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

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.

SUBMITTER: Schmidt SI

PROVIDER: S-EPMC7878834 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Schmidt Sissel Ida SI Bogetofte Helle H Ritter Louise L Agergaard Jette Bach JB Hammerich Ditte D Kabiljagic Amina Arslanagic AA Wlodarczyk Agnieszka A Lopez Silvia Garcia SG Sørensen Mia Dahl MD Jørgensen Mie Lærkegård ML Okarmus Justyna J Serrano Alberto Martínez AM Kristensen Bjarne Winther BW Freude Kristine K Owens Trevor T Meyer Morten M

Stem cell reports 20210121 2

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 res ...[more]

PMID: 33482100

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Project description:IntroductionThe extract of pluripotent stem cells induces dedifferentiation of somatic cells with restricted plasticity.MethodsIn this study, we used the extract of human embryonic stem cells (hESC) to dedifferentiate adipose tissue-derived stem cells (ADSCs) and examined the impact of this reprogramming event on the dopaminergic differentiation of the cells. For this purpose, cytoplasmic extract of ESCs was prepared by repeated freezing and thawing cycles. The plasma membrane of hADSCs was reversibly permeabilized by streptolysin O (SLO), exposed to hESC extract, and resealed by a CaCl2-containing medium.ResultsAs revealed by qPCR analysis, expression of OCT4, SOX2, NANOG, LIN28A, and KLF4 mRNAs were downregulated in the ADSCs one week after extract incubation, while all mRNAs except for KLF4 were upregulated at the end of the second week. For dopaminergic differentiation, control and reprogrammed ADSCs were induced by a serum-free neurobasal medium containing B27 and a cocktail of sonic hedgehog (SHH), basic fibroblast growth factor (bFGF), fibroblastic growth factor 8 (FGF8), and brain-derived neurotrophic factor (BDNF) for 12 days. After differentiation, the expression levels of some neuronal and dopaminergic-related genes, including PAX6, NESTIN, NEFL, GLI1, LMXB1, EN1, NURR1, and TH, significantly increased in the reprogrammed ADSCs compared to the control group. On the whole, two weeks after reprogramming by ESC extract, ADSCs showed an improved dopaminergic differentiation potential.ConclusionThese findings suggest that the cytoplasmic extract of hESCs contains some regulatory factors which induce the expression of pluripotency-associated markers in somatic cells and that the exposure to ESC extract may serve as a simple and rapid strategy to enhance the plasticity of somatic stem cells for cell replacement therapy purposes.HighlightshADSCs have emerged as a valuable candidate for transplantation therapy of neurodegenerative diseases.Several studies have documented dopaminergic dedifferentiation of hADSCs.Implementing ADSCs towards a more pluripotent state using different strategies like somatic cell nuclear transfer.Plain language summaryThe extract of pluripotent stem cells induces dedifferentiation of somatic cells with restricted plasticity. In this study, we used the extract of hESC to dedifferentiate ADSCs and examined the impact of this reprogramming event on the dopaminergic differentiation of the cells. Cytoplasmic extract of ESCs was prepared by repeated freezing and thawing cycles. These cells express several neuron-specific genes, secrete several factors associated with neuroprotection, and exhibit differentiation into neural and glial cells in vitro. In recent years, several studies have documented dopaminergic differentiation of hADSCs.

Dataset Information

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

Publications

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

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