Abstract
BackgroundMicrotubule-stabilizing agents have been demonstrated to modulate axonal sprouting during neuronal disease. One such agent, Epothilone D, has been used to treat spinal cord injury (SCI) by promoting axonal sprouting at the lesion site after SCI. However, the role of Epothilone D in the differentiation of neural stem cells (NSCs) in SCI repair is unknown. In the present study, we mainly explored the effects and mechanisms of Epothilone D on the neuronal differentiation of NSCs and revealed a potential new SCI treatment.MethodsIn vitro differentiation assays, western blotting, and quantitative real-time polymerase chain reaction were used to detect the effects of Epothilone D on NSC differentiation. Retrograde tracing using a pseudotyped rabies virus was then used to detect neuronal circuit construction. RNA sequencing (RNA-Seq) was valuable for exploring the target gene involved in the neuronal differentiation stimulated by Epothilone D. In addition, lentivirus-induced overexpression and RNA interference technology were applied to demonstrate the function of the target gene. Last, an Apol8-NSC-linear ordered collagen scaffold (LOCS) graft was prepared to treat a mouse model of SCI, and functional and electrophysiological evaluations were performed.ResultsWe first revealed that Epothilone D promoted the neuronal differentiation of cultured NSCs and facilitated neuronal relay formation in the injured site after SCI. Furthermore, the RNA-Seq results demonstrated that Apol8 was upregulated during Epothilone D-induced neuronal relay formation. Lentivirus-mediated Apol8 overexpression in NSCs (Apol8-NSCs) promoted NSC differentiation toward neurons, and an Apol8 interference assay showed that Apol8 had a role in promoting neuronal differentiation under the induction of Epothilone D. Last, Apol8-NSC transplantation with LOCS promoted the neuronal differentiation of transplanted NSCs in the lesion site as well as synapse formation, thus improving the motor function of mice with complete spinal cord transection.ConclusionsEpothilone D can promote the neuronal differentiation of NSCs by upregulating Apol8, which may provide a promising therapeutic target for SCI repair.
Highlights
Microtubule-stabilizing agents have been demonstrated to modulate axonal sprouting during neuronal disease
Epothilone D can promote the neuronal differentiation of neural stem cells (NSCs) by upregulating Apol8, which may provide a promising therapeutic target for spinal cord injury (SCI) repair
Epothilone D can facilitate the reconstruction of neural circuits Having shown that Epothilone D can promote the neuronal differentiation of NSCs in vitro, we explored whether NSCs differentiated by Epothilone D
Summary
Microtubule-stabilizing agents have been demonstrated to modulate axonal sprouting during neuronal disease. One such agent, Epothilone D, has been used to treat spinal cord injury (SCI) by promoting axonal sprouting at the lesion site after SCI. The role of Epothilone D in the differentiation of neural stem cells (NSCs) in SCI repair is unknown. Spinal cord injury (SCI) is a serious condition of the central nervous system (CNS), and SCI repair is a great clinical challenge. Functional connections between neurons are lost, nerve impulse transmission terminates, and a large number of astrocytes around the damaged area are activated, which forms a physical barrier or glial scar, in the damaged area, seriously hindering axonal regrowth and the reconstruction of new neural circuits [6]
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