This supplement will use human embryonic stem cells (ESCs) to address the adverse effects of left ventricular (LV) remodeling following myocardial infarction (MI) on ventricular size and function, with particular focus on how such remodeling augments volume overload by causing mitral regurgitation (MR). These are the scientific questions in the parent R01, Effect of Mitral Regurgitation on Ischemic LV Remodeling, and the related R21, Active Patch Therapy of Ischemic MR. Following MI, localized distortion of the heart wall restricts the ability of the attached mitral leaflets to close, causing MR that exacerbates LV remodeling and doubles late mortality. Our initial studies have shown that passive external constraints applied to the MI zone can reverse its shape change and eliminate MR; however, an entire region of myocardium remains immobilized. With collaborating investigators, we have been studying the possibility that injecting autologous skeletal myoblasts into the infarcted wall to thicken and re-shape it can reverse MR, with potential for augmenting contraction as well. However, there may be some limitations of using skeletal myoblasts for this purpose, including absence of connecting gap junctions between grafted and host cells needed for concerted contraction. The next logical step would therefore be to test whether we can reduce LV remodeling and ischemic MR and, at the same time, provide the added benefit of functional tissue by using human embryonic stem cells instead of skeletal myoblasts in a post-infarct MR model. Our colleagues have shown that such undifferentiated cells, under the influence of tissue growth factors, can be committed to a cardiac lineage, with evidence for sarcomeric striations and expression of gap junction protein, allowing integration with surrounding myocardium. Cells derived from embryonic stem cells would therefore be the best candidates to replace damaged muscle with true myocytes, with the greatest potential for actually increasing contractility.
Specific aims i nclude: 1) To establish simple protocols for cardiac commitment of human ESCs and to understand the molecular mechanisms ? underlying this process to prevent tumor formation; 2) To investigate the fate and immunocompatibility ? of cardiac-committed ESCs transplanted into post-MI and failing sheep hearts; and 3) To evaluate the ? improvement of cardiac function after engraftment of cardiac-committed ESCs in sheep with heart failure worsened by MR. NIH cell registry number TE03 (training available). This supplement brings together unique resources and expertise to address this challenge, including groups with extensive experience in cell transplantation into infarcted regions, successful cardiac differentiation of ESCs in other species, and quantitative three-dimensional evaluation of cardiac function. ? ? ?
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