Restoration of Function Following in Utero Fetal MI Is Associated with Increased Cardiac Progenitor Cell Recruitment

Abstract

Background: We have previously shown that following myocardial infarction (MI), the fetal heart has the capability to heal by regeneration with restoration of normal tissue architecture and left ventricular (LV) function. Early in the fetal healing response, there are proliferating cells that surround the infarct; however, it is unknown whether cardiac progenitor cells play a significant role in fetal regenerative cardiac healing. We hypothesized that following fetal MI; there would be migration of nkx 2.5+ cardiac progenitor cells to the area of infarction. Methods: Fetal anteroapical MI encompassing approximately 20% of the LV mass was created in early gestation fetal sheep. The fetal heart was harvested at 3 days following MI. Immunohistochemistry utilizing confocal microscopy was used to identify the presence of nkx 2.5+ cells in the infarct, the border zone, and the uninfarcted myocardium. Age matched uninfarcted fetal sheep heart was the control. Results: Three days following fetal MI, the presence of nkx 2.5+ cells was preferentially increased at the endocardial, the epicardial, and perivascular borders within the anteroapical infarct. Nkx 2.5+ cells were also seen in the border zone and the uninfarcted myocardium; however, the numbers decreased significantly away from the infarct. Nkx 2.5+ cells were identified in control hearts; however, there was no evidence of increased numbers in the apex or clustering around blood vessels within the fetal myocardium. Conclusions: Following fetal MI, nkx 2.5+ cells preferentially migrate to the area of infarction, suggesting that active recruitment of cardiac progenitor cells is partially responsible for the regenerative capacity of the fetal heart following MI. In addition, the increased numbers of nkx 2.5+ cells surrounding blood vessels suggests that some of these cardiac progenitor cells are recruited from the peripheral circulation. Understanding the mechanisms driving recruitment of cardiac progenitor cells to the fetal infarct may help us alter the post-natal response to MI.