Therapy For Spinal Cord Injury Research Articles

Metabolic reprogramming: a new option for the treatment of spinal cord injury

Spinal cord injuries impose a notably economic burden on society, mainly because of the severe after-effects they cause. Despite the ongoing development of various therapies for spinal cord injuries, their effectiveness remains unsatisfactory. However, a deeper understanding of metabolism has opened up a new therapeutic opportunity in the form of metabolic reprogramming. In this review, we explore the metabolic changes that occur during spinal cord injuries, their consequences, and the therapeutic tools available for metabolic reprogramming. Normal spinal cord metabolism is characterized by independent cellular metabolism and intercellular metabolic coupling. However, spinal cord injury results in metabolic disorders that include disturbances in glucose metabolism, lipid metabolism, and mitochondrial dysfunction. These metabolic disturbances lead to corresponding pathological changes, including the failure of axonal regeneration, the accumulation of scarring, and the activation of microglia. To rescue spinal cord injury at the metabolic level, potential metabolic reprogramming approaches have emerged, including replenishing metabolic substrates, reconstituting metabolic couplings, and targeting mitochondrial therapies to alter cell fate. The available evidence suggests that metabolic reprogramming holds great promise as a next-generation approach for the treatment of spinal cord injury. To further advance the metabolic treatment of the spinal cord injury, future efforts should focus on a deeper understanding of neurometabolism, the development of more advanced metabolomics technologies, and the design of highly effective metabolic interventions.

Exosomes Derived from Mesenchymal Stem Cells: Therapeutic Opportunities for Spinal Cord Injury.

Spinal cord injury (SCI) is a serious neurological condition comprising primary and secondary injury and causing severe neurological impairments. The effect of the conventional treatment is limited, including supportive therapy and emergency surgery. Exosomes derived from mesenchymal stem cells (MSCs-Exos) were previously reported to exert its potential therapeutic effects on SCI. Compared with mesenchymal stem cells (MSCs) transplantation for SCI, MSC-Exos showed several superiorities. In the present review, we summarized the revealed data of mechanisms underlying MSC-Exos repairing of SCI and discussed the issues of MSC-Exos use. Thus, in this review we summarized the latest studies on MSCs-Exos in the therapy of SCI and discussed whether MSCs-Exos can be applied to SCI and the prospects of transformation application.

Identification of hub genes and key pathways in spinal cord injury via bioinformatics analysis.

This study aimed to explore the hub genes and related key pathways in Spinal Cord Injury (SCI) based on the bioinformatics analysis. Two microarray datasets (GSE45006, GSE45550) were obtained from the GEO database and were merged and batch-corrected. The differentially expressed genes (DEGs) in SCI were explored with the Limma, and the weighted gene co-expression network analysis (WGCNA) was conducted to explore the module genes. Functional enrichment analysis and Gene set variation analysis (GSVA) were used to investigate the biological functions and key pathways of the key genes related to SCI. Then the protein-protein interaction (PPI) network was generated using the STING online tool, and the hub genes in SCI were identified. Receiver operating characteristic (ROC) curves were applied to assess the diagnostic value of the selected hub genes. We identified 554 DEGs in SCI, and 1236 key genes in SCI were selected via WGCNA. Totally 111 key genes related to SCI were discovered. Furthermore, the functional enrichment analysis showed that these key mRNAs were primarily enriched in the extracellular matrix (ECM)-related pathways and processes associated with wound healing and cell growth. The PPI network further filtered six hub genes (Cd44, Timp1, Loxl1, Col6a1, Col3a1, Col5a1) ranked by the degree, and the diagnostic value of the six hub genes was confirmed by the ROC curves. Six hub genes including Cd44, Timp1, Loxl1, Col6a1, Col3a1, and Col5a1 were identified in SCI, with differential expression and excellent diagnostic value, which might provide insight into the targeted therapy of SCI.

Necroptosis pathway emerged as potential diagnosis markers in spinal cord injury.

The present research focused on identifying necroptosis-related differentially expressed genes (NRDEGs) in spinal cord injury (SCI) to highlight potential therapeutic and prognostic target genes in clinical SCI. Three SCI-related datasets were downloaded, including GSE151371, GSE5296 and GSE47681. MSigDB and KEGG datasets were searched for necroptosis-related genes (NRGs). Differentially expressed genes (DEGs) and NRGs were intersected to obtain NRDEGs. The MCC algorithm was employed to select the first 10 genes as hub genes. A protein-protein interaction (PPI) network related to NRDEGs was developed utilizing STRING. Several databases were searched to predict interactions between hub genes and miRNAs, transcription factors, potential drugs, and small molecules. Immunoassays were performed to identify DEGs using CIBERSORTx. Additionally, qRT-PCR was carried out to verify NRDEGs in an animal model of SCI. Combined analysis of all datasets identified 15 co-expressed DEGs and NRGs. GO and KEGG pathway analyses highlighted DEGs mostly belonged to pathways associated with necroptosis and apoptosis. Hub gene expression analysis showed high accuracy in SCI diagnosis was associated with the expression of CHMP7 and FADD. A total of two hub genes, i.e. CHMP7, FADD, were considered potential targets for SCI therapy.

Exploring the Landscape of Hydrogel Therapy for Spinal Cord Injury: A Bibliometric and Visual Analysis (1991–2023)

BackgroundThis study aimed to conduct a bibliometric analysis of the literature on hydrogel therapy for spinal cord injury to visualize the research status, identify hotspots, and explore the development trends in this field. MethodsWeb of science Core Collection database was searched for relevant studies published between January 1991 and December 2023. Data such as journal title, author information, institutional affiliation, country, citation and keywords were extracted. Bibliometrix, CiteSpace and VOSviewer were used to perform bibliometric analysis of the retrieved data. ResultsA total of 1099 articles pertaining to hydrogel therapy for spinal cord injury were retrieved, revealing an upward trajectory in both annual publication volume and cumulative publication volume. Biomaterials emerged as the journal with the highest number of publications and the most rapid cumulative publication growth, contributing 84 articles. Among authors, Shoichet MS stood out with the highest number of publications and citations, totaling 66 articles. The University of Toronto led in institutional contributions with 65 publications, while China dominated in country-specific publications, accounting for 374 articles.However, to foster significant academic achievements, it is imperative for diverse authors, institutions, and countries to enhance collaboration. Current research in this field concentrates on scaffold architecture, nerve growth factor, the fibrotic microenvironment, and guidance channels. Simultaneously, upcoming research directions prioritize 3D bioprinting, injectable hydrogel, inflammation, and nanoparticles within the realm of hydrogel therapy for spinal cord injuries. ConclusionIn summary, this study provided a comprehensive analysis of the current research status and frontiers of hydrogel therapy for spinal cord injury. The findings provide a foundation for future research and clinical translation efforts of hydrogel therapy in this field.

Current status and future perspectives on stem cell transplantation for spinal cord injury.

Previous assessments of stem cell therapy for spinal cord injuries (SCI) have encountered challenges and constraints. Current research primarily emphasizes safety in early-phase clinical trials, while systematic reviews prioritize effectiveness, often overlooking safety and translational feasibility. This situation prompts inquiries regarding the readiness for clinical adoption. To offer an up-to-date systematic literature review of clinical trial results con cerning stem cell therapy for SCI. A systematic search was conducted across major medical databases [PubMed, Embase, Reference Citation Analysis (RCA), and Cochrane Library] up to October 14, 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "spinal cord", "injury", "clinical trials", "stem cells", "functional outcomes", and "adverse events". Studies included in this review consisted of randomized controlled trials and non-randomized controlled trials reporting on the use of stem cell therapies for the treatment of SCI. In a comprehensive review of 66 studies on stem cell therapies for SCI, 496 papers were initially identified, with 237 chosen for full-text analysis. Among them, 236 were deemed eligible after excluding 170 for various reasons. These studies encompassed 1086 patients with varying SCI levels, with cervical injuries being the most common (42.2%). Bone marrow stem cells were the predominant stem cell type used (71.1%), with various administration methods. Follow-up durations averaged around 84.4 months. The 32.7% of patients showed functional impro vement from American spinal injury association Impairment Scale (AIS) A to B, 40.8% from AIS A to C, 5.3% from AIS A to D, and 2.1% from AIS B to C. Sensory improvements were observed in 30.9% of patients. A relatively small number of adverse events were recorded, including fever (15.1%), headaches (4.3%), muscle tension (3.1%), and dizziness (2.6%), highlighting the potential for SCI recovery with stem cell therapy. In the realm of SCI treatment, stem cell-based therapies show promise, but clinical trials reveal potential adverse events and limitations, underscoring the need for meticulous optimization of transplantation conditions and parameters, caution against swift clinical implementation, a deeper understanding of SCI pathophysiology, and addressing ethical, tumorigenicity, immunogenicity, and immunotoxicity concerns before gradual and careful adoption in clinical practice.

Astrogliosis: A review of the astrocytic mechanisms, imaging modes, and treatments in spinal cord injury patients

Astrocytes are cells in the central nervous system (CNS) that are responsible for many things, such as maintaining blood brain barrier (BBB), regulating synapses in the spinal cord, and responding to spinal cord injury (SCI). Astrogliosis, the astrocytic response to spinal cord injuries (SCIs), helps repair CNS damages by regulating different protein filaments, thus limiting axonal growth. Former studies that were demonstrated through laser capture microdissection and immunohistochemistry (IHC) helped to identify important genes involved in experimental therapies for SCIs. Additionally, there are potential clinical treatments options for SCIs such as hydrogels, mesenchymal stem cells and steroids. Increased imaging modalities indicate that excessive astrogliosis can have adverse effects. These imaging techniques include positron emission tomography (PET), magnetic resonance imaging (MRI), and two-photon laser-scanning microscopy (TPLSM). These techniques illuminate greater details of the astrocytic response to SCIs. Despite these findings, astrogliosis is not well understood by the research community. Many of the studies presented in this literature review are experimental attempts to understand the mechanisms of astrogliosis in SCIs. This literature review aims to summarize the methods of each study in visualizing the mechanisms of astrogliosis and how they play a role in SCIs. Furthermore, this paper is aimed to comprehensively bridge the developments in the treatment for SCI patients based on innovative imaging modalities. Compared to prior studies, this review utilizes more recent understandings of the astrogliosis mechanisms to highlight insights into targeted developments, both clinically and preclinically. Some limitations of this literature review include the limited studies on astrogliosis and its impact on SCIs. Nonetheless, there is ongoing potential in the search for treatments for SCIs.

Interleukin-4 from curcumin-activated OECs emerges as a central modulator for increasing M2 polarization of microglia/macrophage in OEC anti-inflammatory activity for functional repair of spinal cord injury

Microglia/macrophages are major contributors to neuroinflammation in the central nervous system (CNS) injury and exhibit either pro- or anti-inflammatory phenotypes in response to specific microenvironmental signals. Our latest in vivo and in vitro studies demonstrated that curcumin-treated olfactory ensheathing cells (aOECs) can effectively enhance neural survival and axonal outgrowth, and transplantation of aOECs improves the neurological outcome after spinal cord injury (SCI). The therapeutic effect is largely attributed to aOEC anti-inflammatory activity through the modulation of microglial polarization from the M1 to M2 phenotype. However, very little is known about what viable molecules from aOECs are actively responsible for the switch of M1 to M2 microglial phenotypes and the underlying mechanisms of microglial polarization. Herein, we show that Interleukin-4 (IL-4) plays a leading role in triggering the M1 to M2 microglial phenotype, appreciably decreasing the levels of M1 markers IL‑1β, IL‑6, tumour necrosis factor-alpha (TNF-α) and inducible nitric oxide synthase (iNOS) and elevating the levels of M2 markers Arg-1, TGF-β, IL-10, and CD206. Strikingly, blockade of IL-4 signaling by siRNA and a neutralizing antibody in aOEC medium reverses the transition of M1 to M2, and the activated microglia stimulated with the aOEC medium lacking IL-4 significantly decreases neuronal survival and neurite outgrowth. In addition, transplantation of aOECs improved the neurological function deficits after SCI in rats. More importantly, the crosstalk between JAK1/STAT1/3/6-targeted downstream signals and NF-κB/SOCS1/3 signaling predominantly orchestrates IL-4-modulated microglial polarization event. These results provide new insights into the molecular mechanisms of aOECs driving the M1-to-M2 shift of microglia and shed light on new therapies for SCI through the modulation of microglial polarization.

Transplantation of Neural Stem Cells Loaded in an IGF-1 Bioactive Supramolecular Nanofiber Hydrogel for the Effective Treatment of Spinal Cord Injury.

Spinal cord injury (SCI) leads to massive cell death, disruption, and demyelination of axons, resulting in permanent motor and sensory dysfunctions. Stem cell transplantation is a promising therapy for SCI. However, owing to the poor microenvironment that develops following SCI, the bioactivities of these grafted stem cells are limited. Cell implantation combined with biomaterial therapies is widely studied for the development of tissue engineering technology. Herein, an insulin-like growth factor-1 (IGF-1)-bioactive supramolecular nanofiber hydrogel (IGF-1 gel) is synthesized that can activate IGF-1 downstream signaling, prevent the apoptosis of neural stem cells (NSCs), improve their proliferation, and induce their differentiation into neurons and oligodendrocytes. Moreover, implantation of NSCs carried out with IGF-1 gels promotes neurite outgrowth and myelin sheath regeneration at lesion sites following SCI. In addition, IGF-1 gels can enrich extracellular vesicles (EVs) derived from NSCs or from nerve cells differentiated from these NSCs via miRNAs related to axonal regeneration and remyelination, even in an inflammatory environment. These EVs are taken up by autologous endogenous NSCs and regulate their differentiation. This study provides adequate evidence that combined treatment with NSCs and IGF-1 gels is a potential therapeutic strategy for treating SCI.

Unravelling the Road to Recovery: Mechanisms of Wnt Signalling in Spinal Cord Injury.

Spinal cord injury (SCI) is a complex neurodegenerative pathology that consistently harbours a poor prognostic outcome. At present, there are few therapeutic strategies that can halt neuronal cell death and facilitate functional motor recovery. However, recent studies have highlighted the Wnt pathway as a key promoter of axon regeneration following central nervous system (CNS) injuries. Emerging evidence also suggests that the temporal dysregulation of Wnt may drive cell death post-SCI. A major challenge in SCI treatment resides in developing therapeutics that can effectively target inflammation and facilitate glial scar repair. Before Wnt signalling is exploited for SCI therapy, further research is needed to clarify the implications of Wnt on neuroinflammation during chronic stages of injury. In this review, an attempt is made to dissect the impact of canonical and non-canonical Wnt pathways in relation to individual aspects of glial and fibrotic scar formation. Furthermore, it is also highlighted how modulating Wnt activity at chronic time points may aid in limiting lesion expansion and promoting axonal repair.

Epigenetic regulation and factors that influence the effect of iPSCs-derived neural stem/progenitor cells (NS/PCs) in the treatment of spinal cord injury.

Spinal cord injury (SCI) is a severe neurological disorder that causes neurological impairment and disability. Neural stem/progenitor cells (NS/PCs) derived from induced pluripotent stem cells (iPSCs) represent a promising cell therapy strategy for spinal cord regeneration and repair. However, iPSC-derived NS/PCs face many challenges and issues in SCI therapy; one of the most significant challenges is epigenetic regulation and that factors that influence this mechanism. Epigenetics refers to the regulation of gene expression and function by DNA methylation, histone modification, and chromatin structure without changing the DNA sequence. Previous research has shown that epigenetics plays a crucial role in the generation, differentiation, and transplantation of iPSCs, and can influence the quality, safety, and outcome of transplanted cells. In this study, we review the effects of epigenetic regulation and various influencing factors on the role of iPSC-derived NS/PCs in SCI therapy at multiple levels, including epigenetic reprogramming, regulation, and the adaptation of iPSCs during generation, differentiation, and transplantation, as well as the impact of other therapeutic tools (e.g., drugs, electrical stimulation, and scaffolds) on the epigenetic status of transplanted cells. We summarize our main findings and insights in this field and identify future challenges and directions that need to be addressed and explored.

The secretome of macrophages has a differential impact on spinal cord injury recovery according to the polarization protocol.

The inflammatory response after spinal cord injury (SCI) is an important contributor to secondary damage. Infiltrating macrophages can acquire a spectrum of activation states, however, the microenvironment at the SCI site favors macrophage polarization into a pro-inflammatory phenotype, which is one of the reasons why macrophage transplantation has failed. In this study, we investigated the therapeutic potential of the macrophage secretome for SCI recovery. We investigated the effect of the secretome in vitro using peripheral and CNS-derived neurons and human neural stem cells. Moreover, we perform a pre-clinical trial using a SCI compression mice model and analyzed the recovery of motor, sensory and autonomic functions. Instead of transplanting the cells, we injected the paracrine factors and extracellular vesicles that they secrete, avoiding the loss of the phenotype of the transplanted cells due to local environmental cues. We demonstrated that different macrophage phenotypes have a distinct effect on neuronal growth and survival, namely, the alternative activation with IL-10 and TGF-β1 (M(IL-10+TGF-β1)) promotes significant axonal regeneration. We also observed that systemic injection of soluble factors and extracellular vesicles derived from M(IL-10+TGF-β1) macrophages promotes significant functional recovery after compressive SCI and leads to higher survival of spinal cord neurons. Additionally, the M(IL-10+TGF-β1) secretome supported the recovery of bladder function and decreased microglial activation, astrogliosis and fibrotic scar in the spinal cord. Proteomic analysis of the M(IL-10+TGF-β1)-derived secretome identified clusters of proteins involved in axon extension, dendritic spine maintenance, cell polarity establishment, and regulation of astrocytic activation. Overall, our results demonstrated that macrophages-derived soluble factors and extracellular vesicles might be a promising therapy for SCI with possible clinical applications.

Enzyme-immobilized nanoclay hydrogel simultaneously reduces inflammation and scar deposition to treat spinal cord injury

Spinal cord injury (SCI) is a severely disabling pathological condition and always results in sensory and motor functions loss. After SCI, inflammation-mediated secondary tissue damage and subsequent formation of neuroglial scar suppress neuron survival and regeneration, therefore resulting in severe neurofunctional dysfunction. Although nanoclay biomaterials demonstrated useful immunomodulation feature in non-neuronal tissue, it is unclear if they can inhibit inflammation in SCI lesions and promote neurofunctional recovery. In this study, we immobilized chondroitinase ABC enzyme (ChABC), which can degrade chondroitin sulfate proteoglycans (CSPGs) of neuroglial scar, inside nanoclay (Laponite®, Lap) hydrogel through electrostatic interaction. The presented ChABC-immobilized Lap hydrogel (ChABC@Lap) exhibited shear-thinning properties and excellent injectability, allowing to locally deliver it into injured area through a non-invasive manner. Cell biological experiments and SCI rat model research revealed that both pure Lap (without ChABC) and ChABC@Lap hydrogels significantly reduced pro-inflammatory macrophage marker (iNOS) intensity. Importantly, compared with Lap hydrogel, ChABC@Lap hydrogel significantly decreased GFAP and CS-56 marked scar deposition, increased Tuj-1+ neurons regeneration, and promoted NF200+ neurons survival, thereby improving SCI rat of electrophysiological characteristics and motor function. In summary, the designed enzyme-immobilized nanoclay hydrogel offers a promising strategy for SCI therapy through modulating simultaneously inflammation and glial scar deposition.

In Situ Piezoelectric-Catalytic Anti-Inflammation Promotes the Rehabilitation of Acute Spinal Cord Injury in Synergy.

Relieving inflammation via scavenging toxic reactive oxygen species (ROS) during the acute phase of spinal cord injury (SCI) proves to be an effective strategy to mitigate secondary spinal cord injury and improve recovery of motor function. However, commonly used corticosteroid anti-inflammatory drugs show adverse side effects which may induce increased risk of wound infection. Fortunately, hydrogen (H2), featuring selective antioxidant performance, easy penetrability, and excellent biosafety, is being extensively investigated as a potential anti-inflammatory therapeutic gas for the treatment of SCI. In this work, by a facile in situ growth approach of gold nanoparticles (AuNPs) on the piezoelectric BaTiO3, a particulate nanocomposite with Schottky heterojunction (Au@BT) is synthesized, which can generate H2 continuously by catalyzing H+ reduction through piezoelectric catalysis. Further, theoretical calculations are employed to reveal the piezoelectric catalytic mechanism of Au@BT. Transcriptomics analysis and nontargeted large-scale metabolomic analysis reveal the deeper mechanism of the neuroprotective effect of H2 therapy. The as-prepared Au@BT nanoparticle is first explored as a flexible hydrogen gas generator for efficient SCI therapy. This study highlights a promising prospect of nanocatalytic medicine for disease treatments by catalyzing H2 generation; thus, offering a significant alternative to conventional approaches against refractory spinal cord injury.

Research on stem cell therapy for spinal cord injury: a bibliometric and visual analysis from 2018-2023.

Objectives: The aim of this study was to conduct a bibliometric analysis of the literature on stem cell treatment for spinal cord injury to gain an intuitive understanding of how the field is progressing, discover topics of interest, and determine what development trends are emerging in this field. Background: Spinal cord injury and its complications often cause an enormous economic burden, and postinjury repair and treatment have always been challenging in clinical and scientific research. Stem cell therapy for spinal cord injury can prevent immune rejection and induce the release of neuroprotective and anti-inflammatory factors to reduce the production of stress-related proteins, reactive oxygen species, and inflammatory reactions. Methods: We analyzed the number and quality of publications in the field of stem cell therapy in spinal cord injury between 2018.01.01 and 2023.06.30 in the core collection database of Web of Science. CiteSpace and VOSviewer were used to sort and summarize these studies by country, institution, authors' publications, and collaborative networks. In addition, the research topics of interest were identified and summarized. Results: This study ultimately included 2,150 valid papers, with the number of publications showing a gradual upward trend. The country, institution, author and journal with the greatest number of publications and citations are China, the Chinese Academy of Sciences, Dai JW, and the International Journal of Molecular Sciences, respectively. The top three high-frequency keyword clusters were hereditary paraplegia, reactive astrocytes and tissue engineering. Conclusion: With the help of visual analysis, we identified general trends and research topics of interest in the field of spinal cord injury over the last 5years. Our findings suggest that stem cell transplantation for spinal cord injury and exosome therapy may be a focus of future research. This study provides a foundation for future research on stem cell therapy as well as clinical efforts in this field.

Evaluation of human mononuclear umbilical cord blood cells systemic administration efficiency in the acute period of experimental severe spinal cord injury

Aim. To evaluate the efficiency of systemic (intravenous) application of cryopreserved human umbilical cord blood mononuclear cells (HUCBCs) in animal models of acute contusion spinal cord injury for the restoration of hind limb motor function and formation of posttraumatic cysts using clinically significant examination methods.Materials and methods. Adult female Sprague–Dowley rats were used for the study. Severe acute contusion spinal cord injury model was performed using standard “weight‑drop” method. All samples of cryopreserved HUCBCs concentrate were prestored prior to infusion for 3 to 4 years at –196 °C. Hind limbs motor function was evaluated using open‑field technique and standard BBB testing system. Magnetic resonance scanning was performed using high‑field magnetic resonance CleanScan 7.0 T tomography (Bruker BioSpin, Germany).Results. Intravenous infusions of HUCBCs were performed on Day 1 following acute severe spinal cord injury. Motor function assessment demonstrated significant (p <0.05) improvement of hind limbs motor function (up to 40–50 %) comparing to self‑healing outcomes. Moreover, by the Days 4 and 5 after severe spinal cord injury, the volume of posttraumatic cystic cavity decreases significantly (up to 40 %) (p <0.05).Conclusion. The obtained results demonstrated that cryopreserved HUCBCs can be used as an effective source for cell therapy of acute contusion spinal cord injury.

Activating MC4R Promotes Functional Recovery by Repressing Oxidative Stress-Mediated AIM2 Activation Post-spinal Cord Injury.

Spinal cord injury (SCI) is a destructive neurological trauma that induces permanent sensory and motor impairment as well as a deficit in autonomic physiological function. Melanocortin receptor 4 (MC4R) is a G protein-linked receptor that is extensively expressed in the neural system and contributes to inhibiting inflammation, regulating mitochondrial function, and inducing programmed cell death. However, the effect of MC4R in the modulation of oxidative stress and whether this mechanism is related to the role of absent in melanoma 2 (AIM2) in SCI are not confirmed yet. In the current study, we demonstrated that MC4R is significantly increased in the neurons of spinal cords after trauma and oxidative stimulation of cells. Further, activation of MC4R by RO27-3225 effectively improved functional recovery, inhibited AIM2 activation, maintained mitochondrial homeostasis, repressed oxidative stress, and prevented Drp1 translocation to the mitochondria. Meanwhile, treating Drp1 inhibitors would be beneficial in reducing AIM2 activation, and activating AIM2 could abolish the protective effect of MC4R on neuron homeostasis. In conclusion, we demonstrated that MC4R protects against neural injury through a novel process by inhibiting mitochondrial dysfunction, oxidative stress, as well as AIM2 activation, which may serve as an available candidate for SCI therapy.

Advancements and mechanisms of stem cell-based therapies for spinal cord injury in animals.

Spinal cord injury (SCI) is a neurodegenerative disorder of the central nervous system (CNS) that can lead to permanent loss of sensation and voluntary movement beyond the affected area. Extensive preclinical and clinical trials have been conducted to evaluate the safety and effectiveness of stem cells for the treatment of various CNS diseases or disorders, including SCI. However, several challenges hinder nerve cell regeneration in the injured spinal cord, such as extensive cell loss, limited neural cell regeneration capacity, axonal disruption, and the presence of growth-inhibiting molecules, particularly astroglial scarring or glial scars at the injury site in chronic cases. These obstacles pose significant challenges for physicians in restoring normal motor and sensory nerve function in both humans and animals following SCI. This review focuses on SCI pathogenesis, the mechanisms underlying the therapeutic potential of Mesenchymal Stem Cells (MSCs) in SCI, and the potential of stem cell-based therapies as promising avenues for treatment. This review article also included relevant preclinical and clinical data from animal studies.

Spinal Cord Injury: From MicroRNAs to Exosomal MicroRNAs.

Spinal cord injury (SCI) is an unfortunate experience that may generate extensive sensory and motor disabilities due to the destruction and passing of nerve cells. MicroRNAs are small RNA molecules that do not code for proteins but instead serve to regulate protein synthesis by targeting messenger RNA's expression. After SCI, secondary damage like apoptosis, oxidative stress, inflammation, and autophagy occurs, and differentially expressed microRNAs show a function in these procedures. Almost all animal and plant cells release exosomes, which are sophisticated formations of lipid membranes. These exosomes have the capacity to deliver significant materials, such as proteins, RNAs and lipids, to cells in need, regulating their functions and serving as a way of communication. This new method offers a fresh approach to treating spinal cord injury. Obviously, the exosome has the benefit of conveying the transported material across performing regulatory activities and the blood-brain barrier. Among the exosome cargoes, microRNAs, which modulate their mRNA targets, show considerable promise in the pathogenic diagnosis, process, and therapy of SCI. Herein, we describe the roles of microRNAs in SCI. Furthermore, we emphasize the importance of exosomal microRNAs in this disease.

Injectable and Photocurable Gene Scaffold Facilitates Efficient Repair of Spinal Cord Injury.

RNA interference-based gene therapy has led to a strategy for spinal cord injury (SCI) therapy. However, there have been high requirements regarding the optimal gene delivery vector for siRNA-based SCI gene therapy. Here, we developed an injectable and photocurable lipid nanoparticle GelMA (PLNG) hydrogel scaffold for controlled dual siRNA delivery at the SCI wound site. The prepared PLNG scaffold could efficiently protect and retain the bioactivity of the siRNA nanocomplex. It facilitated sustainable siRNA release along with degradation in 7 days. After loading dual siRNA targeting phosphatase and tensin homologue (PTEN) and macrophage migration inhibitory factor (MIF) simultaneously, the locally administered siRNAs/PLNG scaffold efficiently improved the Basso mouse scale (BMS) score and recovered ankle joint movement and plantar stepping after treatment with only three doses. We further proved that the siRNAs/PLNG scaffold successfully regulated the activities of neurons, microglia, and macrophages, thus promoting neuron axon regeneration and remyelination. The protein array results suggested that the siRNAs/PLNG scaffold could increase the expression of growth factors and decrease the expression of inflammatory factors to regulate neuroinflammation in SCI and create a neural repair environment. Our results suggested that the PLNG scaffold siRNA delivery system is a potential candidate for siRNA-based SCI therapy.