Evidence for Cardiomyocyte Repopulation by Extracardiac Progenitors in Transplanted Human Hearts

TLDR

Human myocardium is traditionally viewed as lacking regenerative capacity, yet rodent studies suggest an extracardiac stem cell population, possibly from bone marrow, can generate cardiomyocytes after injury. This study aimed to determine whether similar extracardiac progenitor mechanisms exist in human hearts by analyzing female donor hearts transplanted into male recipients. The authors examined Y chromosome presence in cardiomyocytes of five male patients with long‑term female heart grafts, using post‑mortem tissue to identify host‑derived cells. They found a minute but detectable fraction of Y‑positive cardiomyocytes (mean 0.04%, median 0.016%) that clustered in rejection sites, with one patient showing up to 29% in hot spots, demonstrating that adult humans possess low‑level extracardiac progenitor‑mediated cardiomyocyte repopulation following injury.

Abstract

Human myocardium has long been considered to have essentially no intrinsic regenerative capacity. Recent studies in rodent models, however, have suggested the presence of an extracardiac stem cell population, perhaps in bone marrow, that is capable of some reconstitution of cardiomyocytes after injury. To determine whether similar mechanisms exist in the human heart, we evaluated human female allograft hearts transplanted into male patients. The presence of Y chromosomes in cardiomyocytes would indicate these cells arose from the recipient, rather than the donor heart. We identified 5 male patients who had retained a female heart at least 9 months before death and necropsy. Remarkably, in each case, the transplanted heart contained a minute but readily detectable fraction of Y chromosome-positive cardiomyocytes. The mean percentage of cardiomyocytes arising from the host was estimated to be 0.04% with a median of 0.016%. Most Y-positive cardiomyocytes were associated with regions of acute rejection, suggesting such chimerism involves an injury event. Furthermore, the sole patient whose immediate cause of death was allograft rejection showed a much higher percentage of host-derived cardiomyocytes, up to 29% in local, 1-mm 2 “hot spots.” Thus, adult humans have extracardiac progenitor cells capable of migrating to and repopulating damaged myocardium, but this process occurs at very low levels.