Endocrine lineage biases arise in temporally distinct endocrine progenitors during pancreatic morphogenesis

Nat Commun. 2018 Aug 22;9(1):3356. doi: 10.1038/s41467-018-05740-1.

Abstract

Decoding the molecular composition of individual Ngn3 + endocrine progenitors (EPs) during pancreatic morphogenesis could provide insight into the mechanisms regulating hormonal cell fate. Here, we identify population markers and extensive cellular diversity including four EP subtypes reflecting EP maturation using high-resolution single-cell RNA-sequencing of the e14.5 and e16.5 mouse pancreas. While e14.5 and e16.5 EPs are constantly born and share select genes, these EPs are overall transcriptionally distinct concomitant with changes in the underlying epithelium. As a consequence, e16.5 EPs are not the same as e14.5 EPs: e16.5 EPs have a higher propensity to form beta cells. Analysis of e14.5 and e16.5 EP chromatin states reveals temporal shifts, with enrichment of beta cell motifs in accessible regions at later stages. Finally, we provide transcriptional maps outlining the route progenitors take as they make cell fate decisions, which can be applied to advance the in vitro generation of beta cells.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Female
  • Flow Cytometry
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Developmental / physiology
  • In Situ Hybridization
  • Male
  • Mice, Inbred ICR
  • Morphogenesis / genetics
  • Morphogenesis / physiology*
  • Nerve Tissue Proteins / metabolism*
  • Pancreas / cytology*
  • Pregnancy
  • Stem Cells / cytology
  • Stem Cells / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Nerve Tissue Proteins
  • Neurog3 protein, mouse