Abstract
Fibroblast growth factor (FGF) and epidermal growth factor (EGF) are critical for the development of the nervous system. We previously discovered that FGF2 and EGF had opposite effects on motor neuron differentiation from human fetal neural stem cells (hNSCs), but the underlying mechanisms remain unclear. Here, we show that FGF2 and EGF differentially affect the temporal patterns of Akt and glycogen synthase kinase 3 beta (GSK3β) activation. High levels of phosphatidylinositol 3-kinase (PI3K)/Akt activation accompanied with GSK3β inactivation result in reduction of the motor neuron transcription factor HB9. Inhibition of PI3K/Akt by chemical inhibitors or RNA interference or overexpression of a constitutively active form of GSK3β enhances HB9 expression. Consequently, PI3K inhibition increases hNSCs differentiation into HB9+/microtubule-associated protein 2 (MAP2)+ motor neurons in vitro. More importantly, blocking PI3K not only enhances motor neuron differentiation from hNSCs grafted into the ventral horn of adult rat spinal cords, but also permits ectopic generation of motor neurons in the dorsal horn by overriding environmental influences. Our data suggest that FGF2 and EGF affect the motor neuron fate decision in hNSCs differently through a fine tuning of the PI3K/AKT/GSK3β pathway, and that manipulation of this pathway can enhance motor neuron generation.
Highlights
Neural stem cells (NSCs) can self-renew and differentiate into all three neural lineages
We have previously discovered that priming with FGF2 plus laminin (FL) endowed human NSCs (hNSCs) with the potential to differentiate into motor neurons (MNs), whereas epidermal growth factor (EGF)/laminin or EGF plus leukemia inhibitory factor (LIF)/laminin (ELL) priming inhibited MN formation [9]
It is known that activation of the Fibroblast growth factor (FGF) and EGF receptors, FGFR and EGFR, respectively, could both lead to the activation of the phosphatidylinositol 3kinase (PI3K)/Akt pathway that negatively regulates glycogen synthase kinase 3 beta (GSK3b) [20]
Summary
Neural stem cells (NSCs) can self-renew and differentiate into all three neural lineages (neurons, astrocytes and oligodendrocytes). The final fate that NSCs will adopt depends on the activation of specific signaling pathways, which are stimulated by different ligands, including growth factors [1,2,3]. A second possibility is that they activate the same pathways but with different intensities of activation (e.g. phosphorylation level of downstream proteins) or different duration of activation (e.g. the time that the proteins in the pathway remain phosphorylated) [12] Knowledge of how these factors control MN differentiation from NSCs may have profound significance in therapies for MN disorders, such as amyotrophic lateral sclerosis and spinal cord injury, where MN replacement may be one of the ultimate choices. This discovery could provide insights into stem cell-based therapies to replace MNs lost in diseases
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