Electrophysiological coupling of transplanted cardiomyocytes.

The recent advances in stem cell biology and tissue engineering have paved the way to the development of a new field in biomedicine, regenerative medicine. This approach seeks to circumvent the shortage of organs for transplantation, by combining the above-mentioned technologies in an attempt to replace diseased or absent tissue. The heart represents an attractive candidate for these emerging technologies, and myocardial cell replacement therapy and tissue engineering present exciting new possibilities for assisting the failing myocardium.1,2 Despite the enormous enthusiasm associated with cardiovascular regenerative medicine, several obstacles need to be overcome before such strategies can become a clinical reality. Among the major targets that must be achieved are the needs to find an efficient cell source, which will provide the large number of cardiomyocytes required, overcoming the immune rejection barrier of nonautologous cell sources, and finding means for directing stem cells to differentiate to the cardiomyocyte lineage. Yet, concentration on these “major” unanswered questions may lead one to believe that all other issues with cell therapy have been solved. A closer inspection, however, reveals that this is not the case and many questions still remain open. Even if we could identify the ideal stem cell source, could direct the differentiation of these cells efficiently to cardiomyocytes, and prevent immune rejection we still do not know how many cells should be transplanted, what is the best timing and sites for cell transplantation, and most importantly whether the engrafted cells would survive and integrate appropriately with the existing cell-network of host cardiac tissue. Numerous reports suggest that myocyte transplantation can improve cardiac performance in animal models of myocardial infarction.1,2 However, it is not entirely clear whether this functional improvement is attributable to direct contribution to contractility by the transplanted myocytes or by other indirect mechanisms such as attenuation of the remodeling process, amplification of an endogenous repair process by cardiac resident progenitor cells, or induction of angiogenesis. Because hundred millions of cardiomyocytes are lost during a myocardial infarction that result in heart failure, any significant systolic improvement would require the generation of a large working graft. Such a cell-graft would have to integrate both structurally and functionally with host tissue and participate in the synchronous contraction of the entire heart. Several studies have documented the presence of gap junctions between host and grafted cells.3,4 Yet even the presence of such gap junctions, although necessary for integration, is by no means sufficient and does not guarantee appropriate functional integration. For such integration to occur, currents generated in one cell passing through gap junctions must be sufficient to depolarize neighboring cells. The ability (or the lack of it) of the graft to functionally integrate with host myocardium is a key mechanistic question in cell therapy. This key question is addressed in the paper by Halbach and colleagues in this issue of Circulation Research.5 Murine fetal cardiomyocytes, derived from transgenic animals expressing eGFP, were transplanted into the necrotic area and to adjacent healthy myocardium in the mouse cryoinjury model. Using a novel ex vivo heart slice preparation6 and direct microelectrode recordings from the grafted cells, the authors show that 82% of transplanted fetal cardiac myocytes surrounded by viable host tissue were electrically integrated with host myocardium. In contrast, transplanted cardiomyocytes surrounded by cryoinjured tissue, although showing spontaneous electrical and contractile activity, were not integrated with host tissue. This important study joins the very few published articles that focus on the electrophysiological integration of transplanted cells. In vitro studies showed that cocultured cells were able to form a single functional syncitium.7 Using 2-photon microscopy, Rubart and colleagues were able to document electrical integration (by way of intracellular calcium imaging) between transplanted fetal cardiomyocytes and host cells in the intact heart.4 A similar study by the same group noted the absence of such integration when skeletal myoblasts were used for transplantation.8 Kehat and colleagues were able to document stable long-term electrical integration of human embryonic stem cell derived cardiomyocytes in live animals using electroanatomical mapping.7 The former studies were hampered, however, by the limited ability to assess the efficacy of coupling and the latter was hampered by the low-spatial resolution of the mapping technique. Furthermore, both of these studies did not assess integration in the setting of diseased myocardium. The study of Halbach and colleagues5 is in agreement with the aforementioned studies, claiming that transplanted cardiomyocyte can integrate with the host heart. In this respect, this study compliments previous work by demonstrating, unamThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Sohnis Laboratory for Cardiac Electrophysiology and Regenerative Medicine (L.G.), and the Bruce Rappaport Faculty of Medicine (I.K., L.G.), Technion-Israel Institute of Technology, Haifa, Israel. Correspondence to Lior Gepstein, MD, PhD, Technion’s Faculty of Medicine, POB 9649, Haifa, 31096, Israel. E-mail [email protected]. ac.il (Circ Res. 2007;101:433-435.) © 2007 American Heart Association, Inc.