Abstract
The molecular mechanisms underlying fate decisions of human neural stem cells (hNSCs) between neurogenesis and gliogenesis are critical during neuronal development and neurodegenerative diseases. Despite its crucial role in the murine nervous system, the potential role of the transcription factor NF-κB in the neuronal development of hNSCs is poorly understood. Here, we analyzed NF-κB subunit distribution during glutamatergic differentiation of hNSCs originating from neural crest-derived stem cells. We observed several peaks of specific NF-κB subunits. The most prominent nuclear peak was shown by c-REL subunit during a period of 2–5 days after differentiation onset. Furthermore, c-REL inhibition with pentoxifylline (PTXF) resulted in a complete shift towards oligodendroglial fate, as demonstrated by the presence of OLIG2+/O4+-oligodendrocytes, which showed PDGFRα, NG2 and MBP at the transcript level. In addition c-REL impairment further produced a significant decrease in neuronal survival. Transplantation of PTXF-treated predifferentiated hNSCs into an ex vivo oxidative-stress-mediated demyelination model of mouse organotypic cerebellar slices further led to integration in the white matter and differentiation into MBP+ oligodendrocytes, validating their functionality and therapeutic potential. In summary, we present a human cellular model of neuronal differentiation exhibiting a novel essential function of NF-κB-c-REL in fate choice between neurogenesis and oligodendrogenesis which will potentially be relevant for multiple sclerosis and schizophrenia.
Highlights
The development, function and regeneration of the human brain crucially depend on the generation of neurons, astrocytes and oligodendrocytes by neural stem cells (NSCs) [1]
neural crest-derived stem cells (NCSCs)-derived NSCs is driven by NF-κB-c-REL, while c-REL impairment by pentoxifylline (PTXF) had a strongly significant effect on cell survival, and led to a direct shift from glutamatergic neurons towards oligodendrocytes
NF-κB-p65 activity was implicated in pluripotency maintenance and decreased upon differentiation of human embryonic stem cells [27,28]
Summary
The development, function and regeneration of the human brain crucially depend on the generation of neurons, astrocytes and oligodendrocytes by neural stem cells (NSCs) [1]. Differentiation of NSCs results in the equal proportion of neurons and glia observed in the human brain [2], with particular proportions between distinct glial cell populations. In the cerebral cortex, astrocytes correspond to 20%, microglia to 5% and oligodendrocytes to even 75% of all glial cells [3]. The mechanisms underlying brain development and composition during adulthood crucially depend on fate decisions of NSCs, which are directly linked to the progression of neurodegenerative diseases. Alzheimer’s disease was recently correlated with the inability of NSCs to undergo neuronal differentiation [4].
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