Efficient derivation of functional floor plate tissue from human embryonic stem cells

Cell Stem Cell. 2010 Apr 2;6(4):336-47. doi: 10.1016/j.stem.2010.03.001.

Abstract

The floor plate (FP) is a critical signaling center during neural development located along the ventral midline of the embryo. Little is known about human FP development because of the lack of tissue accessibility. Here we report the efficient derivation of human embryonic stem cell (hESC)-derived FP tissue capable of secreting Netrin-1 and SHH and patterning primary and hESC derived tissues. FP induction in hESCs is dependent on early SHH exposure and occurs at the expense of anterior neurectoderm (AN). Global gene expression and functional studies identify SHH-mediated inhibition of Dkk-1 as key factor in FP versus AN specification. hESC-derived FP tissue is shown to be of anterior SIX6+ character but is responsive to caudalizing factors suppressing SIX6 expression and inducing a shift in usage of region-specific SHH enhancers. These data define the early signals that drive human FP versus AN specification and determine regional identity in hESC-derived FP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Patterning / genetics
  • Cell Differentiation / genetics
  • Cell Lineage / genetics
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / metabolism
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Hedgehog Proteins / metabolism
  • Hepatocyte Nuclear Factor 3-beta / metabolism
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Nerve Tissue Proteins / metabolism
  • Nervous System / cytology*
  • Nervous System / metabolism
  • Neural Plate / embryology
  • Neural Plate / metabolism
  • Time Factors
  • Transcription, Genetic

Substances

  • DKK1 protein, human
  • FOXA2 protein, human
  • FOXG1 protein, human
  • Forkhead Transcription Factors
  • Hedgehog Proteins
  • Intercellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • SHH protein, human
  • Hepatocyte Nuclear Factor 3-beta