Site Of Spinal Cord Injury Research Articles

Macrophage membrane-mediated targeted curcumin biomimetic nanoparticles delivery for diagnosis and treatment of spinal cord injury by suppressing neuroinflammation and ferroptosis

Spinal cord injury (SCI) is a severe and debilitating central nervous system disorder characterized by permanent motor and sensory deficits, with limited effective treatment options available. Recent advancements have been made in the functionalization of biomimetic surfaces of nanoparticles through the incorporation of synthetic bionic and naturally derived cell membranes. One emerging strategy involves integrating biomimetic features into therapeutic agents to achieve low immunogenicity, high targeting specificity, and prolonged drug half-life. In this study, we detail the preparation of nanoparticles via the self-assembly of the amphiphilic diblock copolymer PEG-b-PHPMA with curcumin and PCPDTBT in water, followed by macrophage cell membrane coating using an extrusion method, resulting in the formation of stable curcumin-loaded nanoparticles coated with cell membrane (MM@Cur). Our experimental results demonstrate that MM@Cur treatment specifically targets the SCI site, effectively mitigates ferroptosis and central inflammation in a mouse model featuring spinal cord contusion, and enhances the recovery of the motor function of hind limbs post-SCI. Therefore, our findings highlight MM@Cur as a highly targeted biomimetic nanoparticle possessing potent anti-ferroptosis and anti-inflammatory properties, offering a promising therapeutic approach for the restoration of hind limb function post-spinal cord injury

Curcumin/pEGCG-encapsulated nanoparticles enhance spinal cord injury recovery by regulating CD74 to alleviate oxidative stress and inflammation

Spinal cord injury (SCI) often accompanies impairment of motor function, yet there is currently no highly effective treatment method specifically for this condition. Oxidative stress and inflammation are pivotal factors contributing to severe neurological deficits after SCI. In this study, a type of curcumin (Cur) nanoparticle (HA-CurNPs) was developed to address this challenge by alleviating oxidative stress and inflammation. Through non-covalent interactions, curcumin (Cur) and poly (-)-epigallocatechin-3-gallate (pEGCG) are co-encapsulated within hyaluronic acid (HA), resulting in nanoparticles termed HA-CurNPs. These nanoparticles gradually release curcumin and pEGCG at the SCI site. The released pEGCG and curcumin not only scavenge reactive oxygen species (ROS) and prevents apoptosis, thereby improving the neuronal microenvironment, but also regulate CD74 to promote microglial polarization toward an M2 phenotype, and inhibits M1 polarization, thereby suppressing the inflammatory response and fostering neuronal regeneration. Moreover, in vivo experiments on SCI mice demonstrate that HA-CurNPs effectively protect neuronal cells and myelin, reduce glial scar formation, thereby facilitating the repair of damaged spinal cord tissues, restoring electrical signaling at the injury site, and improving motor functions. Overall, this study demonstrates that HA-CurNPs significantly reduce oxidative stress and inflammation following SCI, markedly improving motor function in SCI mice. This provides a promising therapeutic approach for the treatment of SCI.

Invasive devices to monitor the intraspinal perfusion pressure in the hemodynamic management of acute spinal cord injury: A systematic scoping review.

Various methods for measuring intrathecal pressure (ITP) after spinal cord injury (SCI) to guide hemodynamic management have been investigated. To synthesize the current literature, this current study conducted a scoping review of the use of intrathecal devices to monitor ITP during acute management of SCI with the aim of understanding the association between ITP monitoring with physiological and clinical outcomes. A systematic review of literature following the Cochrane Handbook for Systematic Reviews of Interventions and Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement. All eligible studies were screened for inclusion and exclusion criteria. Data extracted included number of patients included, severity of injury, characteristics of the intervention-intrathecal device used to record the ITP, outcomes -hemodynamic parameters observed, changes in the American Spinal Injury Association (ASIA) Impairment Scale (AIS), total motor scores, association of ITP with other physiological variables. The search yielded a total of 1,698 articles, of which 30 observational studies and 2 randomized clinical trials were deemed eligible based on their use of an intrathecal invasive device to monitor spinal cord perfusion pressure (SCPP) in patients with SCI. Of these, 9 studies used a lumbar drain, 23 a Codman pressure probe and 1 study that used both. These studies underscore the crucial interplay between ITP, the SCPP and physiological variables, with neurological outcome. It is still unclear whether monitoring from a lumbar drain is accurate enough to highlight what is occurring at the site of SCI, which is the main advantage of Codman Probe, however, the latter requires specialized personnel that may not be available in most settings. Minor adverse effects were associated with lumbar drain catheters, while cerebrospinal fluid leak requiring repair (~ 7%) is the main concern with Codman Probes. Future investigation of SCPP protocols via lumbar drains and Codman probes ought to involve multi-centered randomized controlled trials and continued translational investigation with animal models.

Analysis of the Intensity of Nitric Oxide Production in Different Parts of the Spinal Cord after Modeling Combined Cerebral and Spinal Injury.

Using the method of electron paramagnetic resonance spectroscopy, we showed that NO production decreases by 60% (p<0.05) in the region located rostral to the spinal cord injury 7 days after combined injury to the brain and spinal cord. At the same time, NO production did not change in the site of spinal cord injury and caudal to the injury. The intensity of NO production in similar parts of the spinal cord in intact animals remained unchanged.

Decellularized porcine peripheral nerve based injectable hydrogels as a Schwann cell carrier for injured spinal cord regeneration

Objective. To develop a clinically relevant injectable hydrogel derived from decellularized porcine peripheral nerves and with mechanical properties comparable to native central nervous system (CNS) tissue to be used as a delivery vehicle for Schwann cell transplantation to treat spinal cord injury (SCI). Approach. Porcine peripheral nerves (sciatic and peroneal) were decellularized by chemical decellularization using a sodium deoxycholate and DNase (SDD) method previously developed by our group. The decellularized nerves were delipidated using dichloromethane and ethanol solvent and then digested using pepsin enzyme to form injectable hydrogel formulations. Genipin was used as a crosslinker to enhance mechanical properties. The injectability, mechanical properties, and gelation kinetics of the hydrogels were further analyzed using rheology. Schwann cells encapsulated within the injectable hydrogel formulations were passed through a 25-gauge needle and cell viability was assessed using live/dead staining. The ability of the hydrogel to maintain Schwann cell viability against an inflammatory milieu was assessed in vitro using inflamed astrocytes co-cultured with Schwann cells. Main results. The SDD method effectively removes cells and retains extracellular matrix in decellularized tissues. Using rheological studies, we found that delipidation of decellularized porcine peripheral nerves using dichloromethane and ethanol solvent improves gelation kinetics and mechanical strength of hydrogels. The delipidated and decellularized hydrogels crosslinked using genipin mimicked the mechanical strength of CNS tissue. The hydrogels were found to have shear thinning properties desirable for injectable formulations and they also maintained higher Schwann cell viability during injection compared to saline controls. Using in vitro co-culture experiments, we found that the genipin-crosslinked hydrogels also protected Schwann cells from astrocyte-mediated inflammation. Significance. Injectable hydrogels developed using delipidated and decellularized porcine peripheral nerves are a potential clinically relevant solution to deliver Schwann cells, and possibly other therapeutic cells, at the SCI site by maintaining higher cellular viability and increasing therapeutic efficacy for SCI treatment.

Inhibiting SHP2 reduces glycolysis, promotes microglial M1 polarization, and alleviates secondary inflammation following spinal cord injury in a mouse model.

JOURNAL/nrgr/04.03/01300535-202503000-00030/figure1/v/2024-06-17T092413Z/r/image-tiff Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2 (SHP2), encoded by PTPN11, is widely expressed in the human body and plays a role in inflammation through various mechanisms. Therefore, SHP2 is considered a potential target for the treatment of inflammation-related diseases. However, its role in secondary inflammation after spinal cord injury remains unclear. In this study, SHP2 was found to be abundantly expressed in microglia at the site of spinal cord injury. Inhibition of SHP2 expression using siRNA and SHP2 inhibitors attenuated the microglial inflammatory response in an in vitro lipopolysaccharide-induced model of inflammation. Notably, after treatment with SHP2 inhibitors, mice with spinal cord injury exhibited significantly improved hind limb locomotor function and reduced residual urine volume in the bladder. Subsequent in vitro experiments showed that, in microglia stimulated with lipopolysaccharide, inhibiting SHP2 expression promoted M2 polarization and inhibited M1 polarization. Finally, a co-culture experiment was conducted to assess the effect of microglia treated with SHP2 inhibitors on neuronal cells. The results demonstrated that inflammatory factors produced by microglia promoted neuronal apoptosis, while inhibiting SHP2 expression mitigated these effects. Collectively, our findings suggest that SHP2 enhances secondary inflammation and neuronal damage subsequent to spinal cord injury by modulating microglial phenotype. Therefore, inhibiting SHP2 alleviates the inflammatory response in mice with spinal cord injury and promotes functional recovery postinjury.

Salidroside promotes the repair of spinal cord injury by inhibiting astrocyte polarization, promoting neural stem cell proliferation and neuronal differentiation

Spinal cord injury (SCI) remains a formidable challenge, lacking effective treatments. Following SCI, neural stem cells (NSCs) migrate to SCI sites, offering a potential avenue for nerve regeneration, but the effectiveness of this intrinsic repair mechanism remains suboptimal. Salidroside has demonstrated pro-repair attributes in various pathological conditions, including arthritis and cerebral ischemia, and the ability to curtail early-stage inflammation following SCI. However, the specific role of salidroside in the late-stage repair processes of SCI remains less defined. In this investigation, we observed that continuous salidroside treatment in SCI mice improved motor function recovery. Immunofluorescence-staining corroborated salidroside’s capacity to stimulate nerve regeneration and remyelination, suppress glial scar hyperplasia, reduce the activation of neurotoxic A1 astrocytes, and facilitate NSCs migration towards the injured region. Mechanistically, in vitro experiments elucidated salidroside’s significant role in restraining astrocyte proliferation and A1 polarization. It was further established that A1 astrocytes hinder NSCs proliferation while inducing their differentiation into astrocytes. Salidroside effectively ameliorated this inhibition of NSCs proliferation through diminishing c-Jun N-terminal kinase (JNK) pathway phosphorylation and restored their differentiation into neurons by suppressing the signal transducer and activator of transcription 3 (STAT3) pathway. In summary, our findings suggest that salidroside holds promise as a therapeutic agent for traumatic SCI treatment.

Conductive Hydrogel Restores Electrical Conduction to Promote Neurological Recovery in a Rat Model.

Spinal cord injury (SCI), caused by significant physical trauma, as well as other pathological conditions, results in electrical signaling disruption and loss of bodily functional control below the injury site. Conductive biomaterials have been considered a promising approach for treating SCI, owing to their ability to restore electrical connections between intact spinal cord portions across the injury site. In this study, we evaluated the ability of a conductive hydrogel, poly-3-amino-4-methoxybenzoic acid-gelatin (PAMB-G), to restore electrical signaling and improve neuronal regeneration in a rat SCI model generated using the compression clip method. Gelatin or PAMB-G was injected at the SCI site, yielding three groups: Control (saline), Gelatin, and PAMB-G. During the 8-week study, PAMB-G, compared to Control, had significantly lower proinflammatory factor expression, such as for tumor necrosis factor -α (0.388 ± 0.276 for PAMB-G vs. 1.027 ± 0.431 for Control) and monocyte chemoattractant protein (MCP)-1 (0.443 ± 0.201 for PAMB-G vs. 1.662 ± 0.912 for Control). In addition, PAMB-G had lower astrocyte and microglia numbers (35.75 ± 4.349 and 40.75 ± 7.890, respectively) compared to Control (50.75 ± 6.5 and 64.75 ± 10.72) and Gelatin (48.75 ± 4.787 and 71.75 ± 7.411). PAMB-G-treated rats also had significantly greater preservation and regeneration of remaining intact neuronal tissue (0.523 ± 0.059% mean white matter in PAMB-G vs 0.377 ± 0.044% in Control and 0.385 ± 0.051% in Gelatin) caused by reduced apoptosis and increased neuronal growth-associated gene expression. All these processes stemmed from PAMB-G facilitating increased electrical signaling conduction, leading to locomotive functional improvements, in the form of increased Basso-Beattie-Bresnahan scores and steeper angles in the slope test (76.667 ± 5.164 for PAMB-G, vs. 59.167 ± 4.916 for Control and 58.333 ± 4.082 for Gelatin), as well as reduced gastrocnemius muscle atrophy (0.345 ± 0.085 for PAMB-G, vs. 0.244 ± 0.021 for Control and 0.210 ± 0.058 for Gelatin). In conclusion, PAMB-G injection post-SCI resulted in improved electrical signaling conduction, which contributed to lowered inflammation and apoptosis, increased neuronal growth, and greater bodily functional control, suggesting its potential as a viable treatment for SCI.

Normobaric Hyperoxia Treatment after Mid-cervical Contusion Injury in Rats

Severe hypoxia at or near the site of spinal cord injury (SCI) contributes to necrosis and secondary tissue damage. Prior studies of O2 therapy after SCI have primarily used pressurized hyperoxic exposure ( i.e., hyperbaric oxygen). We tested the hypothesis that daily exposure to 100% O2, delivered at atmospheric pressure ( i.e., normobaric hyperoxia) could accelerate the recovery of inspiratory tidal volume after cervical SCI. Three groups of adult male Sprague Dawley rats received a 150 kdyn impact right lateral C4 cervical SCI. In group 1, normobaric hyperoxia (100% O2 at 1 atmosphere pressure, 2 hours) was initiated within 20 min of SCI and continued daily for 7 days. In group 2, the same normobaric hyperoxia paradigm was initiated on day 8 post-injury and continued until day 14. A third group received a sham treatment, consisting of exposure to normobaric normoxia (21% O2, 1 ATA) daily for 14 days. Whole-body plethysmography was used to examine breathing patterns before-, 1-, and 2-weeks post-SCI. All three groups lost and then gained body mass at similar rates over days 1-14 post-SCI. Mortality rates during the first week after SCI were 23% (5/22) in rats not exposed to hyperoxia, and 10% (1/10) in the daily hyperoxia group. Tidal volume (VT) and breathing rate were compared using 2-way repeated measures ANOVA. The breathing rate (br/min) was similar between groups at 1-week post-injury. We observed a trend (p=0.182) for reduced breathing rate at the 2-week time point in the week-1 hyperoxia group (69±18) compared to the week-2 hyperoxia group (89±21) and the normoxia group (83±17). Inspiratory VT (mL/breath) was elevated in the week-1 hyperoxia group (0.59±0.08) as compared to the week-2 hyperoxia (0.44±0.05) and normoxia groups (0.44±0.06) at 1-week post-SCI (p=0.002). When VT was normalized to body weight (mL/breath/kg) the same effect of O2 exposure was observed (p=0.001). The effect was transient, however, and at day 14 post-SCI VT was similar across the three experimental groups (p&gt;0.50). We conclude that normobaric hyperoxia treatment during the first week after cervical SCI alters the pattern of breathing, and may have benefit to recovery. R01HL153140-04. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Quercetin-loaded Human Umbilical cord Mesenchymal Stem Cell-derived sEVs for Spinal Cord Injury Recovery

Following spinal cord injury, the inflammatory environment at the injury site causes local microglia and astrocytes to activate, which worsens the nerve damage in the affected area. Quercetin, an anti-inflammatory agent, has been limited in spinal cord injury due to its poor water solubility and easy degradation. Stem cell-derived extracellular vesicles can go through the blood–brain barrier and are an ideal drug delivery system. In this study, umbilical cord mesenchymal stem cell-derived extracellular vesicles were used to load quercetin to prevent its degradation and allow it to accumulate at the site of spinal cord injury. Our results showed that quercetin-loaded extracellular vesicles could inhibit the activation of microglia to M1 phenotype through the TLR4/NF-κB pathway, and the activation of astrocytes to A1 phenotype through the JAK2/STAT3 pathway. This reduced the production of inflammatory factors, mitigated neuronal damage, and inhibited the growth of astroglial scar, but promoted the recovery of motor function in rats with spinal cord injury.

Injectable, Electroconductive, Free Radical Scavenging Silk Fibroin/Black Phosphorus/Glycyrrhizic Acid Nanocomposite Hydrogel for Enhancing Spinal Cord Repair.

Spinal cord injury (SCI) often leads to a severe permanent disability. A poor inflammatory microenvironment and nerve electric signal conduction block are the main reasons for difficulty in spinal cord nerve regeneration. In this study, black phosphorus (BP) and glycyrrhizic acid (GA) are integrated into methacrylate-modified silk fibroin (SF) to construct a bifunctional injectable hydrogel (SF/BP/GA) with appropriate conductivity and the ability to inhibit inflammation to promote neuronal regeneration after SCI. This work discovers that the SF/BP/GA hydrogel can reduce the oxidative damage mediated by oxygen free radicals, promote the polarization of macrophages toward the anti-inflammatory M2 phenotype, reduce the expression of inflammatory factors, and improve the inflammatory microenvironment. Moreover, it induces neural stem cell (NSC) differentiation and neurosphere formation, restores signal conduction at the SCI site in vivo, and ameliorates motor function in mice with spinal cord hemisection, revealing a significant neural repair effect. An injectable, electroconductive, free-radical-scavenging hydrogel is a promising therapeutic strategy for SCI repair.

Hypothermia effects on neuronal plasticity post spinal cord injury.

SCI is a time-sensitive debilitating neurological condition without treatment options. Although the central nervous system is not programmed for effective endogenous repairs or regeneration, neuroplasticity partially compensates for the dysfunction consequences of SCI. The purpose of our study is to investigate whether early induction of hypothermia impacts neuronal tissue compensatory mechanisms. Our hypothesis is that although neuroplasticity happens within the neuropathways, both above (forelimbs) and below (hindlimbs) the site of spinal cord injury (SCI), hypothermia further influences the upper limbs' SSEP signals, even when the SCI is mid-thoracic. A total of 30 male and female adult rats are randomly assigned to four groups (n = 7): sham group, control group undergoing only laminectomy, injury group with normothermia (37°C), and injury group with hypothermia (32°C +/-0.5°C). The NYU-Impactor is used to induce mid-thoracic (T8) moderate (12.5 mm) midline contusive injury in rats. Somatosensory evoked potential (SSEP) is an objective and non-invasive procedure to assess the functionality of selective neuropathways. SSEP monitoring of baseline, and on days 4 and 7 post-SCI are performed. Statistical analysis shows that there are significant differences between the SSEP signal amplitudes recorded when stimulating either forelimb in the group of rats with normothermia compared to the rats treated with 2h of hypothermia on day 4 (left forelimb, p = 0.0417 and right forelimb, p = 0.0012) and on day 7 (left forelimb, p = 0.0332 and right forelimb, p = 0.0133) post-SCI. Our results show that the forelimbs SSEP signals from the two groups of injuries with and without hypothermia have statistically significant differences on days 4 and 7. This indicates the neuroprotective effect of early hypothermia and its influences on stimulating further the neuroplasticity within the upper limbs neural network post-SCI. Timely detection of neuroplasticity and identifying the endogenous and exogenous factors have clinical applications in planning a more effective rehabilitation and functional electrical stimulation (FES) interventions in SCI patients.

Advancing Spinal Cord Injury Bioimaging and Repair with Multifunctional Gold Nanodots Tracking.

High levels of reactive oxygen species (ROS) are known to play a critical role in the secondary cascade of spinal cord injury (SCI). The scavenging of ROS has emerged as a promising approach for alleviating acute SCI. Moreover, identifying the precise location of the SCI site remains challenging. Enhancing the visualization of the spinal cord and improving the ability to distinguish the lesion site are crucial for accurate and safe treatment. Therefore, there is an urgent clinical need to develop a biomaterial that integrates diagnosis and treatment for SCI. Herein, ultra-small-sized gold nanodots (AuNDs) were designed for dual-mode imaging-guided precision treatment of SCI. The designed AuNDs demonstrate two important functions. First, they effectively scavenge ROS, inhibit oxidative stress, reduce the infiltration of inflammatory cells, and prevent apoptosis. This leads to a significant improvement in SCI repair and promotes a functional recovery after injury. Second, leveraging their excellent dual-mode imaging capabilities, the AuNDs enable rapid and accurate identification of SCI sites. The high contrast observed between the injured and adjacent uninjured areas highlights the tremendous potential of AuNDs for SCI detection. Overall, by integrating ROS scavenging and dual-mode imaging in a single biomaterial, our work on functionalized AuNDs provides a promising strategy for the clinical diagnosis and treatment of SCI.

Functional Polyphenol-Based Nanoparticles Boosted the Neuroprotective Effect of Riluzole for Acute Spinal Cord Injury.

Riluzole is commonly used as a neuroprotective agent for treating traumatic spinal cord injury (SCI), which works by blocking the influx of sodium and calcium ions and reducing glutamate activity. However, its clinical application is limited because of its poor solubility, short half-life, potential organ toxicity, and insufficient bioabilities toward upregulated inflammation and oxidative stress levels. To address this issue, epigallocatechin gallate (EGCG), a natural polyphenol, was employed to fabricate nanoparticles (NPs) with riluzole to enhance the neuroprotective effects. The resulting NPs demonstrated good biocompatibility, excellent antioxidative properties, and promising regulation effects from the M1 to M2 macrophages. Furthermore, an in vivo SCI model was successfully established, and NPs could be obviously aggregated at the SCI site. More interestingly, excellent neuroprotective properties of NPs through regulating the levels of oxidative stress, inflammation, and ion channels could be fully demonstrated in vivo by RNA sequencing and sophisticated biochemistry evaluations. Together, the work provided new opportunities toward the design and fabrication of robust and multifunctional NPs for oxidative stress and inflammation-related diseases via biological integration of natural polyphenols and small-molecule drugs.

Clickable Granular Hydrogel Scaffolds for Delivery of Neural Progenitor Cells to Sites of Spinal Cord Injury.

Spinal cord injury (SCI) is a serious condition with limited treatment options. Neural progenitor cell (NPC) transplantation is a promising treatment option, and the identification of novel biomaterial scaffolds that support NPC engraftment and therapeutic activity is a top research priority. The objective of this study is to evaluate in situ assembled poly (ethylene glycol) (PEG)-based granular hydrogels for NPC delivery in a murine model of SCI. Microgel precursors are synthesized by using thiol-norbornene click chemistry to react four-armed PEG-amide-norbornene with enzymatically degradable and cell adhesive peptides. Unreacted norbornene groups are utilized for in situ assembly into scaffolds using a PEG-di-tetrazine linker. The granular hydrogel scaffolds exhibit good biocompatibility and do not adversely affect the inflammatory response after SCI. Moreover, when used to deliver NPCs, the granular hydrogel scaffolds supported NPC engraftment, do not adversely affect the immune response to the NPC grafts, and successfully support graft differentiation toward neuronal or astrocytic lineages as well as axonal extension into the host tissue. Collectively, these data establish PEG-based granular hydrogel scaffolds as a suitable biomaterial platform for NPC delivery and justify further testing, particularly in the context of more severe SCI.

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.

Engineered Multifunctional Zinc-Organic Framework-Based Aggregation-Induced Emission Nanozyme for Accelerating Spinal Cord Injury Recovery.

Functional recovery following a spinal cord injury (SCI) is challenging. Traditional drug therapies focus on the suppression of immune responses; however, strategies for alleviating oxidative stress are lacking. Herein, we developed the zinc-organic framework (Zn@MOF)-based aggregation-induced emission-active nanozymes for accelerating recovery following SCI. A multifunctional Zn@MOF was modified with the aggregation-induced emission-active molecule 2-(4-azidobutyl)-6-(phenyl(4-(1,2,2-triphenylvinyl)phenyl)amino)-1H-phenalene-1,3-dione via a bioorthogonal reaction, and the resulting nanozymes were denoted as Zn@MOF-TPD. These nanozymes gradually released gallic acid and zinc ions (Zn2+) at the SCI site. The released gallic acid, a scavenger of reactive oxygen species (ROS), promoted antioxidation and alleviated inflammation, re-establishing the balance between ROS production and the antioxidant defense system. The released Zn2+ ions inhibited the activity of matrix metalloproteinase 9 (MMP-9) to facilitate the regeneration of neurons via the ROS-mediated NF-κB pathway following secondary SCI. In addition, Zn@MOF-TPD protected neurons and myelin sheaths against trauma, inhibited glial scar formation, and promoted the proliferation and differentiation of neural stem cells, thereby facilitating the repair of neurons and injured spinal cord tissue and promoting functional recovery in rats with contusive SCI. Altogether, this study suggests that Zn@MOF-TPD nanozymes possess a potential for alleviating oxidative stress-mediated pathophysiological damage and promoting motor recovery following SCI.

Intravenous administration of human amnion-derived mesenchymal stem cells improves gait and sensory function in mouse models of spinal cord injury.

Spinal cord injury (SCI) leads to severe disabilities and remains a significant social and economic challenge. Despite advances in medical research, there are still no effective treatments for SCI. Human amnion-derived mesenchymal stem cells (hAMSCs) have shown potential due to their anti-inflammatory and neuroprotective effects. This study evaluates the therapeutic potential of intravenously administered hAMSCs in SCI models. Three days after induction of SCI with forceps calibrated with a 0.2 mm gap, hAMSCs or vehicle were administered intravenously. Up to 4 weeks of SCI induction, motor function was assessed by scores on the Basso Mouse Locomotor Scale (BMS) and the Basso-Beattie-Bresnahan Scale (BBB), and sensory function by hindlimb withdrawal reflex using von Frey filaments. Six weeks after SCI induction, gait function was assessed using three-dimensional motion analysis. Immunohistochemistry, polymerase chain reaction (PCR), flow cytometry, and ELISA assay were performed to clarify the mechanisms of functional improvement. The hAMSC treatment significantly improved sensory response and gait function. In the SCI site, immunohistochemistry showed a reduction in Iba1-positive cells and PCR revealed decreased TNFα and increased BDNF levels in the hAMSC-treated group. In assessing the systemic inflammatory response, hAMSC treatment reduced monocytic bone marrow-derived suppressor cells (M-MDSCs) and Ly6C-positive inflammatory macrophages in the bone marrow by flow cytometry and serum NO levels by ELISA assay. This study demonstrates the therapeutic potential of the hAMSC in SCI, with improvements in gait and sensory functions and reduced inflammation both locally and systemically. The findings support further investigation of the hAMSC as a potential treatment for SCI, focusing on their ability to modulate inflammation and promote neuroprotection.

PI3K signaling promotes formation of lipid-laden foamy macrophages at the spinal cord injury site

After spinal cord injury (SCI), infiltrating macrophages undergo excessive phagocytosis of myelin and cellular debris, forming lipid-laden foamy macrophages. To understand their role in the cellular pathology of SCI, investigation of the foamy macrophage phenotype in vitro revealed a pro-inflammatory profile, increased reactive oxygen species (ROS) production, and mitochondrial dysfunction. Bioinformatic analysis identified PI3K as a regulator of inflammation in foamy macrophages, and inhibition of this pathway decreased their lipid content, inflammatory cytokines, and ROS production. Macrophage-specific inhibition of PI3K using liposomes significantly decreased foamy macrophages at the injury site after a mid-thoracic contusive SCI in mice. RNA sequencing and in vitro analysis of foamy macrophages revealed increased autophagy and decreased phagocytosis after PI3K inhibition as potential mechanisms for reduced lipid accumulation. Together, our data suggest that the formation of pro-inflammatory foamy macrophages after SCI is due to the activation of PI3K signaling, which increases phagocytosis and decreases autophagy.

Restoring neuronal iron homeostasis revitalizes neurogenesis after spinal cord injury.

Spinal cord injury (SCI) can lead to iron overloading and subsequent neuronal ferroptosis, which hinders the recovery of locomotor function. However, it is still unclear whether the maintenance of neuronal iron homeostasis enables to revitalize intrinsic neurogenesis. Herein, we report the regulation of cellular iron homeostasis after SCI via the chelation of excess iron ions and modulation of the iron transportation pathway using polyphenol-based hydrogels for the revitalization of intrinsic neurogenesis. The reversed iron overloading can promote neural stem/progenitor cell differentiation into neurons and elicit the regenerative potential of newborn neurons, which is accompanied by improved axon reinnervation and remyelination. Notably, polyphenol-based hydrogels significantly increase the neurological motor scores from ~8 to 18 (out of 21) and restore the transmission of sensory and motor electrophysiological signals after SCI. Maintenance of iron homeostasis at the site of SCI using polyphenol-based hydrogels provides a promising paradigm to revitalize neurogenesis for the treatment of iron accumulation-related nervous system diseases.