Engineering the Morphogenesis of Pluripotent Stem Cells

Pluripotent stem cells (PSCs) exhibit a unique ability to recapitulate dynamic morphogenic processes that mimic analogous developmental biology events to yield complex tissue structure and function that results from coordinated multicellular interactions. The recent success in generating a diverse set of “organoids” from PSCs demonstrates their tremendous inherent potential for complex tissue formation. However, the inability to robustly and predictably generate organoids currently limits their use for drug discovery and development, modeling of human development and disease, and regenerative medicine therapies. Thus, we have sought to develop methods to reproducibly and robustly direct the morphogenesis of pluripotent stem cell aggregates to directed microtissues by controlling physical and biochemical elements of the 3D microenvironment. We have systematically examined the effects of numerous factors, such as aggregate formation methods, hydrodynamic forces and presence of various types of biomaterials, on the differentiation and morphogenesis of PSCs. We are also now combining these approaches with novel CRISPR-based cell engineering methods in PSCs to spatially and temporally control the initiation of morphogenic processes and complement our experimental studies with computational modeling approaches. We anticipate that these studies will lead to a greater mechanistic understanding of stem cell biology and tissue development as well as scalable and translatable technologies for manufacturing of PSC-derived products for regenerative medicine.