Induced pluripotent stem cell-derived cardiac progenitors differentiate to cardiomyocytes and form biosynthetic tissues.
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The mammalian heart has little capacity to regenerate, and following injury the myocardium is replaced by non-contractile scar tissue. Consequently, increased wall stress and workload on the remaining myocardium leads to chamber dilation, dysfunction, and heart failure. Cell-based therapy with an autologous, epigenetically reprogrammed, and cardiac-committed progenitor cell source could potentially reverse this process by replacing the damaged myocardium with functional tissue. However, it is unclear whether cardiac progenitor cell-derived cardiomyocytes are capable of attaining levels of structural and functional maturity comparable to that of terminally-fated cardiomyocytes. Here, we first describe the derivation of mouse induced pluripotent stem (iPS) cells, which once differentiated allow for the enrichment of Nkx2-5(+) cardiac progenitors, and the cardiomyocyte-specific expression of the red fluorescent protein. We show that the cardiac progenitors are multipotent and capable of differentiating into endothelial cells, smooth muscle cells and cardiomyocytes. Moreover, cardiac progenitor selection corresponds to cKit(+) cell enrichment, while cardiomyocyte cell-lineage commitment is concomitant with dual expression of either cKit/Flk1 or cKit/Sca-1. We proceed to show that the cardiac progenitor-derived cardiomyocytes are capable of forming electrically and mechanically coupled large-scale 2D cell cultures with mature electrophysiological properties. Finally, we examine the cell progenitors' ability to form electromechanically coherent macroscopic tissues, using a physiologically relevant 3D culture model and demonstrate that following long-term culture the cardiomyocytes align, and form robust electromechanical connections throughout the volume of the biosynthetic tissue construct. We conclude that the iPS cell-derived cardiac progenitors are a robust cell source for tissue engineering applications and a 3D culture platform for pharmacological screening and drug development studies.
Embryonic Stem Cells
Gene Expression Profiling
Induced Pluripotent Stem Cells
Published Version (Please cite this version)10.1371/journal.pone.0065963
Publication InfoChristoforou, Nicolas; Liau, Brian; Chakraborty, Syandan; Chellapan, Malathi; Bursac, Nenad; & Leong, Kam W (2013). Induced pluripotent stem cell-derived cardiac progenitors differentiate to cardiomyocytes and form biosynthetic tissues. PLoS One, 8(6). pp. e65963. 10.1371/journal.pone.0065963. Retrieved from https://hdl.handle.net/10161/8423.
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Professor of Biomedical Engineering
Bursac's research interests include: Stem cell, tissue engineering, and gene based therapies for heart and muscle regeneration; Cardiac electrophysiology and arrhythmias; Organ-on-chip and tissue engineering technologies for disease modeling and therapeutic screening; Small and large animal models of heart and muscle injury, disease, and regeneration. The focus of my research is on application of pluripotent stem cells, tissue engineering, and gene therapy technologies for: 1) basic s
Adjunct Professor of Biomedical Engineering
Professor Leong's research interest focuses on biomaterials design, particularly on synthesis of nanoparticles for DNA-based therapeutics, and nanostructured biomaterials for regenerative medicine Biomaterials Design: design of self-assembled fibers for tissue engineering microfluidics-mediated synthesis of multifunctional nanoparticles for drug and gene delivery synthesis of novel quantum dots for biomedical applications Con
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