Implantation of Mouse Embryonic Stem Cell-Derived Cardiac Progenitor Cells Preserves Function of Infarcted Murine Hearts

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.

Isolation, Characterization and Differentiation Potential of Cardiac Progenitor Cells in Adult Pigs

“…Indeed, cell fusion experiments further demonstrated PACP ability to differentiate in vitro and to give rise to fusion events, reflecting a distinct property common to many types of cardiac progenitors, although this property appeared to be limited to aortaand ventricle-derived cells ( Figure 37). In particular, PACPs showed 5% rate of fusion events, consistent with previous data obtained using different cell types, such as mouse embryonic stem cells, human MSCs and human cardiac stem cells, that reported similar fusion efficiency (Pittenger et al 2004;Christoforou et al 2010;Acquistapace et al 2005). On the other hand, much higher fusion rate has been previously described for human and mouse mesoangioblasts (Galvez et al 2009;Galvez et al 2008;Galli et al 2005).…”

Regenerative Medicine for the Heart: Perspectives on Stem-Cell Therapy

“…When engrafted into infarcted heart, ESC-derived CPCs differentiated into adult-sized CMs with Cx43 expression, reconstitute *20% of the scar tissue in a nonhuman primate model (12). Consistently, unlike PSC-derived CMs, PSC-derived CPCs appear to differentiate into mature CMs and vascular cells in the adult mouse heart without causing teratomas or arrhythmias (24,98). While these studies revealed the unique potential of CPCs to form adult-like CMs for heart regeneration, further investigation will be required to determine their morphological and functional maturation, coupling, and functional integration with host myocardium, and long-term survival and effects on heart function.…”

Cardiac Tissue Engineering

“…Monkey ES cell-derived cardiomyocyte precursors differentiated into cardiomyocytes, and replaced 1/5 of a cardiac scar in primates 8 . MESC derived cardiomyocytes transplanted in rodent hearts (Adler et al, 2010;Christoforou et al, 2010;Lu et al, 2010b), and sheep hearts , also contributed to cardiac repair.…”

“…They justify the approaches taken in my studies to contribute to these areas of research. Although significant achievements have been reported from transplanting ES-derived cardiomyocytes onto animal hearts (Adler et al, 2010;Christoforou et al, 2010;Lu et al, 2010a;Stevens et al, 2009a;van Laake et al, 2009), the lack of a fully characterized cardiomyocyte purification protocol that can ensure a defined population of donor cells, 100% free of cells capable of forming tumours, has stalled progression of applying these findings to humans. In these studies, the use of DHP-R as a cardiomyocyte enrichment strategy may prove to be a valuable tool to purify ES-derived cardiomyocytes.…”