Differential Maturation of the Two Regulated Secretory Pathways in Human iPSC-Derived Neurons

Javier Emperador Melero, Aishwarya G. Nadadhur, Desiree Schut, Jan V. Weering, Vivi M. Heine, Ruud F. Toonen, Matthijs Verhage

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Neurons communicate by regulated secretion of chemical signals from synaptic vesicles (SVs) and dense-core vesicles (DCVs). Here, we investigated the maturation of these two secretory pathways in micro-networks of human iPSC-derived neurons. These micro-networks abundantly expressed endogenous SV and DCV markers, including neuropeptides. DCV transport was microtubule dependent, preferentially anterograde in axons, and 2-fold faster in axons than in dendrites. SV and DCV secretion were strictly Ca2+ and SNARE dependent. DCV secretion capacity matured until day in vitro (DIV) 36, with intense stimulation releasing 6% of the total DCV pool, and then plateaued. This efficiency is comparable with mature mouse neurons. In contrast, SV secretion capacity continued to increase until DIV50, with substantial further increase in secretion efficiency and decrease in silent synapses. These data show that the two secretory pathways can be studied in human neurons and that they mature differentially, with DCV secretion reaching maximum efficiency when that of SVs is still low.

Original languageEnglish
Pages (from-to)659-672
Number of pages14
JournalStem cell reports
Issue number3
Publication statusPublished - 14 Mar 2017


  • Animals
  • Axons
  • Biological Transport
  • Biomarkers
  • Calcium
  • Cell Differentiation
  • Dendrites
  • Humans
  • Induced Pluripotent Stem Cells
  • Journal Article
  • Mice
  • Microtubules
  • Neurons
  • Research Support, Non-U.S. Gov't
  • SNARE Proteins
  • Secretory Pathway
  • Secretory Vesicles
  • Synapses
  • dense-core vesicles
  • human iPSC-derived neurons
  • neuropeptides
  • regulated neurosecretion
  • synaptic transmission

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