Different developmental histories of beta-cells generate functional and proliferative heterogeneity during islet growth

Nat Commun. 2017 Sep 22;8(1):664. doi: 10.1038/s41467-017-00461-3.

Abstract

The proliferative and functional heterogeneity among seemingly uniform cells is a universal phenomenon. Identifying the underlying factors requires single-cell analysis of function and proliferation. Here we show that the pancreatic beta-cells in zebrafish exhibit different growth-promoting and functional properties, which in part reflect differences in the time elapsed since birth of the cells. Calcium imaging shows that the beta-cells in the embryonic islet become functional during early zebrafish development. At later stages, younger beta-cells join the islet following differentiation from post-embryonic progenitors. Notably, the older and younger beta-cells occupy different regions within the islet, which generates topological asymmetries in glucose responsiveness and proliferation. Specifically, the older beta-cells exhibit robust glucose responsiveness, whereas younger beta-cells are more proliferative but less functional. As the islet approaches its mature state, heterogeneity diminishes and beta-cells synchronize function and proliferation. Our work illustrates a dynamic model of heterogeneity based on evolving proliferative and functional beta-cell states.Βeta-cells have recently been shown to be heterogeneous with regard to morphology and function. Here, the authors show that β-cells in zebrafish switch from proliferative to functional states with increasing time since β-cell birth, leading to functional and proliferative heterogeneity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cell Lineage
  • Cell Proliferation
  • Cytological Techniques / methods
  • Embryo, Nonmammalian / cytology
  • Embryo, Nonmammalian / drug effects
  • Glucose / metabolism
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / physiology
  • Islets of Langerhans / cytology*
  • Islets of Langerhans / embryology
  • Tamoxifen / analogs & derivatives
  • Tamoxifen / pharmacology
  • Urocortins / metabolism
  • Zebrafish / embryology*
  • Zebrafish / genetics

Substances

  • Urocortins
  • Tamoxifen
  • afimoxifene
  • Glucose