A platform for generation of chamber specific cardiac tissues and disease modelling
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ABSTRACT:
PROVIDER: PRJNA505893 | ENA |
REPOSITORIES: ENA
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Project description:We report, for the first time, engineering of heteropolar cardiac tissues containing distinct atrial and ventricular ends, and demonstrate their spatially confined responses to serotonin and ranolazine. Uniquely, electrical conditioning for up to 8 months enabled modeling of polygenic left ventricular hypertrophy starting from patient cells.
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Project description:Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to cardiac chamber specification and platform versatility can be overcome. We describe here a scalable tissue-cultivation platform that is cell source agnostic and enables drug testing under electrical pacing. The plastic platform enabled on-line noninvasive recording of passive tension, active force, contractile dynamics, and Ca2+ transients, as well as endpoint assessments of action potentials and conduction velocity. By combining directed cell differentiation with electrical field conditioning, we engineered electrophysiologically distinct atrial and ventricular tissues with chamber-specific drug responses and gene expression. We report, for the first time, engineering of heteropolar cardiac tissues containing distinct atrial and ventricular ends, and we demonstrate their spatially confined responses to serotonin and ranolazine. Uniquely, electrical conditioning for up to 8 months enabled modeling of polygenic left ventricular hypertrophy starting from patient cells.
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Project description:Defective valve and septa formation constitute a substantial part of congenital heart defects affecting the neonate or the adult. During cardiac development, restricted myocardial Bmp2 expression is a key signal for the specification and patterning of the valve-forming field in the atrio-ventricular canal (AVC) region and the initiation of the epithelial-mesenchyme transition (EMT) that gives rise to the valve primordia. We have generated a mouse transgenic line conditionally expressing Bmp2. Nkx2.5Cre-driven Bmp2 overexpression in the myocardium leads to foetal lethality, due to valve and chamber dysmorphogenesis, and rescue of the AVC specification defect of Bmp2-null embryos. Nkx2.5Cre/+;Bmp2tg/+ transgenic embryos show ventricular septal defect, thickened valves, enlarged trabeculae and dilated ventricles, whose endocardium is able to undergo EMT when explanted onto collagen gels. Gene profile and marker analysis indicates that cellular proliferation is increased and chamber differentiation and patterning is impaired in Nkx2.5Cre/+;Bmp2tg/+ embryos, but the ventricular-specific gene expression program is not abolished. We obtained similar results using a second myocardial driver (cTnTCre) to activate Bmp2 expression, but not with an endothelial-specific one (Tie2Cre), as Tie2Cre/+;Bmp2tg/+ mice are normal and survive to adulthood, indicating that Bmp2 must emanate from the myocardium to exert its EMT-driving and cardiomyocyte maturation blocking effect. Forced Bmp2 expression in vitro stimulates EBs proliferation and blocks their progression into cardiomyogenesis, an effect partially rescued by Noggin. These data show that widespread myocardial Bmp2 expression directs ectopic valve primordium formation and maintains chamber myocardium and early cardiac progenitors in a primitive, proliferative state, identifying Bmp2 as a potential factor for the expansion of immature cardiomyocytes.
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Project description:Engineered human cardiac tissues have been utilized for various biomedical applications, including drug testing, disease modeling, and regenerative medicine. However, the applications of cardiac tissues derived from human pluripotent stem cells are often limited due to their immaturity and lack of functionality. Therefore, in this study, we established a perfusable culture system based on in vivo-like heart microenvironments to improve human cardiac tissue fabrication. The integrated culture platform of a microfluidic chip and a three-dimensional heart extracellular matrix enhanced human cardiac tissue development and their structural and functional maturation. These tissues were comprised of cardiovascular lineage cells, including cardiomyocytes and cardiac fibroblasts derived from human induced pluripotent stem cells, as well as vascular endothelial cells. The resultant macroscale human cardiac tissues exhibited improved efficacy in drug testing (small molecules with various levels of arrhythmia risk), disease modeling (long QT syndrome and cardiac fibrosis), and regenerative therapy (myocardial infarction treatment). Therefore, our culture system can serve as a highly effective tissue-engineering platform to provide human cardiac tissues for versatile biomedical applications.
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