Stem Cells and Myocardial Repair

Abstract

Myocardial ischemia sends a warning signal to subtended cardiomyocytes that can both promote protection by preconditioning and result in contractile dysfunction or stunning. If the ischemic period is brief ( 20 minutes), cardiomyocytes survive, contractile function recovers, and the myocardium becomes relatively resistant to subsequent ischemic insult. With prolonged periods of ischemia, cardiomyocyte death occurs by either apoptosis or necrosis, resulting in myocardial infarction. For 75 years, infarcted myocardium has been perceived as irreparable. Surgeons have focused therapeutic attention at the potentially salvageable (but narrow) periinfarction rim, where cardiac cells become hypertrophic to compensate for the functional loss within a zone of infarction. Hyperdynamic cells at the infarct border zone are further challenged by regional deficiency in oxygen-substrate delivery, resulting in cardiac remodeling (pathologic ventricular dilatation). Consequent expansion of the infarct area is caused by enhanced myocyte apoptosis, tissue fibrosis, and heart failure. Traditional dogma suggests that hypoxia controls this entire sequence. The standard surgical approach to cardiac ischemic injury is to acknowledge the loss of the infarcted muscle and to revascularize the rest of the heart in the hope of averting further damage. Compelling evidence has now been presented that all myocardial cells might not be terminally differentiated. A subset of cardiac cells might be able to replicate and form new blood vessels, permitting repopulation of portions of the infarct zone. IS THERE A SELF-RENEWING SOURCE OF CARDIOMYOCYTES? During embryogenesis, the heart grows through cellular division of cardiomyocytes. At birth, cardiomyocytes enter a postmitotic state (Go), and further heart growth occurs by hypertrophy of existing cardiomyocytes. This developmental schema works well during conditions of normoxia, but during ischemia, the myocardium is limited in its capacity to regenerate injured areas by cellular replication. Indeed, the heart attempts to compensate for cardiomyocyte loss after myocardial infarction by further hypertrophy of viable cells, but this maladaptive response frequently results in pathologic ventricular remodeling. Compared with other species, human myocardium has a disproportionately high number of nuclei with increased ploidy. Over 50% of human cardiomyocytes are tetraploid (having two complete sets of chromosomes), so it appears that cellular division in cardiomyocytes is programmed to cease after DNA replication has already occurred. The cellular signals that halt cellular division of postnatal cardiomyocytes are poorly understood. Because fetal cardiomyocytes are capable of replication, attempts have been made to use them as a potential source of cells to repair infarcted myocardium. Several challenges must be overcome for this exciting new therapy to be realized. Implanted cells must be able to survive in the hostile, inflammatory environment of the infarct, and then, to increase myocardial function, they must differentiate into phenotypically mature cells that form intercalated discs and gap junctions with the host myocardium. Recent evidence suggests that limitation of infarct progression can occur after fetal cell transplant even in the absence of ultrastructural connection with the host myocardium. In rodents, fetal and neonatal cardiac cells injected into infarcted myocardium survive within host myocardium and incorporate through intercalated discs and gap junctions. Transplantation of fetal cardiomyocytes into myocardial infarcts of rats improves heart function. On the other hand, Etzion and colleagues No competing interests declared.