Charting human development using a multi-endodermal organ atlas and organoid models

Cell. 2021 Jun 10;184(12):3281-3298.e22. doi: 10.1016/j.cell.2021.04.028. Epub 2021 May 20.


Organs are composed of diverse cell types that traverse transient states during organogenesis. To interrogate this diversity during human development, we generate a single-cell transcriptome atlas from multiple developing endodermal organs of the respiratory and gastrointestinal tract. We illuminate cell states, transcription factors, and organ-specific epithelial stem cell and mesenchyme interactions across lineages. We implement the atlas as a high-dimensional search space to benchmark human pluripotent stem cell (hPSC)-derived intestinal organoids (HIOs) under multiple culture conditions. We show that HIOs recapitulate reference cell states and use HIOs to reconstruct the molecular dynamics of intestinal epithelium and mesenchyme emergence. We show that the mesenchyme-derived niche cue NRG1 enhances intestinal stem cell maturation in vitro and that the homeobox transcription factor CDX2 is required for regionalization of intestinal epithelium and mesenchyme in humans. This work combines cell atlases and organoid technologies to understand how human organ development is orchestrated.

Keywords: CDX2; NRG1; human endoderm development; intestinal organoids; mesenchyme heterogeneity; multi-organ cell atlas; single-cell transcriptomics.

Publication types

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

MeSH terms

  • Anatomy, Artistic*
  • Atlases as Topic*
  • CDX2 Transcription Factor / metabolism
  • Cell Line
  • Embryonic Development*
  • Endoderm / embryology*
  • Epidermal Growth Factor / pharmacology
  • Epithelial Cells / cytology
  • Female
  • Gastrulation
  • Gene Deletion
  • Gene Expression Regulation, Developmental / drug effects
  • Humans
  • Intestines / embryology
  • Male
  • Mesoderm / embryology
  • Middle Aged
  • Models, Biological*
  • Neuregulin-1 / metabolism
  • Organ Specificity
  • Organoids / embryology*
  • Pluripotent Stem Cells / cytology


  • CDX2 Transcription Factor
  • Cdx2 protein, mouse
  • Neuregulin-1
  • Epidermal Growth Factor