期刊
DEVELOPMENT
卷 144, 期 23, 页码 4298-4312出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.149658
关键词
Developmental organoids; Human gastrulation; Morphogenesis; Pluripotent stem cells; Positional information; Reaction-diffusion
资金
- Canadian Institutes for Health Research
- Medicine by Design, a Canada First Research Excellence Program at the University of Toronto
- CREATE Materials, Mimetics, and Manufacturing from the Natural Sciences and Engineering Research Council of Canada
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.
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