Extracardiac Progenitor Cells Repopulate Most Major Cell Types in the Transplanted Human Heart

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Abstract
Background— Extracardiac progenitor cells are capable of repopulating cardiomyocytes at very low levels in the human heart after injury. Here, we explored the extent of endothelial, smooth muscle, and Schwann cell chimerism in patients with sex-mismatched (female-to-male) heart transplants. Methods and Results— Autopsy specimens from 5 patients and endomyocardial biopsies from 7 patients were used for this study. Endothelial, vascular smooth muscle, and Schwann cells were stained with antibodies against CD31 or Ulex europaeus lectin, smooth muscle α-actin, and S-100, respectively, and the Y chromosome was identified with in situ hybridization. Biopsy specimens from 1, 4, 6, and 12 months and 5 and 10 years after heart transplantation were evaluated. Y-positive cells were counted by conventional bright-field microscopy and confirmed by confocal microscopy. Endothelial cells showed the highest degree of chimerism, averaging 24.3±8.2% from extracardiac sources. Schwann cells showed the next highest chimerism, averaging 11.2±2.1%; vascular smooth muscle cells averaged 3.4±1.8%. All 3 cell types showed substantially higher chimerism than we previously observed for cardiomyocytes (0.04±0.05%). Endothelial chimerism was much higher in the microcirculation than in larger vessels. Analysis of serial endomyocardial biopsies revealed that high levels of endothelial chimerism occurred as early as 1 month after transplantation (22±6.6%) with no significant increases even up to 10 years after cardiac transplantation. Conclusions— Extracardiac progenitor cells are capable of repopulating most major cell types in the heart, but they do so with varying frequency. The signals for endothelial progenitor recruitment occur early and could relate to injury during allograft harvest or transplantation. The high degree of endothelial chimerism may have immune implications such as for myocardial rejection or graft vasculopathy.