Re-analysis of single-cell RNA-seq data reveals the origin and roles of cycling myeloid cells.

Cycling myeloid cells (CMCs) are often detected from various tissues using single-cell RNA sequencing (scRNA-seq) datasets, however, their research value was not noticed before. For the first time, our study preliminarily revealed the origin, differentiation, and roles of CMCs in physiological processes. Particularly, subgroup a of cycling myeloid cells (aCMCs) were conclusively identified as belonging to a specific cell type. In an active state, aCMCs rapidly proliferate during the early stages of an embryonic development. With an individual maturing, most aCMCs differentiate into specialized cells, while a small portion of them enter an inactive or dormant state. Under pathological conditions, aCMCs restore their proliferative and differentiation capacities via activation or revival. The present study has set the stage for future research on CMCs by linking them with progenitors of immune cells, and provided a crucial starting point to understand the origin, differentiation, and roles of CMCs in various physiological and pathological processes, particularly those related to traumatic injury, cancer, and pathogen infection, leading to develop targeted therapies or interventions.

Celastrol inhibits oligodendrocyte and neuron ferroptosis to promote spinal cord injury recovery.

BACKGROUND: Spinal cord injury (SCI) is a traumatic injury to the central nervous system and can cause lipid peroxidation in the spinal cord. Ferroptosis, an iron-dependent programmed cell death, plays a key role in the pathophysiology progression of SCI. Celastrol, a widely used antioxidant drug, has potential therapeutic value for nervous system. PURPOSE: To investigate whether celastrol can be a reliable candidate for ferroptosis inhibitor and the molecular mechanism of celastrol in repairing SCI by inhibiting ferroptosis. METHODS: First, a rat SCI model was constructed, and the recovery of motor function was observed after treatment with celastrol. The regulatory effect of celastrol on ferroptosis pathway Nrf2-xCT-GPX4 was detected by Western blot and immunofluorescence. Finally, the ferroptosis model of neurons and oligodendrocytes was constructed in vitro to further verify the mechanism of inhibiting ferroptosis by celastrol. RESULTS: Our results demonstrated that celastrol promoted the recovery of spinal cord tissue and motor function in SCI rats. Further in vitro and in vivo studies showed that celastrol significantly inhibited ferroptosis in neurons and oligodendrocytes and reduced the accumulation of ROS. Finally, we found that celastrol could inhibit ferroptosis by up-regulating the Nrf2-xCT-GPX4 axis to repair SCI. CONCLUSION: Celastrol effectively inhibits ferroptosis after SCI by upregulating the Nrf2-xCT-GPX4 axis, reducing the production of lipid ROS, protecting the survival of neurons and oligodendrocytes, and improving the functional recovery.

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

BACKGROUND: This 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. METHODS: Web 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. RESULTS: A 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. CONCLUSIONS: In 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.

Long-Acting Heterodimeric Paclitaxel-Idebenone Prodrug-Based Nanomedicine Promotes Functional Recovery after Spinal Cord Injury.

After spinal cord injury (SCI), successive systemic administration of microtubule-stabilizing agents has been shown to promote axon regeneration. However, this approach is limited by poor drug bioavailability, especially given the rapid restoration of the blood-spinal cord barrier. There is a pressing need for long-acting formulations of microtubule-stabilizing agents in treating SCI. Here, we conjugated the antioxidant idebenone with microtubule-stabilizing paclitaxel to create a heterodimeric paclitaxel-idebenone prodrug via an acid-activatable, self-immolative ketal linker and then fabricated it into chondroitin sulfate proteoglycan-binding nanomedicine, enabling drug retention within the spinal cord for at least 2 weeks and notable enhancement in hindlimb motor function and axon regeneration after a single intraspinal administration. Additional investigations uncovered that idebenone can suppress the activation of microglia and neuronal ferroptosis, thereby amplifying the therapeutic effect of paclitaxel. This prodrug-based nanomedicine simultaneously accomplishes neuroprotection and axon regeneration, offering a promising therapeutic strategy for SCI.

Sarsasapogenin regulates the immune microenvironment through MAPK/NF-kB signaling pathway and promotes functional recovery after spinal cord injury.

Spinal cord injury (SCI) occurs as a result of traumatic events that damage the spinal cord, leading to motor, sensory, or autonomic function impairment. Sarsasapogenin (SA), a natural steroidal compound, has been reported to have various pharmacological applications, including the treatment of inflammation, diabetic nephropathy, and neuroprotection. However, the therapeutic efficacy and underlying mechanisms of SA in the context of SCI are still unclear. This research aimed to investigate the therapeutic effects and mechanisms of SA against SCI by integrating network pharmacology analysis and experimental verification. Network pharmacology results suggested that SA may effectively treat SCI by targeting key targets such as TNF, RELA, JUN, MAPK14, and MAPK8. The underlying mechanism of this treatment may involve the MAPK (JNK) signaling pathway and inflammation-related signaling pathways such as TNF and Toll-like receptor signaling pathways. These findings highlight the therapeutic potential of SA in SCI treatment and provide valuable insights into its molecular mechanisms of action. In vivo experiments confirmed the reparative effect of SA on SCI in rats and suggested that SA could repair SCI by modulating the immune microenvironment. In vitro experiments further investigated how SA regulates the immune microenvironment by inhibiting the MAPK/NF-kB pathways. Overall, this study successfully utilized a combination of network pharmacology and experimental verification to establish that SA can regulate the immune microenvironment via the MAPK/NF-kB signaling pathway, ultimately facilitating functional recovery from SCI. Furthermore, these findings emphasize the potential of natural compounds from traditional Chinese medicine as a viable therapy for SCI treatment.

Surgical treatment of osteogenesis imperfecta: a summary of the incidence of femoral implant-related complications in children with Sillence type I, III and IV.

PURPOSE: This study explored the incidence of IRCs used in the procedures of the femur in children with osteogenesis imperfecta (OI) and investigated the independent risk factors of IRCs. METHODS: Three hundred eight-eight cases of surgical data about children with OI were included, who were treated with plate, elastic nail, Kirschner wire and telescopic rod. The choice of different procedures depended on the age of children, the status of femur and the availability of devices. Patient demographics and major IRCs were recorded to compare the outcomes of the four procedures. Then, Cox proportional hazard regression was used to analyse the independent risk factors of IRC, and subgroup analysis was applied to further verify the above results. RESULTS: The total incidence of IRC in the four groups was 90.1% (191/212) for plate, 96.8% (30/31) for Kirschner wire, 87.7% (57/65) for elastic nail and 30.0% (24/80) for telescopic rod. The incidence of IRC in the telescopic rod was lower than that in plate, elastic nail and Kirschner wire (P < 0.001). Cox proportional hazard regression analysis confirmed that procedure was the independent risk factor of IRC (HR, 0.191; 95% CI, 0.126-0.288; P < 0.001), fracture (HR, 0.193; 95% CI, 0.109-0.344; P < 0.001) and deformity (HR, 0.086; 95% CI, 0.027-0.272; P < 0.001). In addition, age of surgery was the independent risk factor of fracture (HR, 0.916; 95% CI, 0.882-0.952; P < 0.001) and deformity (HR, 1.052; 95% CI, 1.008-1.098; P = 0.019). Subgroup analysis confirmed that age of surgery, gender, classification, preoperative state and angle did not affect the effect of telescopic rod on reducing the risk of IRCs. CONCLUSIONS: In our cohort, lower incidence of IRCs was observed in telescopic rod group compared with plate, Kirschner wire and elastic nail. Procedure and age of surgery were independent risk factors of fracture. Likewise, procedure and age of surgery were independent risk factors of deformity, and procedure was independent risk factors of IRC.

Coordination function index: A novel indicator for assessing hindlimb locomotor recovery in spinal cord injury rats based on catwalk gait parameters.

In preclinical studies of spinal cord injury (SCI), behavioral assessments are crucial for evaluating treatment effectiveness. Commonly used methods include Basso, Beattie, Bresnahan (BBB) score and the Louisville swim scale (LSS), relying on subjective observations. The CatWalk automated gait analysis system is also widely used in SCI studies, providing extensive gait parameters from footprints. However, these parameters are often used independently or combined simply without utilizing the vast amount of data provided by CatWalk. Therefore, it is necessary to develop a novel approach encompassing multiple CatWalk parameters for a comprehensive and objective assessment of locomotor function. In this work, we screened 208 CatWalk XT gait parameters and identified 38 suitable for assessing hindlimb motor function recovery in a rat thoracic contusion SCI model. Exploratory factor analysis was used to reveal structural relationships among these parameters. Weighted scores for Coordination effectively differentiated hindlimb motor function levels, termed as the Coordinated Function Index (CFI). CFI showed high reliability, exhibiting high correlations with BBB scores, LSS, and T2WI lesion area. Finally, we simplified CFI based on factor loadings and correlation analysis, obtaining a streamlined version with reliable assessment efficacy. In conclusion, we developed a systematic assessment indicator utilizing multiple CatWalk parameters to objectively evaluate hindlimb motor function recovery in rats after thoracic contusion SCI.

Epidemiological and clinical features, treatment status, and economic burden of traumatic spinal cord injury in China: a hospital-based retrospective study.

Traumatic spinal cord injury is potentially catastrophic and can lead to permanent disability or even death. China has the largest population of patients with traumatic spinal cord injury. Previous studies of traumatic spinal cord injury in China have mostly been regional in scope; national-level studies have been rare. To the best of our knowledge, no national-level study of treatment status and economic burden has been performed. This retrospective study aimed to examine the epidemiological and clinical features, treatment status, and economic burden of traumatic spinal cord injury in China at the national level. We included 13,465 traumatic spinal cord injury patients who were injured between January 2013 and December 2018 and treated in 30 hospitals in 11 provinces/municipalities representing all geographical divisions of China. Patient epidemiological and clinical features, treatment status, and total and daily costs were recorded. Trends in the percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department and cost of care were assessed by annual percentage change using the Joinpoint Regression Program. The percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department did not significantly change overall (annual percentage change, -0.5% and 2.1%, respectively). A total of 10,053 (74.7%) patients underwent surgery. Only 2.8% of patients who underwent surgery did so within 24 hours of injury. A total of 2005 (14.9%) patients were treated with high-dose (≥ 500 mg) methylprednisolone sodium succinate/methylprednisolone (MPSS/MP); 615 (4.6%) received it within 8 hours. The total cost for acute traumatic spinal cord injury decreased over the study period (-4.7%), while daily cost did not significantly change (1.0% increase). Our findings indicate that public health initiatives should aim at improving hospitals' ability to complete early surgery within 24 hours, which is associated with improved sensorimotor recovery, increasing the awareness rate of clinical guidelines related to high-dose MPSS/MP to reduce the use of the treatment with insufficient evidence.

Alternating current stimulation promotes neurite outgrowth and plasticity in neurons through activation of the PI3K/AKT signaling pathway.

As a commonly used physical intervention, electrical stimulation (ES) has been demonstrated to be effective in the treatment of central nervous system disorders. Currently, researchers are studying the effects of electrical stimulation on individual neurons and neural networks, which are dependent on factors such as stimulation intensity, duration, location, and neuronal properties. However, the exact mechanism of action of electrical stimulation remains unclear. In some cases, repeated or prolonged electrical stimulation can lead to changes in the morphology or function of the neuron. In this study, immunofluorescence staining and Sholl analysis are used to assess changes in the neurite number and axon length to determine the optimal pattern and stimulation parameters of ES for neurons. Neuronal death and plasticity are detected by TUNEL staining and microelectrode array assays, respectively. mRNA sequencing and bioinformatics analysis are applied to predict the key targets of the action of ES on neurons, and the identified targets are validated by western blot analysis and qRT-PCR. The effects of alternating current stimulation (ACS) on neurons are more significant than those of direct current stimulation (DCS), and the optimal parameters are 3 µA and 20 min. ACS stimulation significantly increases the number of neurites, the length of axons and the spontaneous electrical activity of neurons, significantly elevates the expression of growth-associated protein-43 (GAP-43) without significant changes in the expression of neurotrophic factors. Furthermore, application of PI3K/AKT-specific inhibitors significantly abolishes the beneficial effects of ACS on neurons, confirming that the PI3K/AKT pathway is an important potential signaling pathway in the action of ACS.

The patient-related factors in revision procedures on tibia of patients with osteogenesis imperfecta treated with the Peter-Williams nail.

OBJECTIVE: To investigate the patient-related factors that affect the revision rate for the tibia in patients with osteogenesis imperfecta treated with the Peter-Williams nail, and to explore the relationship between the risk factors and complications postsurgery. METHODS: We retrospectively analysed the data of 211 patients (93 females (44.08%) and 118 males (55.92%)) with osteogenesis imperfecta treated with Peter-Williams. The factors affecting surgical revision were analysed by performing binary logistic regression. Then, a total of 211 patients with type III, type I or type IV OI were divided into five groups according to the results of regression. Statistical comparison of these groups was performed to further investigate the relationship between patient-related factors and revision procedures. Statistical comparison was also performed to analyse the relationship between the classification and postoperative complications. RESULTS: Among the 211 patients who underwent surgery, 40 had type I OI, 109 had type IV OI, and 62 had type III OI. Binary logistic regression revealed that the classification (OR = 3.32, 95% CI 1.06-10.39, P = 0.039) and initial operation age (OR = 0.83, 95% CI 0.76-0.92, P < 0.001) were significantly correlated with revision procedures. In type III patients, the initial operation age was significantly correlated with revision procedures (P < 0.001), and the revision rate was lower in patients aged 9 to12 years (P = 0.001). In type I and IV patients, the initial operation age was not significantly correlated with revision procedures (P = 0.281). Classification had a significant effect on postoperative deformity (P = 0.003). CONCLUSIONS: The study reported that the age of initial surgery and classification were the influencing factors affecting the revision procedures of tibia in patients with osteogenesis imperfecta treated with the Peter-Williams nail. In patients with type III disease, the revision rate was lower individuals aged 9-12 years old, and a higher incidence of postoperative deformity was observed.

Comparison of clinical outcomes associated with spinal cord stimulation (SCS) or conventional medical management (CMM) for chronic pain: a systematic review and meta-analysis.

OBJECTIVE: This study aims to evaluate the efficacy and safety of spinal cord stimulation (SCS) compared to conventional medical management (CMM) for patients diagnosed with chronic pain. Furthermore, the study seeks to compare the utilization of analgesics, as well as the long-term outcomes in terms of quality of life and functional capacity. DATA SOURCES: We systematically searched Cochrane Library, Web of Science, PubMed, and EMBASE for randomized controlled trials from inception up to February 2022. REVIEW METHODS: Inclusion and exclusion criteria were set according to the PICOS criteria. We searched for studies in which SCS was compared with CMM alone for chronic pain. Two reviewers independently identified eligible studies and extracted data. Risk of bias assessments were performed according to Cochrane review criteria and Interventional Pain Management Techniques-quality Appraisal of Reliability and Risk of Bias Assessment (IPM-QRB) criteria. RESULTS: The present meta-analysis comprised eight studies and included a total of 893 patients. Our findings demonstrate that spinal cord stimulation (SCS) in combination with conventional medical management (CMM) is associated with a significant reduction in visual analogue scale (VAS) pain intensity (P = 0.0005) and decreased scores on the McGill Pain Questionnaire (MPQ) (P < 0.0001). Moreover, SCS plus CMM was found to improve patients' quality of life, as evidenced by improvements in SF-36 scores (P < 0.00001), EQ-5D utility index (P = 0.008), and Oswestry Disability Index (ODI) (P < 0.00001). Based on the results of four high-quality randomized controlled trials (RCTs), the level of evidence supporting the efficacy of SCS for the treatment of painful neuropathy is graded as level I to II. In contrast, there is currently only low-level evidence to support the use of high-frequency stimulation and other chronic pain conditions, which can be attributed to a lack of sufficient randomized controlled trials. LIMITATIONS: The principal limitation of our study is the significant heterogeneity observed among the cohorts investigated. The primary source of this heterogeneity is the fact that spinal cord stimulation is indicated for the treatment of multiple chronic pain conditions. Moreover, variations in the stimulation parameters, differences among manufacturers, and the specific surgical implantation settings contribute to the increased heterogeneity observed in our analyses. To address this issue, we conducted a subgroup analysis based on specific situations and performed evidence synthesis to mitigate the potential impact of heterogeneity. These approaches allow for a more precise interpretation of the results and a more accurate evaluation of the quality of the included studies. CONCLUSIONS: SCS is an effective treatment to relieve the pain level of chronic pain, decrease analgesic usage, and increase long-term quality of life and functional capacity.

Which is the best femoral implant in children with osteogenesis imperfecta? a retrospective cohort study of 783 procedures.

BACKGROUND: Osteogenesis imperfecta (OI) is a hereditary genetic disorder characterized by bone fragility and extremity deformities. The surgical management for long-bone fractures and deformities in OI remains a challenge. We aimed to compare clinical outcomes after femoral surgery splinted with the telescopic rod, the plate and screws, the elastic nail and the non-elongating rod in setting of OI. METHODS:  A retrospective cohort study included 783 femoral procedures (mean age 6.00 (interquartile range (IQR) 5.00) years, 335 (42.8%) females) was conducted, and individuals were categorized into four groups according to implants. After verifying comparability among the groups, revision rate and implant survival period were compared among the Sillence types and the same comparison were made among four groups within each Sillence type. The incidence of refractures, deformities, and implant-related complications were also compared among the four groups. RESULTS: There were no significant differences in demographic information among the four groups in terms of sex (p = 0.101), laterality (p = 0.587), Sillence type (p = 0.122), and postoperative follow-up period (p = 0.214). In total, children with Sillence type III had the highest revision rate and the shortest implant survival period; children with Sillence type I had the lowest revision rate and the longest implant survival period; and children with Sillence type IV had the revision rate and the implant survival period between those observed in Sillence types I and III. In Sillence types III and IV, the telescopic rod had lower revision rate (III 24.8%; IV 20.9%) compared to the plate (III 97.2%, p<0.001; IV 80.3%, p<0.001), the elastic nail (III 100.0%, p=0.019; IV 73.9%, p<0.001) and the non-elongating rod (III 65.0%, p<0.001; IV46.9%, p<0.001); the median implant survival period of the telescopic rod (III 48.00 (IQR 28.50) months; IV 43.00 (33.00) months) is longer than the plate (III 11.00 (9.00) months, p<0.001; IV 19.00 (20.00) months, p<0.001), the elastic nail (III 45.00 (37.75) months, p=1.000; IV 19.00 (35.00) months, p=0.028) and the non-elongating rod (III 39.00 (31.75) months, p=0.473; IV 38.50 (29.75) months, p=1.000).A similar trend was observed in Sillence type I (p = 0.063, p = 0.003; respectively). In addition, the incidence of refracture (15.5%), deformity (2.8%) and implant-related complications (23.1%) were also statistically lower in the telescopic rod group. CONCLUSION: In our cohort, lower revision rate and longer implant survival period were observed in telescopic rod group. This was mainly due to the significant lower incidence of refracture, deformity and implant-related complications with the use of telescopic rod.

LC-MS/MS-based arachidonic acid metabolomics in acute spinal cord injury reveals the upregulation of 5-LOX and COX-2 products.

Arachidonic acid (AA) plays a critical role in inflammatory regulation and secondary injury after spinal cord injury (SCI). However, the overall AA metabolism profile in the acute phase of SCI remains elusive. Here we quantified AA metabolomics by High Performance Liquid Chromatography-Tandem Mass Spectrometry-Based Method (LC-MS/MS) using spinal cord tissue collected at 4 h, 24 h and 48 h after contusive SCI in rats. Remarkably, Prostaglandin E2 (PGE2) and Leukotriene B4 (LTB4) were significantly increased throughout the acute SCI. Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), the key enzymes involved in the production of PGE2 and LTB4, were elevated in the lesioned spinal cord tissue, validated by both western blot and immunofluorecnce. The spatial-temporal changes of COX-2 and 5-LOX mainly occurs in neurons both in epicenter and rostral and caudal spinal cord segments after SCI. Our study sheds light on the dynamic microenvironment changes in acute SCI by characterizing the profile of AA metabolism. The COX-2 and 5-LOX may be promising therapeutic target for SCI.

Correlation Analysis Between Magnetic Resonance Imaging-Based Anatomical Assessment and Behavioral Outcome in a Rat Contusion Model of Chronic Thoracic Spinal Cord Injury.

Although plenty of evidences from preclinical studies have led to potential treatments for patients with spinal cord injury (SCI), the failure to translate promising preclinical findings into clinical advances has long puzzled researchers. Thus, a more reliable combination of anatomical assessment and behavioral testing is urgently needed to improve the translational worth of preclinical studies. To address this issue, the present study was designed to relate magnetic resonance imaging (MRI)-based anatomical assessment to behavioral outcome in a rat contusion model. Rats underwent contusion with three different heights to simulate various severities of SCI, and their locomotive functions were evaluated by the grid-walking test, Louisville swim scale (LSS), especially catwalk gait analysis system and basic testing, and Basso, Beattie, Bresnahan (BBB) score. The results showed that the lesion area (LA) is a better indicator for damage assessment compared with other parameters in sagittal T2-weighted MRI (T2WI). Although two samples are marked as outliers by the box plot analysis, LA correlated closely with all of the behavioral testing without ceiling effect and floor effect. Moreover, with a moderate severity of SCI in a contusion height of 25 mm, the smaller the LA of the spinal cord measured on sagittal T2WI the better the functional performance, the smaller the cavity region and glial scar, the more spared the myelin, the higher the volatility, and the thicker the bladder wall. We found that LA significantly related with behavior outcomes, which indicated that LA could be a proxy of damage assessment. The combination of sagittal T2WI and four types of behavioral testing can be used as a reliable scheme to evaluate the prognosis for preclinical studies of SCI.

Autophagy induced by Schwann cell-derived exosomes promotes recovery after spinal cord injury in rats.

Spinal cord injury (SCI) is catastrophic to humans and society. However, there is currently no effective treatment for SCI. Autophagy is known to serve critical roles in both the physiological and pathological processes of the body, but its facilitatory and/or deleterious effects in SCI are yet to be completely elucidated. This study aimed to use primary Schwann cell-derived exosomes (SCDEs) to treat rats after SCI. In the present study, SCDEs were purified and their efficacy in ameliorating the components of SCI was examined. Using both in vivo and in vitro experiments, it was demonstrated that SCDEs increased autophagy and decreased apoptosis after SCI, which promoted axonal protection and the recovery of motor function. Furthermore, it was discovered that an increased number of SCDEs resulted in a decreased expression level of EGFR, which subsequently inhibited the Akt/mTOR signaling pathway, which upregulated the level of autophagy to ultimately induce microtubule acetylation and polymerization. Collectively, the present study identified that SCDEs could induce axonal protection after SCI by increasing autophagy and decreasing apoptosis, and it was suggested that this may involve the EGFR/Akt/mTOR signaling pathway.

Potential of different cells-derived exosomal microRNA cargos for treating spinal cord injury.

Spinal cord injury (SCI) is a disastrous situation that affects many patients worldwide. A profound understanding of the pathology and etiology of SCI is of great importance in inspiring new therapeutic concepts and treatment. In recent years, exosomes, which are complex lipid membrane structures secreted nearly by all kinds of plants and animal cells, can transport their valuable cargoes (e.g., proteins, lipids, RNAs) to the targeted cells and exert their communication and regulation functions, which open up a new field of treatment of SCI. Notably, the exosome's advantage is transporting the carried material to the target cells across the blood-brain barrier and exerting regulatory functions. Among the cargoes of exosomes, microRNAs, through the modulation of their mRNA targets, emerges with great potentiality in the pathological process, diagnosis and treatment of SCI. In this review, we discuss the role of miRNAs transported by different cell-derived exosomes in SCI that are poised to enhance SCI-specific therapeutic capabilities of exosomes.

Inhibition of TGF-ß repairs spinal cord injury by attenuating EphrinB2 expressing through inducing miR-484 from fibroblast.

Spinal cord injury (SCI) can lead to severe loss of motor and sensory function with high disability and mortality. The effective treatment of SCI remains unknown. Here we find systemic injection of TGF-ß neutralizing antibody induces the protection of axon growth, survival of neurons, and functional recovery, whereas erythropoietin-producing hepatoma interactor B2 (EphrinB2) expression and fibroblasts distribution are attenuated. Knockout of TGF-ß type II receptor in fibroblasts can also decrease EphrinB2 expression and improve spinal cord injury recovery. Moreover, miR-488 was confirmed to be the most upregulated gene related to EphrinB2 releasing in fibroblasts after SCI and miR-488 initiates EphrinB2 expression and physical barrier building through MAPK signaling after SCI. Our study points toward elevated levels of active TGF-ß as inducer and promoters of fibroblasts distribution, fibrotic scar formation, and EphrinB2 expression, and deletion of global TGF-ß or the receptor of TGF-ß in Col1α2 lineage fibroblasts significantly improve functional recovery after SCI, which suggest that TGF-ß might be a therapeutic target in SCI.

Exosomes-mediated phenotypic switch of macrophages in the immune microenvironment after spinal cord injury.

Although accumulating evidence indicated that modulating macrophage polarization could ameliorate the immune microenvironment and facilitate the repair of spinal cord injury (SCI), the underlying mechanism of macrophage phenotypic switch is still poorly understood. Exosomes (Exos), a potential tool of cell-to-cell communication, may play important roles in cell reprogramming. Herein, we investigated the roles of macrophages-derived exosomes played for macrophage polarization in the SCI immune microenvironment. In this study, we found the fraction of M2 macrophages was markedly decreased after SCI. Moreover, the M2 macrophages-derived exosomes could increase the percentage of M2 macrophages, decrease that of M1 macrophages while the M1 macrophages-derived exosomes acted oppositely. According to the results of in silico analyses and molecular experiments verification, this phenotypic switch might be mediated by the exosomal miRNA-mRNA network, in which the miR-23a-3p/PTEN/PI3K/AKT axis might play an important role. In conclusion, our study suggests macrophage polarization that regulated by various interventions might be mediated by their own exosomes at last. Moreover, M2 macrophages-derived exosomes could promote M2 macrophage polarization via the potential miRNA-mRNA network. Considering its potential of modulating polarization, M2 macrophages-derived exosomes may be a promising therapeutic agent for SCI repair.