia
authors.initials: S
authors.lastname: Mohsin
authors.affiliation: Biology Department and Integrated Regenerative Research Institute, San Diego State University, San Diego, California.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
authors.affiliation: Department of Medicine, 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; Department of Medicine, 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; Department of Medicine, 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; D004195:Disease Models, Animal; D005260:Female; D005656:Fungal Proteins / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000601:surgery*; D032383:Myocytes, Cardiac / Q000166:cytology*; D033581:Stem Cell Transplantation / Q000379:methods*; D013552:Swine
chemical_list: D005656:Fungal Proteins; D020928:Mitogen-Activated Protein Kinases; C432694:Pim1 protein, Pichia pastoris
keywords: heart failure; human cardiac progenitor cells; injection; pressure volume