title: Preservation of myocardial structure is enhanced by pim-1 engineering of bone marrow cells.
abstract: BACKGROUND
  Bone marrow-derived cells to treat myocardial injury improve cardiac function and support beneficial cardiac remodeling. However, survival of stem cells is limited due to low proliferation of transferred cells.
  
  
  OBJECTIVE
  To demonstrate long-term potential of c-kit(+) bone marrow stem cells (BMCs) enhanced with Pim-1 kinase to promote positive cardiac remodeling.
  
  
  RESULTS
  Lentiviral modification of c-kit(+) BMCs to express Pim-1 (BMCeP) increases proliferation and expression of prosurvival proteins relative to BMCs expressing green fluorescent protein (BMCe). Intramyocardial delivery of BMCeP at time of infarction supports improvements in anterior wall dimensions and prevents left ventricle dilation compared with hearts treated with vehicle alone. Reduction of the akinetic left ventricular wall was observed in BMCeP-treated hearts at 4 and 12 weeks after infarction. Early recovery of cardiac function in BMCeP-injected hearts facilitated modest improvements in hemodynamic function up to 12 weeks after infarction between cell-treated groups. Persistence of BMCeP is improved relative to BMCe within the infarct together with increased recruitment of endogenous c-kit(+) cells. Delivery of BMC populations promotes cellular hypertrophy in the border and infarcted regions coupled with an upregulation of hypertrophic genes. Thus, BMCeP treatment yields improved structural remodeling of infarcted myocardium compared with control BMCs.
  
  
  CONCLUSIONS
  Genetic modification of BMCs with Pim-1 may serve as a therapeutic approach to promote recovery of myocardial structure. Future approaches may take advantage of salutary BMC actions in conjunction with other stem cell types to increase efficacy of cellular therapy and improve myocardial performance in the injured myocardium.
authors.affiliation: San Diego State University Heart Institute, CA, USA.
authors.forename: Pearl
authors.initials: P
authors.lastname: Quijada
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Toko
authors.forename: Kimberlee M
authors.initials: KM
authors.lastname: Fischer
authors.forename: Brandi
authors.initials: B
authors.lastname: Bailey
authors.forename: Patrick
authors.initials: P
authors.lastname: Reilly
authors.forename: Kristin D
authors.initials: KD
authors.lastname: Hunt
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Gude
authors.forename: Daniele
authors.initials: D
authors.lastname: Avitabile
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function; D012038:Regeneration; D015398:Signal Transduction; D013997:Time Factors; D023822:Tissue Engineering / Q000379:methods; D014161:Transduction, Genetic; D014463:Ultrasonography; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D016207:Cytokines; D049452:Green Fluorescent Proteins; D019009:Proto-Oncogene Proteins c-kit; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1