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.
Bibliografisk noteFunding Information:
We thank Dorte Lyholmer, Nadine Becker-von Buch, and Ulla Damgaard Munk for excellent technical assistance and Claire Gudex for proofreading the manuscript. This work was supported by the Innovation Fund Denmark (BrainStem; www.brainstem.dk ), the Lundbeck Foundation , the Danish Parkinson Foundation , the Jascha Foundation , IMK Almene Fond , the A.P. Møller Foundation , and the Faculty of Health Sciences , University of Southern Denmark . Work at the CBMSO was supported by grants (to A.M.S.) SAF-2017-83241-R , RETICS TerCel RD16/0011/0032 .
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