Abstract
Neural stem cells (NSCs) have been shown as a potential source for replacing degenerated neurons in neurodegenerative diseases. However, the therapeutic potential of these cells is limited by the lack of effective methodologies for controlling their differentiation. Inducing endogenous pools of NSCs by small molecule can be considered as a potential approach of generating the desired cell types in large numbers. Here, we reported the characterization of a small molecule (Methyl 3,4-dihydroxybenzoate; MDHB) that selectively induces hippocampal NSCs to differentiate into cholinergic motor neurons which expressed synapsin 1 (SYN1) and postsynaptic density protein 95 (PSD-95). Studies on the mechanisms revealed that MDHB induced the hippocampal NSCs differentiation into cholinergic motor neurons by inhibiting AKT phosphorylation and activating autophosphorylation of GSK3β at tyrosine 216. Furthermore, we found that MDHB enhanced β-catenin degradation and abolished its entering into the nucleus. Collectively, this report provides the strong evidence that MDHB promotes NSCs differentiation into cholinergic motor neurons by enhancing gene Isl1 expression and inhibiting cell cycle progression. It may provide a basis for pharmacological effects of MDHB directed on NSCs.
Highlights
Neural stem cells (NSCs) have the ability of self-renewal and to differentiate into multiple specialized neural cell types, such as neurons, astrocytes and oligodendrocytes, serving as the common source of these fundamental components of the CNS (Gage, 2000)
We showed that the expression of neuronal differentiation transforming acidic coiled-coil 3 (Tacc3) gene and cell cycle are inhibited and cholinergic neuronal differentiation gene Isl1 are up-regulated by MDHB
Since the neuronal differentiation of NSCs is an intricate process, it is not surprising that many substances have been involved in the regulation action (Gauthier-Fisher et al, 2009; Ming and Song, 2009; Akizu et al, 2010; Luo et al, 2010; Park et al, 2016; Vasconcelos et al, 2016)
Summary
Neural stem cells (NSCs) have the ability of self-renewal and to differentiate into multiple specialized neural cell types, such as neurons, astrocytes and oligodendrocytes, serving as the common source of these fundamental components of the CNS (Gage, 2000). NSCs can furnish an unlimited source of cells for cell transplantation therapy to supplement degenerating cells (Ager et al, 2015; Reidling et al, 2018). Facing this potential, some defects, such as the uncontrollability of stem cell differentiation pathway and immune rejection for stem cell therapy, can be surmounted. Kim et al (2009) showed that the phosphorylation levels of β-catenin, target of GSK3β, are increased at later stages in development when stem cell proliferation is declining and cholinergic neuronal differentiation predominates (Ming and Song, 2009). Degradation of β-catenin by activation of GSK3β will inhibit cell proliferation and increase cell differentiation. These finding demonstrate that the activation of GSK3β increases cell differentiation (Kuwabara et al, 2009)
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