title: Repeated transplantation of allogeneic cardiosphere-derived cells boosts therapeutic benefits without immune sensitization in a rat model of myocardial infarction.
abstract: A single dose of allogeneic cardiosphere-derived cells (CDCs) improves cardiac function and reduces scarring, and increases viable myocardium in the infarcted rat and pig heart without eliciting a detrimental immune response. Clinical trials using single doses of allogeneic human CDCs are underway. It is unknown whether repeat dosing confers additional benefit or if it elicits an immune response.
  
  
  
  Wistar-Kyoto rats underwent coronary artery ligation and intramyocardial injection of CDCs, with a second thoracotomy and repeat CDC injection 3 weeks later. Treatment permutations included 2 doses of allogeneic Brown-Norway CDCs (n = 24), syngeneic Wistar-Kyoto CDCs (n = 24), xenogeneic human CDCs (n = 24) or saline (n = 8). Cardiac function was assessed by transthoracic echocardiography, infarct size and inflammatory infiltration by histology, and cellular and humoral immune responses by lymphocyte proliferation and alloantibody assays.
  
  
  
  Repeat dosing of allogeneic and syngeneic CDCs improved ejection fraction by 5.2% (95% CI 2.1 to 8.3) and 6.8% (95% CI 3.8 to 9.8) after the first dose, and by 3.4% (95% CI 0.1% to 6.8%) and 6.4% (95% CI 4.2% to 8.6%) after the second dose. Infarct size was equally reduced with repeat dosing of syngeneic and allogeneic CDCs relative to xenogeneic and control treatments (p < 0.0001). Significant rejection-like infiltrates were present only in the xenogeneic group; likewise, lymphocyte proliferation and antibody assays were positive in the xenogeneic and negative in syngeneic and allogeneic groups.
  
  
  
  Repeat dosing of allogeneic CDCs in immunocompetent rats is safe and effective, consistent with the known immunomodulatory and anti-inflammatory properties of CDCs. These findings motivate clinical testing of repeatedly dosed CDCs for chronic heart disease.
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, USA; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Reich
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, USA.
authors.forename: Eleni
authors.initials: E
authors.lastname: Tseliou
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: de Couto
authors.affiliation: Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Angert
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, USA.
authors.forename: Jackelyn
authors.initials: J
authors.lastname: Valle
authors.affiliation: Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Yuzu
authors.initials: Y
authors.lastname: Kubota
authors.affiliation: Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Luthringer
authors.affiliation: Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: James
authors.initials: J
authors.lastname: Mirocha
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, USA.
authors.forename: Baiming
authors.initials: B
authors.lastname: Sun
authors.affiliation: Capricor, Therapeutics, Inc., Beverly Hills, California, USA.
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Smith
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, USA; Capricor, Therapeutics, Inc., Beverly Hills, California, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Marbán
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California, USA. Electronic address: eduardo.marban@csmc.edu.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
mesh_terms: D000818:Animals; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000175:diagnosis / Q000276:immunology / Q000517:prevention & control*; D007114:Immunization / Q000379:methods*; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000637:transplantation*; D051381:Rats; D011914:Rats, Inbred BN; D011921:Rats, Inbred WKY; D044968:Regenerative Medicine / Q000379:methods; D033581:Stem Cell Transplantation / Q000379:methods*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D016277:Ventricular Function, Left / Q000502:physiology; D020257:Ventricular Remodeling
keywords: cardiosphere-derived cells; cell therapy; regenerative medicine; regneration; stem cells