A novel self-organizing embryonic stem cell system reveals signaling logic underlying the patterning of human ectoderm

George Britton; Idse Heemskerk; Rachel Hodge; Amina A. Qutub; Aryeh Warmflash

doi:10.1242/dev.179093

ABSTRACT

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. 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 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. 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. Thus, our platform is a powerful tool for studying human ectoderm patterning and for improving directed differentiation protocols.

This article has an associated ‘The people behind the papers’ interview.

Footnotes

Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: G.B., A.W.; Methodology: G.B.; Software: I.H.; Validation: G.B.; Investigation: G.B., I.H., R.H.; Writing - original draft: G.B., A.W.; Writing - review & editing: G.B., I.H., R.H., A.A.Q., A.W.; Visualization: G.B.; Supervision: A.A.Q., A.W.; Project administration: A.A.Q., A.W.; Funding acquisition: A.A.Q., A.W.
Funding
This work was supported by the National Institute of General Medical Sciences (R01GM126122), the National Science Foundation (MCB-1553228 and ECCS-1533708), the Cancer Prevention and Research Institute of Texas (RR140073), the University of Texas STARS program and the Simons Foundation (511079). Deposited in PMC for release after 12 months.
Supplementary information
Supplementary information available online at http://dev.biologists.org/lookup/doi/10.1242/dev.179093.supplemental

Received April 8, 2019.
Accepted September 6, 2019.

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