Location: JHE 326H
Engineering effective therapies for heart disease will require restoration of beating myocardium as well as revascularization of the injured or impaired area. Since human postnatal cardiomyocytes are terminally differentiated, it is not possible to obtain these cells and expand them from biopsies of primary tissue. Recent advances in stem cell biology and development of directed differentiation protocols enable derivation of cardiomyocytes from human pluripotent stem cells (hPSC). However, hPSC-derived cardiomyocytes are reflective of very early human development, limiting their utility in the generation of in vitro models of mature myocardium suitable for drug testing or restoration of adult hearts. We developed a new platform that combines three-dimensional cell cultivation in a microfabricated system with electrical stimulation to mature hPSC-derived cardiac tissues. We utilized quantitative structural, molecular and electrophysiological analyses to elucidate the responses of immature human myocardium to electrical stimulation and pacing. We demonstrated that the engineered platform allowed for the generation of 3-dimensional, aligned cardiac tissues (biowires) with frequent striations. Biowires submitted to electrical stimulation markedly increased myofibril ultrastructural organization, displayed elevated conduction velocity and altered both the electrophysiological and calcium handling properties versus non-stimulated controls. These changes were in agreement with cardiomyocyte maturation and were dependent on the stimulation rate. We will also discuss approaches to vascularizing cardiac tissue by development of new perfusable microfabricated scaffolds termed, AngioChips that are also suitable for engineering a human body on a chip. Lastly, placing a functional, beating, cardiac patch onto the heart currently requires opening of the chest. We will discuss shape-memory scaffolds that enable a minimally invasive delivery of engineered tissues in vivo.
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