CAREER: Engineering ex vivo Human Cardiogenesis with Optogenetics

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Human induced pluripotent stem cells (hiPSCs) are a special cell type that under the right environment can transform into any type of cell, which provide an unprecedented opportunity to study human tissue and organ development and potentially be applied to treating disease. More narrowly, hiPSC-derived in vitro organ models, termed organoids, have emerged as powerful tools to construct elaborate tissue-like architectures that can accurately mimic the morphology of numerous tissues or organs, such as the intestines, kidney, and brain. More recently, cardiac organoids were created from hiPSCs, but the spatial control of the specification and organization of multiple cardiac cells remain challenging. This CAREER project seeks to control the formation of organized cardiac organoids from hiPSCs using optogenetics, a biological technique to control the activity of cells or tissues with light, and then use these to study cardiac maturation and heart diseases. The educational mission will be integrated into this research program by engaging students at different levels into interdisciplinary stem cell research and community outreach activities, including interactive coursework, seminars, workshops, research experiences, and a public art exhibition at Purdue Galleries. The investigator’s long-term career goal is to create a transformative, interdisciplinary research and education program that integrates excellence in the science and engineering of stem cell- and gene-based precision medicine with education of future scientists and engineers. Towards this goal, this CAREER project will develop novel tools and standardized methodologies to precisely engineer human organoid morphogenesis with optogenetics for developmental studies and disease modeling. Engineering cardiogenesis in a manner mimicking native heart development will result in superior structural and functional properties of the cardiac organoids. The central hypothesis of this research is that the paracrine and juxtacrine signals induced by heterotypic cell-cell interactions within the three-dimensional (3D) cardiac organoids will enhance cardiomyocyte (CM) maturation and function. To test this hypothesis, three tasks are proposed: (1) establish a 3D optogenetic platform and validate its function in signaling patterning for multicellular morphogenesis; (2) generate cardiac organoids using optogenetics to facilitate and interrogate the maturation of hiPSC-derived CMs in 3D; and (3) investigate the influence of genetic defects on cellular composition, tissue structure and maturation of cardiac organoids. The proposed research will reveal critical factors to achieve maturation of the hiPSC-CMs and elucidate underlying mechanisms of progressive muscle weakness and death in diseased CMs. Since cell maturation is a key element of tissue engineering, this research will have broader ramifications in engineering other hiPSC-derived tissues.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.