TY - JOUR

T1 - Microglia-Secreted Factors Enhance Dopaminergic Differentiation of Tissue- and iPSC-Derived Human Neural Stem Cells

AU - Schmidt, Sissel Ida

AU - Bogetofte, Helle

AU - Ritter, Louise

AU - Agergaard, Jette Bach

AU - Hammerich, Ditte

AU - Kabiljagic, Amina Arslanagic

AU - Wlodarczyk, Agnieszka

AU - Lopez, Silvia Garcia

AU - Sørensen, Mia Dahl

AU - Jørgensen, Mie Lærkegård

AU - Okarmus, Justyna

AU - Serrano, Alberto Martínez

AU - Kristensen, Bjarne Winther

AU - Freude, Kristine

AU - Owens, Trevor

AU - Meyer, Morten

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

U2 - 10.1016/j.stemcr.2020.12.011

DO - 10.1016/j.stemcr.2020.12.011

M3 - Journal article

C2 - 33482100

VL - 16

SP - 1

EP - 14

JO - Stem Cell Reports

JF - Stem Cell Reports

SN - 2213-6711

ER -