Microglia-Secreted Factors Enhance Dopaminergic Differentiation of Tissue- and iPSC-Derived Human Neural Stem Cells

Sissel Ida Schmidt, Helle Bogetofte, Louise Ritter, Jette Bach Agergaard, Ditte Hammerich, Amina Arslanagic Kabiljagic, Agnieszka Wlodarczyk, Silvia Garcia Lopez, Mia Dahl Sørensen, Mie Lærkegård Jørgensen, Justyna Okarmus, Alberto Martínez Serrano, Bjarne Winther Kristensen, Kristine Freude, Trevor Owens, Morten Meyer*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Microglia have recently been established as key regulators of brain development. However, their role in neuronal subtype specification remains largely unknown. Using three different co-culture setups, we show that microglia-secreted factors enhance dopaminergic differentiation of somatic and induced pluripotent stem cell-derived human neural stem cells (NSCs). The effect was consistent across different NSC and microglial cell lines and was independent of prior microglial activation, although restricted to microglia of embryonic origin. We provide evidence that the effect is mediated through reduced cell proliferation and decreased apoptosis and necrosis orchestrated in a sequential manner during the differentiation process. tumor necrosis factor alpha, interleukin-1β, and insulinlike growth factor 1 are identified as key mediators of the effect and shown to directly increase dopaminergic differentiation of human NSCs. These findings demonstrate a positive effect of microglia on dopaminergic neurogenesis and may provide new insights into inductive and protective factors that can stimulate in vitro derivation of dopaminergic neurons.

Original languageEnglish
JournalStem Cell Reports
Volume16
Issue number2
Pages (from-to)281-294
ISSN2213-6711
DOIs
Publication statusPublished - 9. Feb 2021

Keywords

  • co-culture
  • dopamine
  • IGF1
  • IL-1β
  • microglia
  • neuron-microglia interaction
  • NSCs
  • Parkinson's disease
  • secretome analysis
  • TNFα

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