“Development of a Cell-based therapy for Congenital Complete Heart Block”

Doctor's Name: 
Douglas Cowan, B.Sc., M.Sc., Ph.D
Children’s Hospital Boston

This grant is being funded by Grant's Gala and The Jasper Johnson Memorial Fund

The function of the heart is to supply blood and nutrients to the body. Each heart beat is controlled by electrical impulses that travel through the heart’s chambers (Figure 7). In a normal heart, these electrical impulses occur in regular intervals. When something is wrong with the electrical system, the heart does not beat regularly, resulting in a rhythm disorder or ‘arrhythmia’. Complete heart block occurs when impulses can't pass between the atria (upper chambers) and ventricles (lower chambers).

Our goal is to engineer tissues to electrically connect the atria and ventricles in children with complete heart block. These patients are often treated by implanting a pacemaker device, which can result in serious complications. Compared to adults, children need multiple surgeries to account for growth and longevity. Complications that arise from these constraints include lead displacement and fracture (leads connect the pacemaker generator to the heart), ventricular dysfunction, infection, tissue perforation, and generator battery failure; all of which can result in life-threatening arrhythmias. Although improvements in pacemaker devices has provided benefits beyond the treatment of arrhythmia, persistent shortcomings of this technology warrant a search for alternatives, particularly in pediatric patients.

We have already engineered tissues capable of creating an electrical connection between the atria and ventricles of rats. To be clinically-relevant, we designed these tissues to be autologous (i.e. from the same patient), easy to make and implant, and safe. Ideally, our tissues will account for patient growth, function forever, and allow the spread of electrical impulses from upper to lower chambers of the heart. Here, we will refine our approach by studying the following Aims:

Aim 1: Direct the differentiation of a novel, clinically-relevant population of cardiogenic skeletal muscle-derived progenitor (MDCP) cells toward an atrioventricular (AV) node-like conduction cell phenotype to provide electrophysiologically-appropriate impulse propagation through our engineered tissues.

Aim 2:  Implant the improved engineered tissues containing a uniform population of progenitor cells committed to a cardiac lineage in an established Lewis rat model to thoroughly assess atrioventricular conduction through the implanted tissues and determine the fate of the cells contained therein in situ.

MDCP cells have considerable potential to yield therapeutically-relevant quantities of autologously-derived cardiac cells for use in the treatment of complete heart block; however, these cells have not been systematically characterized in the laboratory nor have they been assessed for their ability to survive, integrate, and function in the heart. In Aim 1, we will direct the fate of these cells to a cardiac phenotype using biochemical, electrical, and mechanical stimuli. Stimulated MDCPs will be evaluated for expression of established tissue- and progenitor-specific cell markers as well as for their electrical characteristics. In Aim 2, we will test implanted engineered tissues containing stimulated MDCPs in our rat model by assessing their ability to conduct impulses between the atria and ventricles using state-of-the-art equipment and technologies. Given the uncertainties associated with the use of stem cells in humans, establishing methods to expand and direct the fate of autologous progenitor cells isolated from a practical tissue has clear advantages over therapies that use cells containing foreign genes.

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