title: Immunobiology of fibrin-based engineered heart tissue.
abstract: Different tissue-engineering approaches have been developed to induce and promote cardiac regeneration; however, the impact of the immune system and its responses to the various scaffold components of the engineered grafts remains unclear. Fibrin-based engineered heart tissue (EHT) was generated from neonatal Lewis (Lew) rat heart cells and transplanted onto the left ventricular surface of three different rat strains: syngeneic Lew, allogeneic Brown Norway, and immunodeficient Rowett Nude rats. Interferon spot frequency assay results showed similar degrees of systemic immune activation in the syngeneic and allogeneic groups, whereas no systemic immune response was detectable in the immunodeficient group (p < .001 vs. syngeneic and allogeneic). Histological analysis revealed much higher local infiltration of CD3- and CD68-positive cells in syngeneic and allogeneic rats than in immunodeficient animals. Enzyme-linked immunospot and immunofluorescence experiments revealed matrix-directed TH1-based rejection in syngeneic recipients without collateral impairment of heart cell survival. Bioluminescence imaging was used for in vivo longitudinal monitoring of transplanted luciferase-positive EHT constructs. Survival was documented in syngeneic and immunodeficient recipients for a period of up to 110 days after transplant, whereas in the allogeneic setting, graft survival was limited to only 14 ± 1 days. EHT strategies using autologous cells are promising approaches for cardiac repair applications. Although fibrin-based scaffold components elicited an immune response in our studies, syngeneic cells carried in the EHT were relatively unaffected.
  
  
  CONCLUSIONS
  An initial insight into immunological consequences after transplantation of engineered heart tissue was gained through this study. Most important, this study was able to demonstrate cell survival despite rejection of matrix components. Generation of syngeneic human engineered heart tissue, possibly using human induced pluripotent stem cell technology with subsequent directed rejection of matrix components, may be a potential future approach to replace diseased myocardium.
authors.affiliation: University Heart Center Hamburg, Transplant and Stem Cell Immunobiology Laboratory, Hamburg, Germany; Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, and Cardiovascular Research Center and Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Stanford Cardiovascular Institute and Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, California, USA.
authors.forename: Lenard
authors.initials: L
authors.lastname: Conradi
authors.affiliation: University Heart Center Hamburg, Transplant and Stem Cell Immunobiology Laboratory, Hamburg, Germany; Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, and Cardiovascular Research Center and Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Stanford Cardiovascular Institute and Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, California, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: University Heart Center Hamburg, Transplant and Stem Cell Immunobiology Laboratory, Hamburg, Germany; Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, and Cardiovascular Research Center and Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Stanford Cardiovascular Institute and Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, California, USA.
authors.forename: Evgenios
authors.initials: E
authors.lastname: Neofytou
authors.affiliation: University Heart Center Hamburg, Transplant and Stem Cell Immunobiology Laboratory, Hamburg, Germany; Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, and Cardiovascular Research Center and Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Stanford Cardiovascular Institute and Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, California, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Deuse
authors.affiliation: University Heart Center Hamburg, Transplant and Stem Cell Immunobiology Laboratory, Hamburg, Germany; Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, and Cardiovascular Research Center and Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Stanford Cardiovascular Institute and Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, California, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Peters
authors.affiliation: University Heart Center Hamburg, Transplant and Stem Cell Immunobiology Laboratory, Hamburg, Germany; Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, and Cardiovascular Research Center and Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Stanford Cardiovascular Institute and Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, California, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Eder
authors.affiliation: University Heart Center Hamburg, Transplant and Stem Cell Immunobiology Laboratory, Hamburg, Germany; Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, and Cardiovascular Research Center and Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Stanford Cardiovascular Institute and Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, California, USA.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Hua
authors.affiliation: University Heart Center Hamburg, Transplant and Stem Cell Immunobiology Laboratory, Hamburg, Germany; Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, and Cardiovascular Research Center and Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Stanford Cardiovascular Institute and Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, California, USA.
authors.forename: Arne
authors.initials: A
authors.lastname: Hansen
authors.affiliation: University Heart Center Hamburg, Transplant and Stem Cell Immunobiology Laboratory, Hamburg, Germany; Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, and Cardiovascular Research Center and Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Stanford Cardiovascular Institute and Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, California, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robbins
authors.affiliation: University Heart Center Hamburg, Transplant and Stem Cell Immunobiology Laboratory, Hamburg, Germany; Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, and Cardiovascular Research Center and Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Stanford Cardiovascular Institute and Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, California, USA.
authors.forename: Ramin E
authors.initials: RE
authors.lastname: Beygui
authors.affiliation: University Heart Center Hamburg, Transplant and Stem Cell Immunobiology Laboratory, Hamburg, Germany; Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, and Cardiovascular Research Center and Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Stanford Cardiovascular Institute and Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, California, USA.
authors.forename: Hermann
authors.initials: H
authors.lastname: Reichenspurner
authors.affiliation: University Heart Center Hamburg, Transplant and Stem Cell Immunobiology Laboratory, Hamburg, Germany; Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, and Cardiovascular Research Center and Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Stanford Cardiovascular Institute and Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, California, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.affiliation: University Heart Center Hamburg, Transplant and Stem Cell Immunobiology Laboratory, Hamburg, Germany; Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, and Cardiovascular Research Center and Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Stanford Cardiovascular Institute and Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, California, USA schrepfer@stanford.edu.
authors.forename: Sonja
authors.initials: S
authors.lastname: Schrepfer
mesh_terms: D064591:Allografts; D000818:Animals; D005337:Fibrin / Q000737:chemistry* / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival / Q000276:immunology*; D009206:Myocardium / Q000276:immunology*; D051381:Rats; D018417:Th1 Cells / Q000276:immunology*; D023822:Tissue Engineering; D054457:Tissue Scaffolds; D014185:Transplantation, Isogeneic
chemical_list: D005337:Fibrin
keywords: Bioluminescence imaging; Engineered heart tissue; Immune response; Rat; Rejection; Scaffold