Abstract
Stem cell transplantation holds great promise for the treatment of myocardial infarction injury. We recently described the embryonic stem cell-derived cardiac progenitor cells (CPCs) capable of differentiating into cardiomyocytes, vascular endothelium, and smooth muscle. In this study, we hypothesized that transplanted CPCs will preserve function of the infarcted heart by participating in both muscle replacement and neovascularization. Differentiated CPCs formed functional electromechanical junctions with cardiomyocytes in vitro and conducted action potentials over cm-scale distances. When transplanted into infarcted mouse hearts, CPCs engrafted long-term in the infarct zone and surrounding myocardium without causing teratomas or arrhythmias. The grafted cells differentiated into cross-striated cardiomyocytes forming gap junctions with the host cells, while also contributing to neovascularization. Serial echocardiography and pressure-volume catheterization demonstrated attenuated ventricular dilatation and preserved left ventricular fractional shortening, systolic and diastolic function. Our results demonstrate that CPCs can engraft, differentiate, and preserve the functional output of the infarcted heart.
Highlights
Cardiomyocyte loss as a result of myocardial infarction (MI) injury is considered irreversible with the heart lacking sufficient capacity for self-regeneration
Mouse embryonic stem cells (ESCs) were induced to differentiate in suspension forming aggregates termed embryoid bodies (EBs) and initial detection of green fluorescent protein (GFP) coincided with initiation of Nkx2-5 expression on differentiation day 5 (Figs. 1a, b)
The main aim of this study was the determination of the therapeutic capacity of the recently described ESC-derived cardiac progenitor cells [14] to treat myocardial infarction injury
Summary
Cardiomyocyte loss as a result of myocardial infarction (MI) injury is considered irreversible with the heart lacking sufficient capacity for self-regeneration. Cell-based cardiac therapies are proposed as an attractive therapeutic alternative to reverse cardiomyocyte loss, repair the injured myocardium and prevent heart failure. A variety of cell sources, both of adult and embryonic origin, have been investigated for use in heart repair with mixed outcomes [1,2]. The use of adult cells is attractive because of their immunocompatible nature, ease of isolation, restricted differentiation potential, and capacity to proliferate rapidly. Embryonic stem cells (ESCs) are able to differentiate into relatively large numbers of early stage cardiomyocytes that functionally integrate with host heart cells [3,4,5]. While ESC-derived cardiomyocytes have been successfully applied for the treatment of myocardial infarction in animal models [6,7,8,9], their clinical application is currently hampered by their neoplastic and immunogenic potential [10]
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