Engraftment of connexin 43-expressing cells prevents post-infarct arrhythmia

Abstract

Ventricular tachyarrhythmias are the main cause of sudden death in patients after myocardial infarction. Here we show that transplantation of embryonic cardiomyocytes (eCMs) in myocardial infarcts protects against the induction of ventricular tachycardia (VT) in mice. Engraftment of eCMs, but not skeletal myoblasts (SMs), bone marrow cells or cardiac myofibroblasts, markedly decreased the incidence of VT induced by in vivo pacing. eCM engraftment results in improved electrical coupling between the surrounding myocardium and the infarct region, and Ca2+ signals from engrafted eCMs expressing a genetically encoded Ca2+ indicator could be entrained during sinoatrial cardiac activation in vivo. eCM grafts also increased conduction velocity and decreased the incidence of conduction block within the infarct. VT protection is critically dependent on expression of the gap-junction protein connexin 43 (Cx43; also known as Gja1): SMs genetically engineered to express Cx43 conferred a similar protection to that of eCMs against induced VT. Thus, engraftment of Cx43-expressing myocytes has the potential to reduce life-threatening post-infarct arrhythmias through the augmentation of intercellular coupling, suggesting autologous strategies for cardiac cell-based therapy.

Cardiomyocytes from phorbol myristate acetate-activated mesenchymal stem cells restore electromechanical function in infarcted rat hearts

“…We showed that the transplantation of a unique cell type from MSCs exhibiting cardiogenic properties into the infarcted heart could help avoid problems caused by heterogeneity between the implanted cells and the myocardium, leading to further improvements in contractile function and electrical safety. Moreover, our result that Cx43 expression was markedly increased in the ccMSCs is supported by the result that Cx43-expressing cells prevent postinfarct arrhythmia (19). It is also reported that NE influences the contractile properties of the heart and induces a series of changes characteristic of the hypertrophic phenotype through α-adrenergic receptors in cardiomyocytes (14).…”

“…We investigated the expression pattern of Cx43 in MSC-or ccMSC-engrafted regions because the incidence of VT is critically protected by the expression of Cx43 (19). We observed that Cx43 was expressed in a punctate fashion predominantly throughout the plasma membrane in the MSC-engrafted region, whereas Cx43 was detected mainly as plaques in the ccMSC-engrafted region, which indicated that the engrafted ccMSCs were well coupled with host cardiomyocytes through Cx43 (Fig.…”

Prospective isolation of human embryonic stem cell-derived cardiovascular progenitors that integrate into human fetal heart tissue

“…Human fetal heart tissues with QP transplantation were removed from the mouse ear and immediately sectioned, and real-time Ca 2+ transients were measured in areas with QP-derived GFP-positive cells. GFP-positive cells demonstrated periodic Ca 2+ oscillations similar to-and synchronized with-the host cells (24). The Ca 2+ oscillations responded to increasing frequencies of external electrical stimulation.…”

c-kit expression identifies cardiovascular precursors in the neonatal heart

“…To analyze c-kit expression following myocardial injury, we induced cryolesions in the left ventricle of adult c-kit BAC -EGFP mice (19). Seven days after cryolesion there was marked expression of fluorescent cells in the infarct and the border zone, with fluorescent cells often associated with vessels within the infarcts, and modestly fluorescent striated cardiomyocytes surrounding the border zone (Fig.…”