Browsing by Author "Britton, George Leslie"

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    A novel self-organizing embryonic stem cell system reveals signaling logic underlying the patterning of human ectoderm in two- and three-dimensions
    (2020-08-04) Britton, George Leslie; Warmflash, Aryeh
    During development, the ectoderm is patterned by a combination of BMP and WNT signaling. Research in model organisms has provided substantial insight into this process; however, there are currently no systems in which to study ectodermal patterning in humans as it transitions from a two-dimensional to a three-dimensional tissue. Further, the complexity of neural plate border specification has made it difficult to transition from discovering the genes involved to deeper mechanistic understanding. Here, we develop an in vitro model of human ectodermal patterning in both two- and three-dimensions, in which human embryonic stem cells self-organize to form robust and quantitatively reproducible patterns corresponding to the complete medial-lateral axis of the embryonic ectoderm. Importantly, this organized tissue undergoes morphogenesis to form a close neural tube with an overlaying surface ectoderm, similar to what is found in vivo. Using this platform, we show that the duration of endogenous WNT signaling is a crucial control parameter, and that cells sense relative levels of BMP and WNT signaling in making fate decisions. These insights allowed us to develop an improved protocol for placodal differentiation in standard culture. Thus, our platform is a powerful tool for studying human ectoderm patterning and three-dimensional self-organization of neural structures that is otherwise impossible to study in utero.