Transplantation of Wnt5a-modified NSCs promotes tissue repair and locomotor functional recovery after spinal cord injury

Xiang Li,Le Wang,Yong Wan,Ying Tuo,Zhiming Peng,Xiaoyang Zhao,Lingli Long,Ningning Chen,Xiaofang Lu,Kai Zhu

doi:10.1038/s12276-020-00536-0

Abstract

Traditional therapeutic strategies for spinal cord injury (SCI) are insufficient to repair locomotor function because of the failure of axonal reconnection and neuronal regeneration in the injured central nervous system (CNS). Neural stem cell (NSC) transplantation has been considered a potential strategy and is generally feasible for repairing the neural circuit after SCI; however, the most formidable problem is that the neuronal differentiation rate of NSCs is quite limited. Therefore, it is essential to induce the neuronal differentiation of NSCs and improve the differentiation rate of NSCs in spinal cord repair. Our results demonstrate that both Wnt5a and miRNA200b-3p could promote NSC differentiation into neurons and that Wnt5a upregulated miRNA200b-3p expression through MAPK/JNK signaling to promote NSC differentiation into neurons. Wnt5a could reduce RhoA expression by upregulating miRNA200b-3p expression to inhibit activation of the RhoA/Rock signaling pathway, which has been reported to suppress neuronal differentiation. Overexpression of RhoA abolished the neurogenic capacity of Wnt5a and miRNA200b-3p. In vivo, miRNA200b-3p was critical for Wnt5a-induced NSC differentiation into neurons to promote motor functional and histological recovery after SCI by suppressing RhoA/Rock signaling. These findings provide more insight into SCI and help with the identification of novel treatment strategies.

Highlights

Spinal cord injury (SCI) is considered to be a refractory disease with devastating physical, psychosocial, and vocational implications for patients and caregivers despite enormous advances in medical and surgical treatments[1,2]
To investigate whether the neurogenic effect of Wnt5a depends on inhibition of the RhoA/Rock[1] pathway, neural stem cell (NSC) were treated with Wnt5a (10 ng/mL) for 3 days, and the real-time quantitative reverse transcription PCR (RT-qPCR) and WB results showed that Wnt5a suppressed RhoA and Rock[1] gene expression (Fig. 2b, c)
An agent that is able to suppress negative effects on neuronal differentiation and simultaneously promote neurogenesis in the microenvironment would be of great benefit for the treatment of traumatic spinal cord injury

Summary

Introduction

Spinal cord injury (SCI) is considered to be a refractory disease with devastating physical, psychosocial, and vocational implications for patients and caregivers despite enormous advances in medical and surgical treatments[1,2]. Cell transplantation has been considered a potential strategy to repair the neural circuit after SCI6,7. Several studies have reported that neural stem cell (NSC) transplantation results in partial repair due to the neuronal differentiation of NSCs8,9. In most SCI cases, only a few exogenous NSCs differentiate into neurons, while most of them differentiate into astrocytes, which is a disadvantage in spinal cord repair[10,11]. The challenging points are increasing the differentiation rate of neurons and promoting the differentiated NSCs to reconnect the neural circuit

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