Cardiomyocytes of Noncardiac Origin in Myocardial Biopsies of Human Transplanted Hearts

Abstract

Background — Cell replacement therapy with stem cells able to differentiate into cardiomyocytes has been discussed as a method for remodeling damaged myocardium. A physiological or pathophysiological situation in which this phenomenon might be relevant is not known. We studied the origin of cardiomyocytes in myocardial biopsies of male patients that had undergone sex-mismatched cardiac transplantation to determine whether cells containing a Y chromosome (and therefore being of recipient origin) are able to differentiate into cardiomyocytes. Methods and Results — Myocardial biopsies (n=21) were obtained from the right ventricles of male patients (n=13) who had undergone sex-mismatched heart transplantation. Tissue from 1 nontransplanted male and myocardial biopsies from sex-matched heart–transplanted patients served as controls. Cells from donor and recipient origins were identified by fluorescence in situ hybridization with the use of specific probes for X and Y chromosomes on paraffin sections of the biopsies. Cell types were identified by using immunostaining procedures on the same tissue sections. Cardiomyocytes of recipient origin were detected in 8 of 13 male recipients of female hearts. They were connected by gap junctions with adjacent myocytes. Of the cardiomyocyte nuclei, 0.16±0.04% (mean±SEM, median 0.09%) contained the Y-chromosomal marker. There was no detectable correlation with the extent or number of rejection episodes, time of transplantation, or medical treatment regimen. Conclusions — These results show that regeneration by cells of noncardiac origin (differentiated into cardiomyocytes and physiologically linked to neighboring myocytes) can be detected even in small myocardial biopsies. This may lead to new diagnostic and therapeutic strategies in the treatment of myocardial infarction, inflammatory heart disease, and/or heart failure.