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

Affiliation

Schmidt SI(1), Bogetofte H(1), Ritter L(1), Agergaard JB(1), Hammerich D(1), Kabiljagic AA(1), Wlodarczyk A(1), Lopez SG(2), Sørensen MD(3), Jørgensen ML(1), Okarmus J(1), Serrano AM(2), Kristensen BW(4), Freude K(5), Owens T(6), Meyer M(7).
Author information:
(1)Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, DK.
(2)Department of Molecular Biology and Center of Molecular Biology Severo Ochoa, University Autonoma Madrid-C.S.I.C., Madrid, ES.
(3)Department of Pathology, Odense University Hospital, Odense, DK.
(4)Department of Pathology, Odense University Hospital, Odense, DK; BRIDGE - Brain Research Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, DK.
(5)Faculty of Health and Medical Sciences, Department of Veterinary and Animal Sciences, Section for Pathobiological Sciences, University of Copenhagen, Copenhagen, DK.
(6)Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, DK; BRIDGE - Brain Research Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, DK.
(7)Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, DK; Department of Neurology, Odense University Hospital, Odense, DK; BRIDGE - Brain Research Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, DK. Electronic address: [Email]

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.