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. 

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Spinal cord injury: molecular mechanisms and therapeutic interventions

BACKGROUND Neurotoxic microglia and astrocytes begin to activate and participate in pathological processes after spinal cord injury (SCI), subsequently causing severe secondary damage and affecting tissue repair. We have previously reported that photobiomodulation (PBM) can promote functional recovery by reducing neuroinflammation after SCI, but little is known about the underlying mechanism. Therefore, we aimed to investigate whether PBM ameliorates neuroinflammation by modulating the activation of microglia and astrocytes after SCI. METHODS Male Sprague-Dawley rats were randomly divided into three groups: a sham control group, an SCI + vehicle group and an SCI + PBM group. PBM was performed for two consecutive weeks after clip-compression SCI models were established. The activation of neurotoxic microglia and astrocytes, the level of tissue apoptosis, the number of motor neurons and the recovery of motor function were evaluated at different days post-injury (1, 3, 7, 14, and 28 days post-injury, dpi). Lipocalin 2 (Lcn2) and Janus kinase-2 (JAK2)-signal transducer and activator of transcription-3 (STAT3) signaling were regarded as potential targets by which PBM affected neurotoxic microglia and astrocytes. In in vitro experiments, primary microglia and astrocytes were irradiated with PBM and cotreated with cucurbitacin I (a JAK2-STAT3 pathway inhibitor), an adenovirus (shRNA-Lcn2) and recombinant Lcn2 protein. RESULTS PBM promoted the recovery of motor function, inhibited the activation of neurotoxic microglia and astrocytes, alleviated neuroinflammation and tissue apoptosis, and increased the number of neurons retained after SCI. The upregulation of Lcn2 and the activation of the JAK2-STAT3 pathway after SCI were suppressed by PBM. In vitro experiments also showed that Lcn2 and JAK2-STAT3 were mutually promoted and that PBM interfered with this interaction, inhibiting the activation of microglia and astrocytes. CONCLUSION Lcn2/JAK2-STAT3 crosstalk is involved in the activation of neurotoxic microglia and astrocytes after SCI, and this process can be suppressed by PBM.

Photobiomodulation inhibits the activation of neurotoxic microglia and astrocytes by inhibiting Lcn2/JAK2-STAT3 crosstalk after spinal cord injury in male rats.

After spinal cord injury (SCI), reactive astrocytes can be classified into two distinctive phenotypes according to their different functions: neurotoxic (A1) astrocytes and neuroprotective (A2) astrocytes. Our previous studies proved that photobiomodulation (PBM) can promote motor function recovery and improve tissue repair after SCI, but little is known about the underlying mechanism. Therefore, we aimed to investigate whether PBM contributes to repair after SCI by regulating the activation of astrocytes. Male rats subjected to clip-compression SCI were treated with PBM for two consecutive weeks, and the results showed that recovery of motor function was improved, the lesion cavity size was reduced, and the number of neurons retained was increased. We determined the time course of A1/A2 astrocyte activation after SCI by RNA sequencing (RNA-Seq) and verified that PBM inhibited A1 astrocyte activation and promoted A2 astrocyte activation at 7 days postinjury (dpi) and 14 dpi. Subsequently, potential signaling pathways related to A1/A2 astrocyte activation were identified by GO function analysis and KEGG pathway analysis and then studied in animal experiments and preliminarily analyzed in cultured astrocytes. Next, we observed that the expression of basic fibroblast growth factor (bFGF) and transforming growth factor-β (TGF-β) was upregulated by PBM and that both factors contributed to the transformation of A1/A2 astrocytes in a dose-dependent manner. Finally, we found that PBM reduced the neurotoxicity of A1 astrocytes to dorsal root ganglion (DRG) neurons. In conclusion, PBM can promote better recovery after SCI, which may be related to the transformation of A1/A2 reactive astrocytes.

Photobiomodulation Promotes Repair Following Spinal Cord Injury by Regulating the Transformation of A1/A2 Reactive Astrocytes.

The repair and motor functional recovery after spinal cord injury (SCI) has remained a clinical challenge. Injury-induced gliosis and inflammation lead to a physical barrier and an extremely inhibitory microenvironment, which in turn hinders the recovery of SCI. TLR4-NF-κB is a classic implant-related innate immunomodulation signaling pathway and part of numerous biomaterial-based treatment strategies for SCI. Numerous experimental studies have demonstrated that the regulation of TLR4-NF-κB signaling pathway plays an important role in the alleviation of inflammatory responses, the modulation of autophagy, apoptosis and ferroptosis, and the enhancement of anti-oxidative effect post-SCI. An increasing number of novel biomaterials have been fabricated as scaffolds and carriers, loaded with phytochemicals and drugs, to inhibit the progression of SCI through regulation of TLR4-NF-κB. This review summarizes the empirical strategies for the recovery after SCI through individual or composite biomaterials that mediate the TLR4-NF-κB signaling pathway.

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Strategies for Biomaterial-Based Spinal Cord Injury Repair via the TLR4-NF-κB Signaling Pathway

Spinal cord injury (SCI) is a catastrophic disease with a complex pathogenesis that includes inflammation, oxidative stress, and glial scar formation. Macrophages are the main mediators of the inflammatory response and are distributed in the epicentre of the SCI. Macrophages have neurotoxic and neuroprotective phenotypes (also known as classically and alternatively activated macrophages or M1 and M2 macrophages) that are associated with pro- or anti- inflammatory gene expression. Our previous study demonstrated that photobiomodulation (PBM) alters the polarization state of macrophages in the SCI region towards the M2 phenotype and promotes the recovery of motor function in rats with SCI. However, the mechanism by which PBM promotes SCI repair remains largely undefined. This study is based on the replacement of conventional percutaneous irradiation with implantable biofibre optic in vivo irradiation. The aim was to further investigate the effects of PBM on SCI in mice under new irradiation patterns and its potential mechanisms of action. PBM was administered to male mice with clamped SCI for four consecutive weeks and significantly promoted the recovery of motor function in mice. Analysis of the macrophage phenotypes in the epicentre of the SCI in mice showed that PBM mainly inhibited the neurotoxic activation of macrophages in the SCI area and reduced the secretion of inflammatory factors such as IL-1α and IL-6; PBM had no effect on M2 macrophages. Immediately afterwards, we constructed in vitro models of the inflammatory polarization of macrophages and PBM intervention. We found that PBM attenuated the neurotoxicity of M1 macrophages on VSC 4.1 motor neurons and dorsal root ganglion (DRG) neurons. The effects of PBM on neurotoxic macrophages and the possible mechanisms of action were analysed using RNA sequencing (RNA-seq), which confirmed that the main role of PBM was to modulate the inflammatory response and immune system processes. Analysis of the differentially expressed genes (DEGs) associated with the inflammatory response showed that PBM had the most significant regulatory effects on genes such as interleukin (IL)-1α, IL-6, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) and had obvious inhibitory effects on inflammation-related Notch1 and hypoxia-inducible factor-1α (HIF-1α) pathway genes. RNA-seq analysis of the effect of PBM on gene expression in resting-state macrophages and M2 macrophages did not show significant differences (data not shown). In conclusion, PBM promoted better motor recovery after SCI in mice by inhibiting the neurotoxic polarization of macrophages and the release of inflammatory mediators by acting on the Notch1-HIF-1α/NF-κB Signalling Pathway.

/pdf/photobiomodulation-attenuates-neurotoxic-polarization-of-3apd8pk6.pdf

Photobiomodulation Attenuates Neurotoxic Polarization of Macrophages by Inhibiting the Notch1-HIF-1α/NF-κB Signalling Pathway in Mice With Spinal Cord Injury

Spinal cord injury (SCI) stimulates reactive astrogliosis and the infiltration of macrophages, which interact with each other at the injured area. We previously found Photobiomodulation (PBM) significantly decreases the number of M1 macrophages at the injured area of SCI. But the exact nature of the astrocyte response following PBM and relationship with the macrophage have not been explored in detail. In this study, a BALB/c mice model with standardized bilateral spinal cord compression and a macrophage-astrocyte co-culture model were applied to study effects of PBM on astrocytes. Results showed that PBM inhibit the expression of the astrocyte markers glial fibrillary acidic protein (GFAP) and the secretion of chondroitin sulfate proteoglycans (CSPG) in the para-epicenter area, decrease the number of M1 macrophage in vivo. The in vitro experiments indicated M1 macrophages promote the cell viability of astrocytes and the expression of CSPG. However, PBM significantly inhibited the expression of GFAP, decreased activation of astrocyte, and downregulated the expression of CSPG by regulating M1 macrophages. These results demonstrate that PBM may regulate the interaction between macrophages and astrocytes after spinal cord injury, which inhibited the formation of glial scar.

Photobiomodulation Therapy Inhibit the Activation and Secretory of Astrocytes by Altering Macrophage Polarization

Macrophages play key roles in the secondary injury stage of spinal cord injury (SCI). M1 macrophages occupy the lesion area and secrete high levels of inflammatory factors that hinder lesion repair, and M2 macrophages can secrete neurotrophic factors and promote axonal regeneration. The regulation of macrophage secretion after SCI is critical for injury repair. Low-level laser therapy (810-nm) (LLLT) can boost functional rehabilitation in rats after SCI; however, the mechanisms remain unclear. To explore this issue, we established an in vitro model of low-level laser irradiation of M1 macrophages, and the effects of LLLT on M1 macrophage polarization and neurotrophic factor secretion and the related mechanisms were investigated. The results showed that LLLT irradiation decreased the expression of M1 macrophage-specific markers, and increased the expression of M2 macrophage-specific markers. Through forward and reverse experiments, we verified that LLLT can promote the secretion of various neurotrophic factors by activating the PKA-CREB pathway in macrophages and finally promote the regeneration of axons. Accordingly, LLLT may be an effective therapeutic approach for SCI with clinical application prospects.

Low-level laser therapy 810-nm up-regulates macrophage secretion of neurotrophic factors via PKA-CREB and promotes neuronal axon regeneration in vitro.

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Photobiomodulation Therapy Inhibit the Activation and Secretory of Astrocytes by Altering Macrophage Polarization

Low-level laser therapy 810-nm up-regulates macrophage secretion of neurotrophic factors via PKA-CREB and promotes neuronal axon regeneration in vitro.