Abstract
SummaryMicroglia 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.
Highlights
Neurogenesis is a complex process comprising several steps that require regulation by the microenvironment
To address the role of microglia and their activation state in dopaminergic neurogenesis, we investigated whether microglia-secreted factors enhanced dopaminergic differentiation of somatic and induced pluripotent stem cellderived human neural stem cells (NSCs) in vitro
Independent of the microglial cell type and NSC lines, co-culturing NSCs with microglia during differentiation increased the content of dopaminergic neurons in the cultures
Summary
Neurogenesis is a complex process comprising several steps that require regulation by the microenvironment. As microglia are present in the brain before the emergence of neurons and other glia, they may play an important role in providing a proper microenvironment for embryonic neurogenesis. This hypothesis is supported by studies showing that colony-stimulating factor 1 receptor knockout mice, which lack microglia, display abnormal brain development (Elmore et al, 2014), and that microglia can induce developmental apoptosis and thereby regulate the size of the neural precursor pool (Cunningham et al, 2013; Marin-Teva et al, 2004; Tronnes et al, 2016; Wakselman et al, 2008). Microglia have been reported to modulate synaptogenesis through local synthesis of neurotrophic factors (Miyamoto et al, 2016; Parkhurst et al, 2013), participate in synaptic pruning (Paolicelli et al, 2011; Schafer et al, 2012), and guide axonal outgrowth (Pont-Lezica et al, 2014; Squarzoni et al, 2014)
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