title: Human umbilical cord blood-derived mononuclear cells improve murine ventricular function upon intramyocardial delivery in right ventricular chronic pressure overload.
abstract: BACKGROUND
  Stem cell therapy has emerged as potential therapeutic strategy for damaged heart muscles. Umbilical cord blood (UCB) cells are the most prevalent stem cell source available, yet have not been fully tested in cardiac regeneration. Herein, studies were performed to evaluate the cardiovascular safety and beneficial effect of mononuclear cells (MNCs) isolated from human umbilical cord blood upon intramyocardial delivery in a murine model of right ventricle (RV) heart failure due to pressure overload.
  
  
  METHODS
  UCB-derived MNCs were delivered into the myocardium of a diseased RV cardiac model. Pulmonary artery banding (PAB) was used to produce pressure overload in athymic nude mice that were then injected intramyocardially with UCB-MNCs (0.4×10^6 cells/heart). Cardiac functions were then monitored by telemetry, echocardiography, magnetic resonance imaging (MRI) and pathologic analysis of heart samples to determine the ability for cell-based repair.
  
  
  RESULTS
  The cardio-toxicity studies provided evidence that UCB cell transplantation has a safe therapeutic window between 0.4 to 0.8 million cells/heart without altering QT or ST-segments or the morphology of electrocardiograph waves. The PAB cohort demonstrated significant changes in RV chamber dilation and functional defects consistent with severe pressure overload. Using cardiac MRI analysis, UCB-MNC transplantation in the setting of PAB demonstrated an improvement in RV structure and function in this surgical mouse model. The RV volume load in PAB-only mice was 24.09±3.9 compared to 11.05±2.09 in the cell group (mm3, P-value<0.005). The analysis of pathogenic gene expression (BNP, ANP, Acta1, Myh7) in the cell-transplanted group showed a significant reversal with respect to the diseased PAB mice with a robust increase in cardiac progenitor gene expression such as GATA4, Kdr, Mef2c and Nkx2.5. Histological analysis indicated significant fibrosis in the RV in response to PAB that was reduced following UCB-MNC's transplantation along with concomitant increased Ki-67 expression and CD31 positive vessels as a marker of angiogenesis within the myocardium.
  
  
  CONCLUSIONS
  These findings indicate that human UCB-derived MNCs promote an adaptive regenerative response in the right ventricle upon intramyocardial transplantation in the setting of chronic pressure overload heart failure.
authors.affiliation: General Internal Medicine and Transplant Center, Mayo Clinic, Rochester, MN, USA. oommen.saji@mayo.edu.|Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA. oommen.saji@mayo.edu.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. oommen.saji@mayo.edu.
authors.forename: Saji
authors.initials: S
authors.lastname: Oommen
authors.affiliation: Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA. yamada.satsuki@mayo.edu.|Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA. yamada.satsuki@mayo.edu.
authors.forename: Satsuki
authors.initials: S
authors.lastname: Yamada
authors.affiliation: General Internal Medicine and Transplant Center, Mayo Clinic, Rochester, MN, USA. canteroPeral.susana@mayo.edu.|Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA. canteroPeral.susana@mayo.edu.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. canteroPeral.susana@mayo.edu.|Autonomous University of Barcelona, Program of Doctorate of Internal Medicine, Barcelona, Spain. canteroPeral.susana@mayo.edu.
authors.forename: Susana
authors.initials: S
authors.lastname: Cantero Peral
authors.affiliation: Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA. campbell.katherine@mayo.edu.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. campbell.katherine@mayo.edu.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Campbell
authors.affiliation: General Internal Medicine and Transplant Center, Mayo Clinic, Rochester, MN, USA. bruinsma.elizabeth@mayo.edu.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Bruinsma
authors.affiliation: Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA. terzic.andre@mayo.edu.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. terzic.andre@mayo.edu.|Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA. terzic.andre@mayo.edu.|Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA. terzic.andre@mayo.edu.
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
authors.affiliation: General Internal Medicine and Transplant Center, Mayo Clinic, Rochester, MN, USA. nelson.timothy@mayo.edu.|Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA. nelson.timothy@mayo.edu.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. nelson.timothy@mayo.edu.|Department of Medicine, Mayo Clinic, 200 First Street, SW, Rochester, MN, 55905, USA. nelson.timothy@mayo.edu.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Nelson
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D005312:Fetal Blood / Q000166:cytology*; D048091:Guided Tissue Regeneration / Q000379:methods; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008819:Mice, Nude; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology; D018497:Ventricular Dysfunction, Right / Q000628:therapy*; D016278:Ventricular Function, Right / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology