title: Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction.
abstract: BACKGROUND
  Because mesenchymal stem cells (MSCs) induce proliferation and differentiation of c-kit(+) cardiac stem cells (CSCs) in vivo and in vitro, we hypothesized that combining human (h) MSCs with c-kit(+) hCSCs produces greater infarct size reduction compared with either cell administered alone after myocardial infarction (MI).
  
  
  RESULTS
  Yorkshire swine underwent balloon occlusion of the left anterior descending coronary artery followed by reperfusion and were immunosuppressed after MI with cyclosporine and methylprednisolone. Intramyocardial combination hCSCs/hMSCs (1 million cells/200 million cells, n=5), hCSCs alone (1 million cells, n=5), hMSCs alone (200 million cells, n=5), or placebo (phosphate-buffered saline; n=5) was injected into the infarct border zones at 14 days after MI. Phenotypic response to cell therapy was assessed by cardiac magnetic resonance imaging and micromanometer conductance catheterization hemodynamics. Although each cell therapy group had reduced MI size relative to placebo (P<0.05), the MI size reduction was 2-fold greater in combination versus either cell therapy alone (P<0.05). Accompanying enhanced MI size reduction were substantial improvement in left ventricular chamber compliance (end-diastolic pressure-volume relationship; P<0.01) and contractility (preload recruitable stroke work and dP/dtmax; P<0.05) in combination-treated swine. Ejection fraction was restored to baseline in cell-treated pigs, whereas placebo pigs had persistently depressed left ventricular function (P<0.05). Immunohistochemistry showed 7-fold enhanced engraftment of stem cells in the combination therapy group versus either cell type alone (P<0.001).
  
  
  CONCLUSIONS
  Combining hMSCs and hCSCs as a cell therapeutic enhances scar size reduction and restores diastolic and systolic function toward normal after MI. Taken together, these findings illustrate important biological interactions between c-kit(+) CSCs and MSCs that enhance cell-based therapeutic responses.
authors.affiliation: Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Williams
authors.forename: Konstantinos E
authors.initials: KE
authors.lastname: Hatzistergos
authors.forename: Benjamin
authors.initials: B
authors.lastname: Addicott
authors.forename: Fred
authors.initials: F
authors.lastname: McCall
authors.forename: Decio
authors.initials: D
authors.lastname: Carvalho
authors.forename: Viky
authors.initials: V
authors.lastname: Suncion
authors.forename: Azorides R
authors.initials: AR
authors.lastname: Morales
authors.forename: Jose
authors.initials: J
authors.lastname: Da Silva
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
authors.forename: Alan W
authors.initials: AW
authors.lastname: Heldman
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D003971:Diastole / Q000502:physiology; D004195:Disease Models, Animal; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology; D034421:Sus scrofa; D013599:Systole / Q000502:physiology; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D016277:Ventricular Function, Left / Q000502:physiology
chemical_list: D019009:Proto-Oncogene Proteins c-kit