| Description | Molecular Engineering and Sciences Seminar Series
Engineering human pluripotent stem cell morphogenesis to control organoid development
Abstract: Human pluripotent stem cells (PSCs) provide a unique substrate to study fundamental principles of developmental biology including the morphogenesis of multicellular aggregates into functional tissues commonly referred to as “organoids”. We are particularly interested in understanding how form and function arise in complex multicellular systems in order to engineer tissues from human PSCs. Using an inducible CRISPRi system in iPSCs, we examined the effects of silencing E-cadherin or ROCK1 to impact intercellular adhesion or cortical tension, respectively. We found that knock-down of both molecules rapidly silenced their expression and upon mixing CRISPRi cells with wild type hiPSCs, unique multicellular patterns were formed without adversely affecting pluripotency. However, upon treatment with morphogenic stimuli, divergent patterns of cell fate commitment were observed. Furthermore, we created a data-driven computational model of iPSC self-organization and performed pattern optimization studies in silico that predicted precise experimental conditions capable of yielding unique, previously unobserved patterns. Experimental validation of the predicted patterns demonstrated the powerful ability to combine cell engineering with computational modeling to predictably control the morphogenic behaviors of human PSCs. In addition to studying early symmetry breaking events, we are engineering cardiac microtissues from human PSCs using either 1) forced aggregation of multiple differentiated cell types or 2) cardiac organotypic methods. These complementary routes to create microscale models of cardiac tissue ex vivo offer some distinct advantages with respect to each other and together yield new insights into the phenotypic and functional effects of heterotypic culture on developing tissues. Examples of cardiac microtissues and organoids created by our lab will be contrasted and discussed. Robust and reproducible methods of directing human PSC morphogenesis should enable new fundamental discoveries about human embryogenesis and yield functional tissue constructs for biomedical therapy development. This weekly seminar brings together students, faculty and invited guests from various disciplines across campus to explore current trends in molecular engineering and nanotechnology. It is a forum for active interdisciplinary discussions. These talks are open to the public and attract a diverse audience of students and faculty. |
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