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Development. 2017 Dec 1;144(23):4298-4312. doi: 10.1242/dev.149658. Epub 2017 Sep 4.

A stepwise model of reaction-diffusion and positional information governs self-organized human peri-gastrulation-like patterning.

Author information

1
Institute of Biomaterials and Biomedical Engineering (IBBME), University of Toronto, Toronto, Ontario, M5S 3E1, Canada.
2
Collaborative Program in Developmental Biology, University of Toronto, Toronto, Ontario, M5S 3E1, Canada.
3
Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, M5S 3E1, Canada.
4
Ted Rogers Centre for Heart Research, University of Toronto, Toronto, Ontario, M5G 1M1, Canada.
5
Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, M5S 3G5, Canada.
6
Institute of Biomaterials and Biomedical Engineering (IBBME), University of Toronto, Toronto, Ontario, M5S 3E1, Canada peter.zandstra@utoronto.ca.
7
Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, M5S 3ES, Canada.
8
Medicine by Design: A Canada First Research Excellence Fund Program, University of Toronto, Toronto, Ontario, M5S 3E1, Canada.

Abstract

How position-dependent cell fate acquisition occurs during embryogenesis is a central question in developmental biology. To study this process, we developed a defined, high-throughput assay to induce peri-gastrulation-associated patterning in geometrically confined human pluripotent stem cell (hPSC) colonies. We observed that, upon BMP4 treatment, phosphorylated SMAD1 (pSMAD1) activity in the colonies organized into a radial gradient. We developed a reaction-diffusion (RD)-based computational model and observed that the self-organization of pSMAD1 signaling was consistent with the RD principle. Consequent fate acquisition occurred as a function of both pSMAD1 signaling strength and duration of induction, consistent with the positional-information (PI) paradigm. We propose that the self-organized peri-gastrulation-like fate patterning in BMP4-treated geometrically confined hPSC colonies arises via a stepwise model of RD followed by PI. This two-step model predicted experimental responses to perturbations of key parameters such as colony size and BMP4 dose. Furthermore, it also predicted experimental conditions that resulted in RD-like periodic patterning in large hPSC colonies, and rescued peri-gastrulation-like patterning in colony sizes previously thought to be reticent to this behavior.

KEYWORDS:

Developmental organoids; Human gastrulation; Morphogenesis; Pluripotent stem cells; Positional information; Reaction-diffusion

PMID:
28870989
PMCID:
PMC5769627
DOI:
10.1242/dev.149658
[Indexed for MEDLINE]
Free PMC Article

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