title: Mesenchymal stromal cells improve cardiac function and left ventricular remodeling in a heart transplantation model.
abstract: BACKGROUND
  Ischemia/reperfusion (I/R) injury is an inevitable consequence of organ transplantation and a major determinant of patient and graft survival in heart transplantation. Bone marrow-mesenchymal stromal cell (BM-MSC) treatment is a potentially effective cell therapy for cardiac disease. We investigated the effects of intravenous delivery of BM-MSCs in the acute phase post-transplant in a heterotopic heart transplantation (HHT) model associated with I/R injury.
  
  
  METHODS
  Hearts of wild-type Lewis (WT LEW) rats were harvested and transplanted heterotopically into the necks of recipient WT LEW rats. Forty-eight hours after HHT, BM-MSCs were injected intravenously into animals in the experimental group, whereas controls received normal saline (NS).
  
  
  RESULTS
  Eight days after BM-MSC injection, fractional shortening of transplanted hearts was significantly higher and left ventricular systolic diameter was lower in the BM-MSC group compared with controls, whereas no differences were found 28 days after infusion. A reduction in ventricular remodeling and cardiac fibrosis was observed by histochemical analysis and confirmed by cardiac magnetic resonance imaging in the BM-MSC group. The perivascular stromal cells' density and the number of capillaries were increased whereas the number of apoptotic cells decreased significantly in transplanted hearts in the BM-MSC group compared with the NS group.
  
  
  CONCLUSIONS
  We showed early improvement in cardiac function and subsequent enhanced ventricular remodeling, reduced cardiac fibrosis, augmented neo-vascularization and decreased cardiomyocyte apoptosis of the transplanted heart in a heterotopic transplantation model after intravenous infusion of BM-derived MSCs. Our data suggest that clinical studies with BM-MSCs are warranted to understand their effects on cardiac graft and transplant recipient survival.
authors.affiliation: Cell Therapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. Electronic address: montanari.sonia@gmail.com.
authors.forename: Sonia
authors.initials: S
authors.lastname: Montanari
authors.affiliation: Cell Therapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto.
authors.forename: Victor
authors.initials: V
authors.lastname: Dayan
authors.affiliation: Cell Therapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Yannarelli
authors.affiliation: Division of Cardiology, Peter Munk Cardiac Center, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Filio
authors.initials: F
authors.lastname: Billia
authors.affiliation: Cell Therapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto.
authors.forename: Sowmya
authors.initials: S
authors.lastname: Viswanathan
authors.affiliation: Division of Cardiology, Department of Medicine, Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Connelly
authors.affiliation: Cell Therapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Armand
authors.initials: A
authors.lastname: Keating
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D016027:Heart Transplantation; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D019028:Magnetic Resonance Imaging, Cine; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D015428:Myocardial Reperfusion Injury / Q000175:diagnosis / Q000503:physiopathology / Q000628:therapy*; D051381:Rats; D011917:Rats, Inbred Lew; D014463:Ultrasonography; D016277:Ventricular Function, Left / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*
keywords: apoptosis; heterotopic heart transplantation; immunomodulation; ischemia reperfusion injury; mesenchymal stromal cells; neovascularization; ventricular remodeling