Continuous engraftment and differentiation of male recipient Y-chromosome-positive cardiomyocytes in donor female human heart transplants.
BACKGROUND
The mechanisms of stem cell engraftment and differentiation in transplanted organs are still unknown. The aim of our study was to assess the time course of extracardiac progenitor cell colonization of cardiac allografts using the human sex-mismatched heart transplant model. The possible mechanisms by which stem cells acquire a cardiac phenotypic lineage were also investigated.


METHODS
Thirty-four endomyocardial biopsies were obtained from 17 sex-mismatched orthotopic heart transplant patients (mean age, 43.50 +/- 23.95 years). Cells of recipient origin were identified by fluorescence in situ hybridization for combined XY-chromosomes.


RESULTS
The mean incremental number of cardiomyocytes of recipient origin per month was 0.064 +/- 0.04, suggesting ongoing engraftment and transdifferentiation in the absence of cell fusion. Regression analysis showed a positive correlation between the Y-chromosome-positive cardiomyocytes and the rejection score (r(2) = 0.99; 95% confidence interval -0.14 + 0.02; p = 0.006) suggesting that colonization was more pronounced in cases of more severe cardiac injury. At multivariable analysis, time since transplantation was the only independent predictor of the proportion of XY-chromosome-positive cardiac cell engraftment (beta = 0.025, p < 0.0001, 95% confidence interval, 0.012-0.038).


CONCLUSIONS
The phenotypic transformation in this human chronic heart injury model is the result of transdifferentiation of male stem cells (atrial or circulating cells) into new cardiomyocytes. Immunologic injury predicts recipient cardiomyocyte engraftment and may be one of the mobilizing stimuli.
Angelini
Annalisa
A
Medical-Diagnostic Sciences and Special Therapies, University of Padua Medical School, Padua, Italy. annalisa.angelini@unipd.it
Castellani
Chiara
C
Tona
Francesco
F
Gambino
Antonio
A
Caforio
Alida P
AP
Feltrin
Giuseppe
G
Della Barbera
Mila
M
Valente
Marialuisa
M
Gerosa
Gino
G
Thiene
Gaetano
G
D000328:Adult; D000368:Aged; D001706:Biopsy; D002454:Cell Differentiation / Q000502:physiology*; D041322:Chromosomes, Human, Y; D005260:Female; D006085:Graft Survival / Q000502:physiology*; D016027:Heart Transplantation / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015999:Multivariate Analysis; D009206:Myocardium / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D010641:Phenotype; D012044:Regression Analysis; D012727:Sex Characteristics; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000502:physiology*; D013997:Time Factors