Spinal cord injury: molecular mechanisms and therapeutic interventions

Abstract

Spinal cord injury (SCI) remains a severe condition with an extremely high disability rate. The challenges of SCI repair include its complex pathological mechanisms and the difficulties of neural regeneration in the central nervous system. In the past few decades, researchers have attempted to completely elucidate the pathological mechanism of SCI and identify effective strategies to promote axon regeneration and neural circuit remodeling, but the results have not been ideal. Recently, new pathological mechanisms of SCI, especially the interactions between immune and neural cell responses, have been revealed by single-cell sequencing and spatial transcriptome analysis. With the development of bioactive materials and stem cells, more attention has been focused on forming intermediate neural networks to promote neural regeneration and neural circuit reconstruction than on promoting axonal regeneration in the corticospinal tract. Furthermore, technologies to control physical parameters such as electricity, magnetism and ultrasound have been constantly innovated and applied in neural cell fate regulation. Among these advanced novel strategies and technologies, stem cell therapy, biomaterial transplantation, and electromagnetic stimulation have entered into the stage of clinical trials, and some of them have already been applied in clinical treatment. In this review, we outline the overall epidemiology and pathophysiology of SCI, expound on the latest research progress related to neural regeneration and circuit reconstruction in detail, and propose future directions for SCI repair and clinical applications.

Fig. 1

Two main repair strategies and related signaling pathway of neural circuit reconstruction after SCI. a Type I: CST extension. PTEN and suppressor of cytokine signaling 3 (SOCS3) deletion could effectively enhance the CST traced with biotin dextran amine (BDA), which showed the regenerative ability of adult corticospinal neurons.^, b Signaling pathways involved such as PI3K pathway, Ras pathway, PLC pathway, and PTEN/mTOR pathway. The figure was created with BioRender.com. c Type II: establishment of intermediate neuron bridging network. SCI mice were significantly improved by LDH-NT3 implantation. d Signaling pathways involved such as Wnt/β-Catenin pathway and TGFβ/SMAD pathway. The figure was created with BioRender.com

Fig. 2

A schematic illustration of molecular (a) and cellular (b) changes post SCI.

Fig. 3

Schematic depiction of various advanced therapeutic strategies for repairing SCI based on the studies. Strategies including bioactive substances regulating, cell therapy, biomaterials transplantation, and physical controlling, are applied to repair SCI from different perspectives. Meanwhile, the combined use of these strategies has also received increasing attention from researchers. The figure is generated from BioRender.com

Fig. 4

Advanced biomaterials for bioactive molecule delivery and microenvironment regulation. a, b Functionalized aligned Col-FB fibrous hydrogel induced NSPC migration and neuronal differentiation. Adapted with permission from ref. Copyright 2022, American Chemical Society. c–e The LDH/LDH-NT3 transplantation promoted the process of neural regeneration and neural circuit reconstruction in the lesion sites of SCI mice. Adapted with permission from ref. Copyright 2021, American Chemical Society