BMP4 patterns Smad activity and generates stereotyped cell fate organization in spinal organoids

Development. 2019 Jul 25;146(14):dev175430. doi: 10.1242/dev.175430.


Bone morphogenetic proteins (BMPs) are secreted regulators of cell fate in several developing tissues. In the embryonic spinal cord, they control the emergence of the neural crest, roof plate and distinct subsets of dorsal interneurons. Although a gradient of BMP activity has been proposed to determine cell type identity in vivo, whether this is sufficient for pattern formation in vitro is unclear. Here, we demonstrate that exposure to BMP4 initiates distinct spatial dynamics of BMP signalling within the self-emerging epithelia of both mouse and human pluripotent stem cell-derived spinal organoids. The pattern of BMP signalling results in the stereotyped spatial arrangement of dorsal neural tube cell types, and concentration, timing and duration of BMP4 exposure modulate these patterns. Moreover, differences in the duration of competence time-windows between mouse and human account for the species-specific tempo of neural differentiation. Together, this study describes efficient methods for generating patterned subsets of dorsal interneurons in spinal organoids and supports the conclusion that graded BMP activity orchestrates the spatial organization of the dorsal neural tube cellular diversity in mouse and human.

Keywords: Bone morphogenetic proteins; Organoid; Patterning; Pluripotent stem cells differentiation; Relay and associating spinal dorsal interneurons; Self-organization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 4 / physiology*
  • Cell Differentiation / genetics*
  • Cell Lineage / genetics
  • Cells, Cultured
  • Embryo, Mammalian
  • Gene Expression Regulation, Developmental
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / physiology
  • Interneurons / cytology
  • Interneurons / physiology
  • Mice
  • Neural Crest / cytology
  • Neural Crest / physiology
  • Neural Tube / cytology
  • Neural Tube / embryology
  • Neurons / cytology
  • Neurons / physiology
  • Organoids / cytology
  • Organoids / physiology*
  • Signal Transduction / genetics
  • Smad Proteins / genetics
  • Smad Proteins / metabolism*
  • Spine / cytology*


  • BMP4 protein, human
  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 4
  • Smad Proteins