Spinal Cord Injury Regeneration Research Articles

Neurophilic peptide-reinforced dual-fiber-network bioactive hydrogels for spinal cord injury repair

Spinal cord injury (SCI) is a challenging central nervous system disorder that characterized by microenvironmental disturbances following injury, which can be addressed by simulating the microenvironment of the spinal cord regeneration. Herein, we report the design and synthesis of bioactive hydrogels with a dual-fiber-network (DFN) porous structure, using self-assembled peptide nanofibers (PNFs) and natural cellulose nanofibers (CNFs). A neurophilic peptide is further introduced to enhance nervous regeneration capability of the pre-prepared PNF/CNF hydrogels, which then exhibit excellent neuro-affinity, self-healing ability, biodegradability, and biocompatibility, facilitating targeted SCI repair and regeneration through the hydrogel injection. The in vitro experiments reveal that the DFN hydrogel can enhance the proliferation and migration of bone marrow mesenchymal stem cells, and induce neural stem cell (NSC) proliferation with enhanced neuronal differentiation and axonal growth. Additionally, the in vivo studies validate that the hydrogel attenuates the post-SCI inflammation, inhibits reactive astrocyte proliferation, and facilitates endogenous NSC proliferation and migration, as well as promotes neuronal growth and axonal regeneration. The potential mechanism of SCI repair is ascribed to the hydrogel-induced activation of the PI3K/AKT/mTOR pathway, which alleviates inflammatory response, inhibits excessive reactive response of glial cells, and promotes NSC differentiation into neurons. This neurophilic peptide-reinforced DFN bioactive hydrogel system, with its comprehensive approach to SCI repair, holds great potential for clinical applications.

Biomimetic electrospun PVDF/self-assembling peptide piezoelectric scaffolds for neural stem cell transplantation in neural tissue engineering.

Piezoelectric materials can provide in situ electrical stimulation without external chemical or physical support, opening new frontiers for future bioelectric therapies. Polyvinylidene fluoride (PVDF) possesses piezoelectricity and biocompatibility, making it an electroactive biomaterial capable of enhancing bioactivity through instantaneous electrical stimulation, which indicates significant potential in tissue engineering. In this study, we developed electroactive and biomimetic scaffolds made of electrospun PVDF and self-assembling peptides (SAPs) to enhance stem cell transplantation for spinal cord injury regeneration. We investigated the morphology and crystalline polymorphs of the electrospun scaffolds. Morphological studies demonstrated the benefit of using mixed sodium dodecyl sulfate (SDS) and SAPs as additives to form thinner, uniform, and defect-free fibers. Regarding electroactive phases, β and γ phases-evidence of electroactivity-were predominant in aligned scaffolds and scaffolds modified with SDS and SAPs. In vitro studies showed that neural stem cells (NSCs) seeded on electrospun PVDF with additives exhibited desirable proliferation and differentiation compared to the gold standard. Furthermore, the orientation of the fibers influenced scaffold topography, resulting in a higher degree of cell orientation in fiber-aligned scaffolds compared to randomly oriented ones.

Roles of cerebrospinal fluid-contacting neurons as potential neural stem cells in the repair and regeneration of spinal cord injuries.

Cerebrospinal fluid-contacting neurons (CSF-cNs) represent a distinct group of interneurons characterized by their prominent apical globular protrusions penetrating the spinal cord's central canal and their basal axons extending towards adjacent cells. Identified nearly a century back, the specific roles and attributes of CSF-cNs have just started to emerge due to the historical lack of definitive markers. Recent findings have confirmed that CSF-cNs expressing PKD2L1 possess attributes of neural stem cells, suggesting a critical function in the regeneration processes following spinal cord injuries. This review aims to elucidate the molecular markers of CSF-cNs as potential neural stem cells during spinal cord development and assess their roles post-spinal cord injury, with an emphasis on their potential therapeutic implications for spinal cord repair.

Il34 rescues metronidazole-induced impairment of spinal cord regeneration in zebrafish central nervous system.

Metronidazole (MTZ), a commonly used anti-infective drug in clinical practice, has also been employed as a prodrug in cell-targeted ablation systems in scientific research, exhibiting significant application value. However, it has been demonstrated that MTZ can induce neurotoxic symptoms to some extent during its use, and there is currently a lack of effective means to circumvent its toxicity in both clinical and research settings, which limits its application. Therefore, exploring the specific mechanisms underlying MTZ-induced neurotoxic symptoms and elucidating countermeasures will enhance the practical value of MTZ. In this study, using a zebrafish spinal cord injury regeneration model, we confirmed that MTZ neurotoxicity leads to impaired axon regeneration in the central nervous system. By overexpressing il34 in the central nervous system of zebrafish, we eliminated the inhibitory effect of MTZ on axonal regeneration and demonstrated that the pro-regenerative effect against MTZ neurotoxicity is not caused by excessive macrophages/microglia chemoattracted by interleukin 34(Il34). Transcriptome sequencing analysis and GO enrichment analysis of differentially expressed genes between groups revealed that Il34 may counteract MTZ neurotoxicity and promote spinal cord injury repair through biological processes that enhance cellular adhesion and cell location. In summary, our work uncovers a possible cause of MTZ neurotoxicity and provides a new perspective for eliminating MTZ toxicity.

A conductive piezoelectric hydrogel combined with perampanel and wireless electrical stimulation for spinal cord injury repair

After experiencing spinal cord injury (SCI), the interruption of electrical signal transmission impedes both nerve regeneration and functional recovery. Despite its potential as a treatment for spinal cord injury, intrathecal electrical stimulation (ES) is hindered by the risk of infection and the need for a subsequent operation to remove the tethered electrical interface, thereby severely limiting its effectiveness and clinical applicability. Herein, we constructed a conductive piezoelectric hydrogel (SFBP/PER) with ultrasound-triggered wireless ES capability and satisfied conductivity for SCI regeneration. The fabrication process involved the integration of perampanel and polypyrrole-modified BaTiO3 nanoparticles into silk fibroin, followed by enzymatic crosslinking at physiological temperature. We demonstrate that the SFBP/PER hydrogel exhibits anti-glutamate excitotoxicity and antioxidative capabilities in vitro. In vivo, experiments revealed that the SFBP/PER hydrogel significantly enhanced recovery of SCI rats by mitigating oxidative stress, apoptosis, and inflammation, reducing lesion cavities, enhancing remyelination, and promoting the regeneration of functional neurons. This study presents a novel approach utilizing a conductive piezoelectric hydrogel system for in vivo ES in tissue engineering applications.

ROS-responsive nanoparticle delivery of ferroptosis inhibitor prodrug to facilitate mesenchymal stem cell-mediated spinal cord injury repair

Spinal cord injury (SCI) is a traumatic condition that results in impaired motor and sensory function. Ferroptosis is one of the main causes of neural cell death and loss of neurological function in the spinal cord, and ferroptosis inhibitors are effective in reducing inflammation and repairing SCI. Although human umbilical cord mesenchymal stem cells (Huc-MSCs) can ameliorate inflammatory microenvironments and promote neural regeneration in SCI, their efficacy is greatly limited by the local microenvironment after SCI. Therefore, in this study, we constructed a drug-release nanoparticle system with synergistic Huc-MSCs and ferroptosis inhibitor, in which we anchored Huc-MSCs by a Tz-A6 peptide based on the CD44-targeting sequence, and combined with the reactive oxygen species (ROS)-responsive drug nanocarrier mPEG-b-Lys-BECI-TCO at the other end for SCI repair. Meanwhile, we also modified the classic ferroptosis inhibitor Ferrostatin-1 (Fer-1) and synthesized a new prodrug Feborastatin-1 (Feb-1). The results showed that this treatment regimen significantly inhibited the ferroptosis and inflammatory response after SCI, and promoted the recovery of neurological function in rats with SCI. This study developed a combination therapy for the treatment of SCI and also provides a new strategy for the construction of a drug-coordinated cell therapy system.

MG53/GMs/HA-Dex neural scaffold promotes the functional recovery of spinal cord injury by alleviating neuroinflammation

The adverse microenvironment, including neuroinflammation, hinders the recovery of spinal cord injury (SCI). Regulating microglial polarization to alleviate neuroinflammation at the injury site is an effective strategy for SCI recovery. MG53 protein exerts obvious repair ability on multiple tissues damage, but with short half-life. In this study, we composited an innovative MG53/GMs/HA-Dex neural scaffold using gelatin microspheres (GMs), hyaluronic acid (HA), and dextran (Dex) loaded with MG53 protein. This novel neural scaffold could respond to MMP-2/9 protein and stably release MG53 protein with good physicochemical properties and biocompatibility. In addition, it significantly improved the motor function of SCI mice, suppressed M1 polarization of microglia and neuroinflammation, and promoted neurogenesis and axon regeneration. Further mechanistic experiments demonstrated that MG53/GMs/HA-Dex hydrogel inhibited the JAK2/STAT3 signaling pathway. Thus, this MG53/GMs/HA-Dex neural scaffold promotes the functional recovery of SCI mice by alleviating neuroinflammation, which provides a new intervention strategy for the neural regeneration and functional repair of SCI.

Treatment of Syringomyelia Characterized by Focal Dilatation of the Central Canal Using Mesenchymal Stem Cells and Neural Stem Cells.

Syringomyelia is a progressive chronic disease that leads to nerve pain, sensory dissociation, and dyskinesia. Symptoms often do not improve after surgery. Stem cells have been widely explored for the treatment of nervous system diseases due to their immunoregulatory and neural replacement abilities. In this study, we used a rat model of syringomyelia characterized by focal dilatation of the central canal to explore an effective transplantation scheme and evaluate the effect of mesenchymal stem cells and induced neural stem cells for the treatment of syringomyelia. The results showed that cell transplantation could not only promote syrinx shrinkage but also stimulate the proliferation of ependymal cells, and the effect of this result was related to the transplantation location. These reactions appeared only when the cells were transplanted into the cavity. Additionally, we discovered that cell transplantation transformed activated microglia into the M2 phenotype. IGF1-expressing M2 microglia may play a significant role in the repair of nerve pain. Cell transplantation can promote cavity shrinkage and regulate the local inflammatory environment. Moreover, the proliferation of ependymal cells may indicate the activation of endogenous stem cells, which is important for the regeneration and repair of spinal cord injury.

Transcriptome profile analysis in spinal cord injury rats with transplantation of menstrual blood-derived stem cells.

Menstrual blood-derived stem cells (MenSCs) are vital in treating many degenerative and traumatic disorders. However, the underlying molecular mechanisms remain obscure in MenSCs-treating spinal cord injury (SCI) rats. MenSCs were adopted into the injured sites of rat spinal cords at day 7 post surgery and the tissues were harvested for total RNA sequencing analysis at day 21 after surgery to investigate the expression patterns of RNAs. The differentially expressed genes (DEGs) were analyzed with volcano and heatmap plot. DEGs were sequentially analyzed by weighted gene co-expression network, functional enrichment, and competitive endogenous RNAs (ceRNA) network analysis. Next, expression of selected miRNAs, lncRNAs, circRNAs and mRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Bioinformatics packages and extra databases were enrolled to scoop the genes functions and their interaction relationships. A total of 89 lncRNAs, 65 circRNAs, 120 miRNAs and 422 mRNAs were significantly upregulated and 65 lncRNAs, 72 circRNAs, 74 miRNAs, and 190 mRNAs were significantly downregulated in the MenSCs treated rats compared to SCI ones. Current investigation revealed that MenSCs treatment improve the recovery of the injured rats and the most significantly involved pathways in SCI regeneration were cell adhesion molecules, nature killer cell mediated cytotoxicity, primary immunodeficiency, chemokine signaling pathway, T cell receptor signaling pathway and B cell receptor signaling pathway. Moreover, the lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA ceRNA network of SCI was constructed. Finally, the protein-protein interaction (PPI) network was constructed using the top 100 DE mRNAs. The constructed PPI network included 47 nodes and 70 edges. In summary, the above results revealed the expression profile and potential functions of differentially expressed (DE) RNAs in the injured spinal cords of rats in the MenSCs-treated and SCI groups, and this study may provide new clues to understand the mechanisms of MenSCs in treating SCI.

Chronic Spinal Cord Injury Regeneration with Combined Therapy Comprising Neural Stem/Progenitor Cell Transplantation, Rehabilitation, and Semaphorin 3A Inhibitor.

Spinal cord injury (SCI) often results in various long-term sequelae, and chronically injured spinal cords exhibit a refractory feature, showing a limited response to cell transplantation therapies. To our knowledge, no preclinical studies have reported a treatment approach with results surpassing those of treatment comprising rehabilitation alone. In this study of rats with SCI, we propose a novel combined therapy involving a semaphorin 3A inhibitor (Sema3Ai), which enhances axonal regeneration, as the third treatment element in combination with neural stem/progenitor cell transplantation and rehabilitation. This comprehensive therapeutic strategy achieved significant improvements in host-derived neuronal and oligodendrocyte differentiation at the SCI epicenter and promoted axonal regeneration even in the chronically injured spinal cord. The elongated axons established functional electrical connections, contributing to significant enhancements in locomotor mobility when compared with animals treated with transplantation and rehabilitation. As a result, our combined transplantation, Sema3Ai, and rehabilitation treatment have the potential to serve as a critical step forward for chronic SCI patients, improving their ability to regain motor function.

The Protein Acetylation after Traumatic Spinal Cord Injury: Mechanisms and Therapeutic Opportunities.

Spinal cord injury (SCI) leads to deficits of various normal functions and is difficult to return to a normal state. Histone and non-histone protein acetylation after SCI is well documented and regulates spinal cord plasticity, axonal growth, and sensory axon regeneration. However, our understanding of protein acetylation after SCI is still limited. In this review, we summarize current research on the role of acetylation of histone and non-histone proteins in regulating neuron growth and axonal regeneration in SCI. Furthermore, we discuss inhibitors and activators targeting acetylation-related enzymes, such as α-tubulin acetyltransferase 1 (αTAT1), histone deacetylase 6 (HDAC6), and sirtuin 2 (SIRT2), to provide promising opportunities for recovery from SCI. In conclusion, a comprehensive understanding of protein acetylation and deacetylation in SCI may contribute to the development of SCI treatment.

Individualized bio-scaffold encapsulating siPTEN-loaded exosomes for promoting neuronal regeneration in spinal cord injury

Biological scaffold implants loaded with exosomes were acknowledged as a promising strategy for the treatment of spinal cord injury. In this study, we constructed an individualized biomimetic scaffold based on combination of multimodal imaging and 3D printing technology, featuring sustained release, biodegradability, and strongly biocompatibility. The scaffold incorporated mesenchymal stem cell-derived exosomes to alleviate inflammatory response in microenvironment and reduce scar formation of ECM molecule deposition. Furthermore, to effectively enhance neuronal repair and regeneration, siRNAs targeting PTEN were introduced into exosomes. The engineered exosomes within scaffold induced endogenous neuronal regeneration and enhanced axonal growth through PTEN/PI3K/AKT/mTOR signaling pathway. Additionally, implantation of scaffold could bridge the severed ends, thus providing spatial signals to modulate the organization of neural cells, facilitating the reconstruction of complex neural networks, and restoring nerve conduction. Collectively, the individualized 3D printed bio-scaffold encapsulated siPTEN-loaded exosomes could offer great promise for the prospective clinical translation in spinal cord injury therapy.

Local Spinal Cord Injury Treatment Using a Dental Pulp Stem Cell Encapsulated H2S Releasing Multifunctional Injectable Hydrogel.

Spinal cord injury (SCI) commonly induces nerve damage and nerve cell degeneration. In this work, a novel dental pulp stem cells (DPSCs) encapsulated thermoresponsive injectable hydrogel with sustained hydrogen sulfide (H2S) delivery is demonstrated for SCI repair. For controlled and sustained H2S gas therapy, a clinically tested H2S donor (JK) loaded octysilane functionalized mesoporous silica nanoparticles (OMSNs) are incorporated into the thermosensitive hydrogel made from Pluronic F127 (PF-127). The JK-loaded functionalized MSNs (OMSF@JK) promote preferential M2-like polarization of macrophages and neuronal differentiation of DPSCs in vitro. OMSF@JK incorporated PF-127 injectable hydrogel (PF-OMSF@JK) has a soft consistency similar to that of the human spinal cord and thus, shows a high cytocompatibility with DPSCs. The cross-sectional micromorphology of the hydrogel shows a continuous porous structure. Last, the PF-OMSF@JK composite hydrogel considerably improves the in vivo SCI regeneration in Sprague-Dawley rats through a reduction in inflammation and neuronal differentiation of the incorporated stem cells as confirmed using western blotting and immunohistochemistry. The highly encouraging in vivo results prove that this novel design on hydrogel is a promising therapy for SCI regeneration with the potential for clinical translation.

Hydrogel-encapsulated extracellular vesicles for the regeneration of spinal cord injury.

Spinal cord injury (SCI) is a critical neurological condition that may impair motor, sensory, and autonomous functions. At the cellular level, inflammation, impairment of axonal regeneration, and neuronal death are responsible for SCI-related complications. Regarding the high mortality and morbidity rates associated with SCI, there is a need for effective treatment. Despite advances in SCI repair, an optimal treatment for complete recovery after SCI has not been found so far. Therefore, an effective strategy is needed to promote neuronal regeneration and repair after SCI. In recent years, regenerative treatments have become a potential option for achieving improved functional recovery after SCI by promoting the growth of new neurons, protecting surviving neurons, and preventing additional damage to the spinal cord. Transplantation of cells and cells-derived extracellular vesicles (EVs) can be effective for SCI recovery. However, there are some limitations and challenges related to cell-based strategies. Ethical concerns and limited efficacy due to the low survival rate, immune rejection, and tumor formation are limitations of cell-based therapies. Using EVs is a helpful strategy to overcome these limitations. It should be considered that short half-life, poor accumulation, rapid clearance, and difficulty in targeting specific tissues are limitations of EVs-based therapies. Hydrogel-encapsulated exosomes have overcome these limitations by enhancing the efficacy of exosomes through maintaining their bioactivity, protecting EVs from rapid clearance, and facilitating the sustained release of EVs at the target site. These hydrogel-encapsulated EVs can promote neuroregeneration through improving functional recovery, reducing inflammation, and enhancing neuronal regeneration after SCI. This review aims to provide an overview of the current research status, challenges, and future clinical opportunities of hydrogel-encapsulated EVs in the treatment of SCI.

Building-Block Size Mediates Microporous Annealed Particle Hydrogel Tube Microenvironment Following Spinal Cord Injury.

Spinal cord injury (SCI) is a life-altering event, which often results in loss of sensory and motor function below the level of trauma. Biomaterial therapies have been widely investigated in SCI to promote directional regeneration but are often limited by their pre-constructed size and shape. Herein, the design parameters of microporous annealed particles (MAPs) are investigated with tubular geometries that conform to the injury and direct axons across the defect to support functional recovery. MAP tubes prepared from 20-, 40-, and 60-micron polyethylene glycol (PEG) beads are generated and implanted in a T9-10 murine hemisection model of SCI. Tubes attenuate glial and fibrotic scarring, increase innate immune cell density, and reduce inflammatory phenotypes in a bead size-dependent manner. Tubes composed of 60-micron beads increase the cell density of the chronic macrophage response, while neutrophil infiltration and phenotypes do not deviate from those seen in controls. At 8 weeks postinjury, implantation of tubes composed of 60-micron beads results in enhanced locomotor function, robust axonal ingrowth, and remyelination through both lumens and the inter-tube space. Collectively, these studies demonstrate the importance of bead size in MAP construction and highlight PEG tubes as a biomaterial therapy to promote regeneration and functional recovery in SCI.

Piezoelectric composite hydrogel with wireless electrical stimulation enhances motor functional recovery of spinal cord injury

Electrical stimulation (ES) can restore motor function after spinal cord injury (SCI). However, traditional intraspinal ES has many disadvantages, such as the need for a complex circuitry device, an external power source, and a second surgery to remove the implant. Piezoelectric materials have received increasing attention due to their potential to convert ambient mechanical energy into ES without an external power source or implantation of electrodes. Herein, a novel polydopamine (PDA) coated barium titanate (BaTiO3) nanoparticles (BaTiO3@PDA) incorporated silk fibroin (SF) hydrogel (SFBT) was established. The SFBT hydrogel was crosslinked by horseradish peroxidase (HRP)/hydrogel peroxide (H2O2) to integrate the piezoelectric potency of BaTiO3 with the thermal sensitivity of HRP/H2O2 for SCI recovery. The hydrogel containing 5% (w/v) BaTiO3@PDA nanoparticles (SFBT-5), which was selected for in vivo study, exhibited a short gelation time (5 min), suitable storage modulus (925 ± 35 Pa), and wireless ES (average current of 124 nA). Moreover, Basso-Beattie-Bresnahan (BBB) scores test and footprint analysis demonstrated that the SFBT-5 hydrogel successfully enhanced motor functional recovery of SCI. In histopathological assessments, the SFBT-5 hydrogel significantly accelerated spinal cord healing, as indicated by smaller lesion cavities (∼16.7% of the SCI group). Meanwhile, the SFBT-5 hydrogel accelerated neurogenesis, facilitated axon regrowth and synapse formation, and promoted remyelination. Overall, this study highlights the potential of piezoelectric hydrogels for SCI regeneration.

3D bio-printed living nerve-like fibers refine the ecological niche for long-distance spinal cord injury regeneration.

3D bioprinting holds great promise toward fabricating biomimetic living constructs in a bottom-up assembly manner. To date, various emergences of living constructs have been bioprinted for in vitro applications, while the conspicuous potential serving for in vivo implantable therapies in spinal cord injury (SCI) has been relatively overlooked. Herein, living nerve-like fibers are prepared via extrusion-based 3D bioprinting for SCI therapy. The living nerve-like fibers are comprised of neural stem cells (NSCs) embedded within a designed hydrogel that mimics the extracellular matrix (ECM), assembled into a highly spatial ordered architecture, similar to densely arranged bundles of the nerve fibers. The pro-neurogenesis ability of these living nerve-like fibers is tested in a 4mm-long complete transected SCI rat model. Evidence shows that living nerve-like fibers refine the ecological niche of the defect site by immune modulation, angiogenesis, neurogenesis, neural relay formations, and neural circuit remodeling, leading to outstanding functional reconstruction, revealing an evolution process of this living construct after implantation. This effective strategy, based on biomimetic living constructs, opens a new perspective on SCI therapies.

Neural regeneration ability of Polypyrrole-Collagen-Quercetin composite in the spinal cord injury

Spinal cord injury (SCI) is a major clinical problem in young patients. The major hurdle in SCI regeneration is the replacement of lost nerve communication signals due to injury. Here we have prepared a biocompatible electrical conductive composite such as Collagen-Polypyrrole combined with Quercetin (Col-PPy-Qur) composite. The prepared composites are characterized for their chemical functionality and morphology by the FTIR and SEM & TEM analysis, respectively. The Col-PPy-Qur composite observed electrical conductivity at 0.0653 s/cm due to the conductive Polypyrrole polymer present in the composite. The Col-PPy-Qur composite exhibits a mechanical strength of 0.1281 mPa, similar to the native human spinal cord's mechanical strength. In order to explore the regeneration potential, the viability of the composite has been tested with human astrocyte cells (HACs). The Tuj1 and GFAF marker expression was quantized by RT-PCR analysis. Increased Tuj1 and decreased GFAF expression by the Col-PPy-Qur composite indicated the potential differentiation ability of the HACs into neuron cells. The results indicated that the Col-PPy-Qur composite could have good regeneration and differentiation ability, better biocompatibility, and suitable mechanical and conductivity properties. It can act as an excellent strategy for spinal cord regeneration in the nearer future.

The role of stem cell secretome on spinal cord injury regeneration: a systematic review and meta-analysis

Background: The treatment of spinal cord injuries (SCIs) is a controversial topic and is not yet effective. Stem cell secretome is an emerging alternative treatment that uses the paracrine effect of stem cells. Although there have been many studies on this subject, there are still differences regarding the origin, dose, route of secretome administration, type of experimental animal, phase of the SCI, and outputs evaluated. The topic needs a systematic review and meta-analysis. Methods: This systematic review and meta-analysis were reported based on criteria from Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The authors searched PubMed, ScienceDirect, Cochrane Library, and Google Scholar with multiple electronic databases until October 2021. Results: Twenty-eight studies that met the inclusion criteria were included in this research. The stem cell secretome was very beneficial as the axonal regeneration agent (n=12); it increases the locomotor recovery (n=28) and growth factors (n=2) and reduces the size of the cystic cavity (n=1) and lesion extension (n=14). We recognized 28 studies that met our inclusion criteria. Stem cell secretome therapies showed improvement in the locomotor score (standard mean difference [SMD]: 0.94; 95% confidence interval [CI]: 0.75–1.13, p<0.000001, I2=90%) and reduction in the lesion size (SMD: 5.06; 95% CI: 3.44–6.67, p<0.00001, I2=94%). Conclusion: The stem cell secretome greatly affects treating SCI rodent models. Future studies should focus on chronic SCIs in the primary research, translational research, and neurological research stage of stem cell secretome.

LncRNA TSIX aggravates spinal cord injury by regulating the PI3K/AKT pathway via the miR-532-3p/DDOST axis.

Long noncoding RNA (lncRNA)-X-inactive-specific transcript (TSIX) expression is upregulated in spinal cord tissues following spinal cord injury (SCI). However, the role of lncRNA-TSIX in SCI remains elusive. SCI animal model was established using C57BL/6 mice. LncRNA TSIX and miR-532-3p expression were determined usingquantitative reverse transcription polymerase chain reaction (qRT-PCR). Apoptosis, cell proliferation, and migration were evaluated by transferase dUTP nick end labeling staining, CCK-8, and Transwell assays, respectively. The interaction of miR-532-3p with lncRNA TSIX and DDOST was explored via a dual-luciferase reporter system. Hematoxylin-eosin staining and the Basso, Beattie, and Bresnahan locomotor rating (BBB) scale were performed to investigate SCI progression. The expression of the lncRNA TSIX was found to be significantly upregulated in the serum of SCI patients and spinal cord tissues of SCI mice. The overexpression of lncRNA TSIX enhanced spinal cord neural stem cell (SC-NSC) proliferation and migration in vitro while inhibiting apoptosis and inflammatory cell infiltration in vivo. Moreover, lncRNA TSIX acted as a molecular sponge for miR-532-3p, and the knockdown of miR-532-3p promoted proliferation and migration and inhibited apoptosis of SC-NSCs. Moreover, DDOST was found to be the downstream target of miR-532-3p, and DDOST overexpression showed a similar effect as miR-532-3p silencing on the proliferation, migration, and apoptosis of SC-NSCs. Furthermore, we found that lncRNA TSIX overexpression promoted the activation of the PI3K/AKT signaling pathway. LncRNA TSIX aggravates SCI by regulating the PI3K/AKT pathway via the miR-532-3p/DDOST axis, indicating potential applications for targeted therapy of SCI regeneration.