title: Cardiac fibrosis in human transplanted hearts is mainly driven by cells of intracardiac origin.
abstract: OBJECTIVE
  The aim of our study was to determine the origin of collagen in the progression of myocardial fibrosis in human adult transplanted hearts.
  
  
  BACKGROUND
  Changes in the cardiac interstitial collagen network are thought to contribute to abnormal stiffness and function of the myocardium. The origin of fibrosis-mediating fibroblasts remains incompletely understood, and conflicting data from animal models suggest that they are either derived intracardially or immigrate from extracardiac sources.
  
  
  METHODS
  We studied endomyocardial biopsy specimens from 7 sex-mismatched (female donor heart to a male recipient) heart transplant recipients by a combination of chromogen in situ hybridization using probes specific for Y chromosomes with immunohistochemistry. On the basis of differences in genetic polymorphisms in the type III collagen gene between donor and recipient tissue, we quantitatively determined origin-specific type III collagen gene expression in fibrotic areas containing fibroblasts of putative extracardiac origin.
  
  
  RESULTS
  In areas of increased cardiac fibrosis years after heart transplantation, a substantial number of Y chromosome-positive spindle-shaped cells with a fibroblast-like appearance were detected. Many of these cells were identified as macrophages, and measurement of origin-specific type III collagen synthesis identified cells of intracardiac origin as the main source for collagen turnover in human cardiac fibrosis.
  
  
  CONCLUSIONS
  Our data suggest that, in human myocardium, cardiac fibrosis due to chronic allograft rejection up to 15 years after transplantation or scar formation provoked by mechanical trauma is mainly driven by fibroblasts of intracardiac origin. Antifibrotic treatment strategies, therefore, should target molecular mechanisms that induce fibrillogenesis of cells with intracardiac origin.
authors.affiliation: Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, Graz, Austria. martin.pichler@medunigraz.at
authors.forename: Martin
authors.initials: M
authors.lastname: Pichler
authors.forename: Peter P
authors.initials: PP
authors.lastname: Rainer
authors.forename: Silvia
authors.initials: S
authors.lastname: Schauer
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D024061:Collagen Type III / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis; D006084:Graft Rejection / Q000473:pathology*; D006335:Heart Injuries / Q000473:pathology; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology*
chemical_list: C439971:COL3A1 protein, human; D024061:Collagen Type III