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). CONCLUSION: 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.