title: Age-Dependent Effect of Pediatric Cardiac Progenitor Cells After Juvenile Heart Failure.
abstract: Children with congenital heart diseases have increased morbidity and mortality, despite various surgical treatments, therefore warranting better treatment strategies. Here we investigate the role of age of human pediatric cardiac progenitor cells (hCPCs) on ventricular remodeling in a model of juvenile heart failure. hCPCs isolated from children undergoing reconstructive surgeries were divided into 3 groups based on age: neonate (1 day to 1 month), infant (1 month to 1 year), and child (1 to 5 years). Adolescent athymic rats were subjected to sham or pulmonary artery banding surgery to generate a model of right ventricular (RV) heart failure. Two weeks after surgery, hCPCs were injected in RV musculature noninvasively. Analysis of cardiac function 4 weeks post-transplantation demonstrated significantly increased tricuspid annular plane systolic excursion and RV ejection fraction and significantly decreased wall thickness and fibrosis in rats transplanted with neonatal hCPCs compared with saline-injected rats. Computational modeling and systems biology analysis were performed on arrays and gave insights into potential mechanisms at the microRNA and gene level. Mechanisms including migration and proliferation assays, as suggested by computational modeling, showed improved chemotactic and proliferative capacity of neonatal hCPCs compared with infant/child hCPCs. In vivo immunostaining further suggested increased recruitment of stem cell antigen 1-positive cells in the right ventricle. This is the first study to assess the role of hCPC age in juvenile RV heart failure. Interestingly, the reparative potential of hCPCs is age-dependent, with neonatal hCPCs exerting the maximum beneficial effect compared with infant and child hCPCs.
  
  
  CONCLUSIONS
  Stem cell therapy for children with congenital heart defects is moving forward, with several completed and ongoing clinical trials. Although there are studies showing how children differ from adults, few focus on the differences among children. This study using human cardiac progenitor cells shows age-related changes in the reparative ability of cells in a model of pediatric heart failure and uses computational and systems biology to elucidate potential mechanisms.
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia, USA Division of Cardiology, School of Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: Udit
authors.initials: U
authors.lastname: Agarwal
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia, USA Division of Cardiology, School of Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: Amanda W
authors.initials: AW
authors.lastname: Smith
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia, USA Division of Cardiology, School of Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: French
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia, USA Division of Cardiology, School of Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: Archana V
authors.initials: AV
authors.lastname: Boopathy
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: George
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia, USA.
authors.forename: David
authors.initials: D
authors.lastname: Trac
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia, USA Division of Cardiology, School of Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: Milton E
authors.initials: ME
authors.lastname: Brown
authors.affiliation: Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Shen
authors.affiliation: Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Department of Cardiothoracic Surgery, School of Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: Janet D
authors.initials: JD
authors.lastname: Fernandez
authors.affiliation: Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Kogon
authors.affiliation: Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Kanter
authors.affiliation: Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
authors.forename: Baahaldin
authors.initials: B
authors.lastname: Alsoufi
authors.affiliation: Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: Mary B
authors.initials: MB
authors.lastname: Wagner
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia, USA.
authors.forename: Manu O
authors.initials: MO
authors.lastname: Platt
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia, USA Division of Cardiology, School of Medicine, Emory University, Atlanta, Georgia, USA michael.davis@bme.emory.edu.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Davis
mesh_terms: D000328:Adult; D000375:Aging / Q000502:physiology*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002675:Child, Preschool; D006330:Heart Defects, Congenital / Q000473:pathology / Q000628:therapy*; D006333:Heart Failure / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009206:Myocardium / Q000166:cytology*; D051381:Rats; D011923:Rats, Nude; D055647:Rats, Transgenic; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D020257:Ventricular Remodeling
keywords: Cell transplantation; Computational biology; Heart failure; Pediatrics; Progenitor cell