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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Body Patterning / genetics
  • Body Patterning / physiology*
  • Bone Morphogenetic Protein 4 / physiology
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Colony-Forming Units Assay / methods
  • Gastrulation / genetics
  • Gastrulation / physiology*
  • High-Throughput Screening Assays / methods
  • Humans
  • Models, Biological*
  • Nodal Protein / physiology
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / physiology
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Smad1 Protein / physiology

Substances

  • BMP4 protein, human
  • Bone Morphogenetic Protein 4
  • Carrier Proteins
  • NODAL protein, human
  • Nodal Protein
  • RNA, Small Interfering
  • SMAD1 protein, human
  • Smad1 Protein
  • noggin protein

Grant support