Elektrophysiologische Eigenschaften von Stammzellen

Zusammenfassung

Die Implantation von Stammzellen zur Regeneration von Herzmuskelgewebe nach Myokardinfarkt stellt ein neues Therapieverfahren zur Verbesserung der Ventrikelfunktion dar. Als Mechanismen werden Transdifferenzierung von Stammzellen in Kardiomyozyten, Neubildung von Gefäßen und Effekte parakriner Faktoren diskutiert. In vielen Organen sind Stammzellen gefunden worden, die u. a. auch in kardiogene Richtung differenzieren können.

Die elektrophysiologischen Eigenschaften von spontan kontrahierenden Myozyten, die sich aus embryonalen Stammzellen oder aus Stammzellen der Skelettmuskulatur („skeletal precursors of cardiomyocytes“ [SPOCs]) entwickeln, ähneln denen von Herzmuskelzellen. Undifferenzierte mesenchymale Stammzellen sind elektrisch nicht erregbar, obwohl sie einige kardiale Ionenkanäle exprimieren, die auch funktionell nachweisbar sind. Bei Kokultur mit neonatalen Kardiomyozyten bilden alle untersuchten Stammzellen untereinander elektrisch leitende Gap Junctions aus, mit einer Ausnahme, den aus Satellitenzellen abgeleiteten Myoblasten. Dementsprechend ist die Erregungsausbreitung in Kokulturen von Myoblasten und Herzmuskelzellen gestört, es können kreisende Erregungen auftreten. Möglicherweise erklärt dieser Pathomechanismus die erhöhte Arrhythmieanfälligkeit von Myokardinfarktpatienten nach Implantation von Myoblasten.

Abstract

New concepts for treatment of myocardial infarction include the implantation of adult stem cells for regeneration of damaged muscle tissue. Several clinical trials have demonstrated a small, but significant improvement of ventricular function. Transdifferentiation of stem cells into cardiomyocytes, formation of new vessels and paracrine factors have been discussed as putative mechanisms for the therapeutic effect. Several types of stem cells have been used clinically including myoblasts derived from skeletal muscle satellite cells, bone marrow-derived stem cells or blood-derived mononuclear progenitor cells. In addition, multiple organs were shown to contain a small number of stem cells that could differentiate into cardiomyocytes.

Embryonic stem cells differentiate into spontaneously beating cells that have varying electrophysiological properties. Their action potentials resemble those of cardiac pacemaker cell, atrial or ventricular myocytes (Figure 1) suggesting true differentiation into cardiomyocytes. Beating cells derived from a newly described population of skeletal muscle-derived cells (“skeletal precursors of cardiomyocytes” [SPOCs]) also exhibit spontaneous action potentials, however, unlike cardiac pacemaker cells, their electrical activity is suppressed with the sodium channel blocker tetrodotoxin (Figure 2). Undifferentiated bone marrow-derived mesenchymal stem cells are not electrically excitable. Nevertheless, they express functional ion channels like L-type Ca²⁺ channels, albeit not in every cell. Co-culturing stem cells with neonatal rat ventricular myocytes induces good electrical contacts between cells via gap junction formation. Excitatory wave fronts spread evenly in the co-culture. By contrast, gap junctions fail to form when myoblasts are co-cultured with neonatal cardiomyocytes and reentry arrhythmias develop. This pathomechanism could serve as an explanation for the enhanced clinical risk of arrhythmia after transplantation of myoblasts into the infarcted hearts.