Astrocyte-derived small extracellular vesicles promote synapse formation via fibulin-2-mediated TGF-β signaling

Cell Rep. 2021 Mar 9;34(10):108829. doi: 10.1016/j.celrep.2021.108829.


Neuronal synapse formation is critical for brain development and depends on secreted factors from astrocytes. Here, we report that small extracellular vesicles (EVs) secreted from primary astrocytes, but not from neurons or C6 glioma cells, greatly enhance spine and synapse formation by primary cortical neurons. A comparative proteomics analysis of small EVs from astrocytes, neurons, and C6 glioma cells identified fibulin-2 as a promising EV cargo to regulate synaptogenesis. Treatment of cortical neurons with recombinant fibulin-2 increased the formation of spines and synapses, similar to the effect of small EVs. In addition, treatment of neurons with fibulin-2 or astrocyte-derived small EVs led to increased phosphorylation of Smad2, an indicator of TGF-β signaling. Finally, the effects of fibulin-2 and astrocyte-derived small EVs on synapse formation were reversed by inhibiting transforming growth factor β (TGF-β) signaling. These data suggest a model in which astrocyte EVs promote synapse formation via fibulin-2-mediated activation of TGF-β signaling.

Keywords: Astrocyte-derived small extracellular vesicles; TGF-β signaling; fibulin-2; synaptogenesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Astrocytes / metabolism
  • Calcium-Binding Proteins / antagonists & inhibitors
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Cells, Cultured
  • Dendritic Spines / physiology
  • Extracellular Matrix Proteins / antagonists & inhibitors
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism*
  • Extracellular Vesicles / metabolism*
  • Female
  • HSP70 Heat-Shock Proteins / metabolism
  • Humans
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Phosphorylation / drug effects
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / pharmacology
  • Signal Transduction* / drug effects
  • Smad2 Protein / metabolism
  • Synapses / physiology*
  • Transforming Growth Factor beta / metabolism


  • Calcium-Binding Proteins
  • Extracellular Matrix Proteins
  • HSP70 Heat-Shock Proteins
  • RNA, Small Interfering
  • Recombinant Proteins
  • Smad2 Protein
  • Transforming Growth Factor beta
  • fibulin 2