Author + information
- Toon A.B. van Veen, PhD⁎ (, )
- Jacques M.T. de Bakker, PhD and
- Marcel A.G. van der Heyden, PhD
- ↵⁎Heart Lung Center Utrecht, Department of Medical Physiology, Yalelaan 50, 3584 CM Utrecht, the Netherlands
In a recent study, Beeres et al. (1) addressed the potency of human adult bone marrow mesenchymal stem cells (MSCs) to connect separated sheets of cultured cardiomyocytes electrically. Thereby they touch upon a delicate and important feature with respect to cardiac regeneration by means of cell therapy (i.e., functional coupling and action potential propagation).
In the last years numerous studies have been performed to investigate applicability of stem cells or stem-cell–derived cardiomyocytes in cardiac regeneration strategies. In vitro studies revealed that several sources of stem cells could be differentiated with varying levels of success into cardiomyocytes. In general, the phenotype of most sources of stem-cell–derived cardiomyocytes appears rather immature. In contrast to host ventricular myocardium, these cells display spontaneous electrical activity, thereby baring the seeds of creating an ectopic focus upon transplantation. To optimally support a compromised myocardium upon engraftment, donor cells preferably should be as similar as—and integrate mechanically and electrically with—the receiving host myocardium. If not, transplantation of cells will not only fail to chronically increase the contractile capacity of the heart but, even more deleterious, will disturb impulse formation and propagation. This risk was acknowledged in a study by Menasche et al. (2), who showed the onset of lethal ventricular tachyarrhythmias upon transplantation of the recipient’s own myoblasts. The fact that these cells do not, or hardly express gap junctions and thereby create a large excitable gap to the host myocardium—together with their potency to display aberrant electrical activity—probably explains the observed arrhythmias. Abraham et al. (3) showed that a genetically increased level of gap junctions tempered this arrhythmogenic behavior in vitro.
In the study by Beeres et al. (1), the investigators confirm the requirement of sufficient coupling between host and donor cells because fibroblasts and skeletal myoblasts were unable to restore impulse propagation, whereas MSCs expressing gap junctions did. However, the impulse was propagated passively over rather short distances, and because the cells are not excitable, they will be unable to carry the action potential over larger distances. Moreover, upon transplantation, it is unlikely that they will support the contractility by lack of a well-developed functional contractile apparatus (4). As mentioned by Beeres et al. (1), these engrafted cells do not trigger the onset of arrhythmias, which in our opinion relates to this inexcitable characteristic of these functionally coupled cells. We believe that if donor cardiomyocytes are desired to engraft in order to support the contractile capacity, the combination of functional electrical coupling and spontaneous activity has to be ruled out by eliminating the latter. As shown by Kehat et al. (5), transplantation of clustered human embryonic stem cells that express gap junctions and are spontaneously active enables ectopic pacemaking (5).
To engraft cells safely in the compromised heart in order to support it mechanically, intercellular coupling to host cells has to be optimized while spontaneous activity should be depressed. With the results from the study by Beeres and the other studies cited, scientists are challenged to develop such strategies in which the aspect of electrical interaction is included and controlled.
- American College of Cardiology Foundation
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