Glial Scar Formation Research Articles

Function of GSK‑3 signaling in spinal cord injury (Review).

Spinal cord injury (SCI) is a major social problem with a heavy burden on patient physiology and psychology. Glial scar formation and irreversible neuron loss are the two key points during SCI progression. During the acute phase of spinal cord injury, glial scars form, limiting the progression of inflammation. However, in the subacute or chronic phase, glial scarring inhibits axon regeneration. Following spinal cord injury, irreversible loss of neurons leads to further aggravation of spinal cord injury. Several therapies have been developed to improve either glial scar or neuron loss; however, few therapies reach the stage of clinical trials and there are no mainstream therapies for SCI. Exploring the key mechanism of SCI is crucial for finding further treatments. Glycogen synthase kinase-3 (GSK-3) is a widely expressed kinase with important physiological and pathophysiological functions in vivo. Dysfunction of the GSK-3 signaling pathway during SCI has been widely discussed for controlling neurite growth in vitro and in vivo, improving the proliferation and neuronal differentiation of endogenous neural stem cells and functional recovery from spinal cord injury. SCI can decrease the phosphorylated (p)/total (t)-GSK-3β ratio, which leads to an increase in apoptosis, whereas treatment with GSK-3 inhibitors can promote neurogenesis. In addition, several therapies for the treatment of SCI involve signaling pathways associated with GSK-3. Furthermore, signaling pathways associated with GSK-3 also participate in the pathological process of neuropathic pain that remains following SCI. The present review summarized the roles of GSK-3 signaling in SCI to aid in the understanding of GSK-3 signaling during the pathological processes of SCI and to provide evidence for the development of comprehensive treatments.

Conditioned medium from human dental pulp stem cells treats spinal cord injury by inhibiting microglial pyroptosis.

Human dental pulp stem cell transplantation has been shown to be an effective therapeutic strategy for spinal cord injury. However, whether the human dental pulp stem cell secretome can contribute to functional recovery after spinal cord injury remains unclear. In the present study, we established a rat model of spinal cord injury based on impact injury froma dropped weight and then intraperitoneally injected the rats with conditioned medium from human dental pulp stem cells. We found that the conditioned medium effectively promoted the recovery of sensory and motor functions in rats with spinal cord injury, decreased expression of the microglial pyroptosis markers NLRP3, GSDMD, caspase-1, and interleukin-1β, promoted axonal and myelin regeneration, and inhibited the formation of glial scars. In addition, in a lipopolysaccharide-induced BV2 microglia model, conditioned medium from human dental pulp stem cells protected cells from pyroptosis by inhibiting the NLRP3/caspase-1/interleukin-1β pathway. These results indicate that conditioned medium from human dental pulp stem cells can reduce microglial pyroptosis by inhibiting the NLRP3/caspase-1/interleukin-1β pathway, thereby promoting the recovery of neurological function after spinal cord injury. Therefore, conditioned medium from human dental pulp stem cells may become an alternative therapy for spinal cord injury.

Maresin-1 prevents blood-spinal cord barrier disruption associated with TRPV4 elevation in the experimental model of spinal cord injury

Recently, we reported the TRPV4 ion channel activation and its association with secondary damage after spinal cord injury (SCI). TRPV4 activation is linked with blood-spinal cord barrier (BSCB) disruption, endothelial damage, and inflammation after SCI. Specialized pro-resolving mediators (SPM) are endogenous lipid mediators released for inflammation resolution. Studies suggest that SPM could act as an endogenous antagonist of ion channels directly or indirectly at the plasma membrane. Herein, we studied the effect of maresin-1, a docosahexaenoic acid (DHA)-derived SPM, in SCI-induced TRPV4 expression and subsequent associated damage. First, employing a particular agonist (4αPDD) in endothelial and neuronal cell lines, we examined the potential of maresin-1 to block TRPV4 activation. Then we quantify the DHA levels in plasma and epicenter of the spinal cord in sham and at 1, 3, 7, 14, 21, and 28-days post-injury (DPI) using LC-MS. Then, we exogenously administered maresin-1 using two dosing regimens i.e., single-dose (1 μg) and multiple-dose (1 μg/day for seven days), to confirm its role in the TRPV4 inhibition and its linked damage. After SCI, DHA levels decrease in the spinal cord epicenter area as well as in the plasma. Treatment with maresin-1 attenuates TRPV4 expression, inflammatory cytokines, and chemokines and impedes neutrophil infiltration. Furthermore, treatment with maresin-1 prevents BSCB disruption, alleviates glial scar formation, and improves functional recovery. Thus, our results suggest that maresin-1 could modulate TRPV4 expression and could be a safe and promising approach to target inflammation and BSCB damage after SCI.

The Promising Role of a Zebrafish Model Employed in Neural Regeneration Following a Spinal Cord Injury.

Spinal cord injury (SCI) is a devastating event that results in a wide range of physical impairments and disabilities. Despite the advances in our understanding of the biological response to injured tissue, no effective treatments are available for SCIs at present. Some studies have addressed this issue by exploring the potential of cell transplantation therapy. However, because of the abnormal microenvironment in injured tissue, the survival rate of transplanted cells is often low, thus limiting the efficacy of such treatments. Many studies have attempted to overcome these obstacles using a variety of cell types and animal models. Recent studies have shown the utility of zebrafish as a model of neural regeneration following SCIs, including the proliferation and migration of various cell types and the involvement of various progenitor cells. In this review, we discuss some of the current challenges in SCI research, including the accurate identification of cell types involved in neural regeneration, the adverse microenvironment created by SCIs, attenuated immune responses that inhibit nerve regeneration, and glial scar formation that prevents axonal regeneration. More in-depth studies are needed to fully understand the neural regeneration mechanisms, proteins, and signaling pathways involved in the complex interactions between the SCI microenvironment and transplanted cells in non-mammals, particularly in the zebrafish model, which could, in turn, lead to new therapeutic approaches to treat SCIs in humans and other mammals.

Astrocytic Extracellular Vesicles Regulated by Microglial Inflammatory Responses Improve Stroke Recovery.

There are no effective treatments for post-stroke glial scar formation, which inhibits axonal outgrowth and functional recovery after stroke. We investigated whether astrocytic extracellular vesicles (AEVs) regulated by microglia modulate glial scars and improve stroke recovery. We found that peri-infarct glial scars comprised reactive astrocytes with proliferating C3d and decreased S100A10 expression in chronic stroke. In cultured astrocytes, microglia-conditioned media and treatment with P2Y1 receptor antagonists increased and reduced the area of S100A10- and C3d-expressing reactive astrocytes, respectively, by suppressing mitogen-activated protein kinase/nuclear factor-κβ (NF-κB)/tumor necrosis factor-α (TNF-α)/interleukin-1β signaling after oxygen-glucose deprivation. Intracerebral administrations of AEVs enriched miR-146a-5p, downregulated NF-κB, and suppressed TNF-α expressions, by transforming reactive astrocytes to those with S100A10 preponderance, causing functional recovery in rats subjected to middle cerebral artery occlusion. Modulating neuroinflammation in post-stroke glial scars could permit axonal outgrowth, thus providing a basis for stroke recovery with neuroprotective AEVs.

In Situ Cross-Linkable Hyaluronic-Ferulic Acid Conjugate Containing Bucladesine Nanoparticles Promotes Neural Regeneration after Spinal Cord Injury.

Dysfunctional clinical outcomes following spinal cord injury (SCI) result from glial scar formation, leading to the inhibition of new axon growth and impaired regeneration. Nevertheless, nerve regeneration after SCI is possible, provided that the state of neuron development in the injured environment is improved. Hence, biomaterial-based therapy would be a promising strategy to endow a desirable environment for tissue repair. Herein, we designed a novel multifunctional injectable hydrogel with antioxidant, neuroprotective, and neuroregenerative effects. Bucladesine-encapsulated chitosan nanoparticles (BCS NPs) were first prepared and embedded in a matrix of thiol-functionalized hyaluronic acid modified with ferulic acid (HASH-FA). The target hydrogel (HSP-F/BCS) was then created through Michael-type addition between HASH-FA containing BCS NPs and four-arm polyethylene glycol-maleimide (4-Arm-PEG-Mal). The obtained hydrogel with shear thinning behavior showed viscoelastic and mechanical properties similar to the normal nerve tissue. FA conjugation significantly improved the antioxidant activity of HA, and suppressed intracellular ROS formation. In situ injection of the HSP-F/BCS hydrogel in a rat contusion model of SCI inhibited glial scar progression, reduced microglia/macrophage infiltration, promoted angiogenesis, and induced myelinated axon regeneration. As a result, a significant improvement in motor performance was observed compared to other experimental groups. Taken together, the HSP-F/BCS hydrogel developed in this study could be a promising system for SCI repair.

Targeted delivery of CD163+ macrophage-derived small extracellular vesicles via RGD peptides promote vascular regeneration and stabilization after spinal cord injury

Targeted delivery of small extracellular vesicles (sEVs) with low immunogenicity and fewer undesirable side effects are needed for spinal cord injury (SCI) therapy. Here, we show that RGD (Arg-Gly-Asp) peptide-decorated CD163+ macrophage-derived sEVs can deliver TGF-β to the neovascular endothelial cells of the injured site and improve neurological function after SCI. CD163+ macrophages are M2 macrophages that express TGF-β and are reported to promote angiogenesis and vascular stabilization in various diseases. Enriched TGF-β EVs were crucial in angiogenesis and tissue repair. However, TGF-β also boosts the formation of fibrous or glial scars, detrimental to neurological recovery. Our results found RGD-modified CD163+ sEVs accumulated in the injured region and were taken up by neovascular endothelial cells. Furthermore, RGD-CD163+ sEVs promoted vascular regeneration and stabilization in vitro and in vivo, resulting in substantial functional recovery post-SCI. These data suggest that RGD-CD163+ sEVs may be a potential strategy for treating SCI.

The Role of Resveratrol on Spinal Cord Injury: from Bench to Bedside.

Spinal cord injury (SCI) is a severe and disabling injury of the central nervous system, with complex pathological mechanisms leading to sensory and motor dysfunction. Pathological processes, such as oxidative stress, inflammatory response, apoptosis, and glial scarring are important factors that aggravate SCI. Therefore, the inhibition of these pathological processes may contribute to the treatment of SCI. Currently, the pathogenesis of SCI remains under investigation as SCI treatment has not progressed considerably. Resveratrol, a natural polyphenol with anti-inflammatory and antioxidant properties, is considered a potential therapeutic drug for various diseases and plays a beneficial role in nerve damage. Preclinical studies have confirmed that signaling pathways are closely related to the pathological processes in SCI, and resveratrol is believed to exert therapeutic effects in SCI by activating the related signaling pathways. Based on current research on the pathways of resveratrol and its role in SCI, resveratrol may be a potentially effective treatment for SCI. This review summarizes the role of resveratrol in promoting the recovery of nerve function by regulating oxidative stress, inflammation, apoptosis, and glial scar formation in SCI through various mechanisms and pathways, as well as the deficiency of resveratrol in SCI research and the current and anticipated research trends of resveratrol. In addition, this review provides a background for further studies on the molecular mechanisms of SCI and the development of potential therapeutic agents. This information could also help clinicians understand the known mechanisms of action of resveratrol and provide better treatment options for patients with SCI.

3D collagen porous scaffold carrying PLGA-PTX/SDF-1α recruits and promotes neural stem cell differentiation for spinal cord injury repair

Spinal Cord Injury (SCI), one of the major factors of disability, can cause irreversible motor and sensory impairment. There are no effective therapeutic drugs and technologies available in domestic or foreign countries currently. Neural stem cells (NSCs), with the potential for multidirectional differentiation, are a potential treatment for SCI. However, it has been demonstrated that NSCs primarily differentiated into astrocytes rather than neurons due to the inflammatory microenvironment, and the current challenge remains to direct the differentiation of NSCs into neurons in the lesion site. It was reported that the microtubule-stabilizing agent paclitaxel (PTX) was able to promote the differentiation of NSCs into neurons rather than astrocytes after SCI. SDF-1α can recruit NSCs and thus guide the migration of stem cells. In this study, we developed a functional collagen scaffold by loading SDF-1α and nanoparticle-encapsulated PLGA-PTX into a 3D collagen porous scaffold, allowing for slow release of PTX. When the functional scaffolds were implanted into the injury site, it provided a neural regeneration conduit channel for the migration of NSCs and neuronal differentiation. Neural regeneration promoted the recovery of motor function and reduced glial scar formation after SCI. In conclusion, a 3D collagen porous scaffold combined with PLGA-PTX and SDF-1α is a promising therapeutic strategy for SCI repair.

Cooperation of long noncoding RNA LOC100909675 and transcriptional regulator CTCF modulates Cdk1 transcript to control astrocyte proliferation

Astrocyte activation and proliferation contribute to glial scar formation during spinal cord injury (SCI), which limits nerve regeneration. LncRNAs are involved in astrocyte proliferation and act as novel epigenetic regulators. Here, we found that lncRNA-LOC100909675 (LOC9675) expression promptly increased after SCI and that reducing its expression decreased the proliferation and migration of the cultured spinal astrocytes. Depletion of LOC9675 reduced astrocyte proliferation and facilitated axonal regrowth after SCI. FISH detection and RT‒qPCR assays using nuclear/cytoplasmic RNAs revealed LOC9675 mainly localized in astrocytic nuclei. We next used RNA-seq to analyze gene expression profile alterations in LOC9675-depleted astrocytes and identified the Cdk1 gene as a hub candidate. Our RNA pull-down and RNA immunoprecipitation assays showed that LOC9675 directly interacted with the transcriptional regulator CTCF. Luciferase reporter and ChIP assays, together with down/upregulated expression investigation, revealed that CTCF is a novel regulator of the Cdk1 gene. Interestingly, we found that with the simultaneous overexpression of CTCF and LOC9675 in astrocytes, the Cdk1 transcript was restored to the normal level. We then designed the deletion construct of LOC9675 by removing its interacting region with CTCF, and found this effect disappeared. A transcription inhibition assay using actinomycin D revealed that LOC9675 could stabilize Cdk1 mRNA, while LOC9675 depletion or binding with CTCF reduced Cdk1 mRNA stability. These data suggest that the cooperation between CTCF and LOC9675 regulates Cdk1 transcription at a steady level, thereby strictly controlling astrocyte proliferation. This study provides a novel perspective on the regulation of the Cdk1 gene transcript by lncRNA LOC9675.

Proteomic profiling of the brain from the wobbler mouse model of amyotrophic lateral sclerosis reveals elevated levels of the astrogliosis marker glial fibrillary acidic protein.

The wobbler mouse is a widely used model system of amyotrophic lateral sclerosis and exhibits progressive neurodegeneration and neuroinflammation in association with skeletal muscle wasting. This study has used wobbler brain preparations for the systematic and mass spectrometric determination of proteome-wide changes. The proteomic characterization of total protein extracts from wobbler specimens was carried out with the help of an Orbitrap mass spectrometer and revealed elevated levels of glia cell marker proteins, i.e., glial fibrillary acidic protein and the actin-binding protein coronin. In contrast, the abundance of the actin-binding protein neurabin and the scaffolding protein named piccolo of the presynaptic cytomatrix were shown to be reduced. The increased abundance of glial fibrillary acidic protein, which is frequently used in neuropathological studies as a marker protein of glial scar formation, was confirmed by immunoblotting. In analogy, the proteomic profiling of the brain from another established murine model of motor neuron disease, the SOD1mouse, also showed increased levels of this intermediate filament protein. This suggests that neurodegenerative processes are associated with astrogliosis in both the wobbler and SOD1 brain.

Evaluation of the Optimal Number of Implanted Mesenchymal Stem Cells for the Treatment of Post-Traumatic Syrinx and Recovery of Motor Activity after Chronic Spinal Cord Injury.

The present work aims at determining the most effective dose (number) of mesenchymal stem cells (MSC) for its transplantation in order to treat chronic spinal cord injury (SCI) in mature Sprague-Dawley rats (n=24). MSC were obtained from bone marrow of 4-6-month-old Sprague-Dawley rats. Four weeks after SCI, MSC suspension (4 μl) was injected to experimental animals into the injured area in doses of 4×105, 8×105, or 106. Using MRI, diffusion tensor imaging (DTI), diffusion tensor tractography (DTT), immunohistochemistry, histological staining, and behavioral tests, we studied the effect of transplantation of MSC in different doses on the following parameters in rats with SCI: the size of lesion cavity and post-traumatic syrinx (PTS), glial scar formation, neuronal fibers remodeling, axonal regeneration and sprouting, vascularization, expression of neuronal factors, and motor functions. MSC administration improved motor function in rats after SCI due to stimulation of regeneration and sprouting of the axons, enhanced recovery of locomotor functions, reduction of PTS and the glial scar, and stimulation of vascularization and expression of the neurotrophic factors. The effects of MSC were dose-dependent; the most effective dose was 106 cells.

Microneedle/CD-MOF-mediated transdural controlled release of methylprednisolone sodium succinate after spinal cord injury.

A new method of transdural delivering drugs to the spinal cord has been developed, involving the use of microneedles (MNs) and a β-cyclodextrin metal-organic framework (CD-MOF). This epidural microneedle array, dubbed MNs@CD-MOF@MPSS, can be utilized to deliver methylprednisolone sodium succinate (MPSS) to the site of spinal cord injury (SCI) in a controlled manner. MNs allows to generate micropores in the dura for direct drug delivery to the spinal cord, overcoming tissue barriers and targeting damaged regions. Additionally, the CD-MOF provides a secondary extended release after separating from the MNs. In in vitro study, inward MNs increased cellular absorption of MPSS and then reduced LPS-induced M1 polarization of microglia. And animal studies have shown that this method of drug delivery results in improved BMS scores and a reduction in M1 phenotype microphage and glial scar formation. Furthermore, the downregulation of the NLRP3-positive inflammasome and related pro-inflammatory cytokines was observed. In conclusion, this new drug platform has potential for clinical application in spinal cord diseases and is a valuable composite for minimally transdural controlled drug delivery. STATEMENT OF SIGNIFICANCE: This research presents a new epidural microneedle patch made up of microneedles (MNs) and a β-cyclodextrin metal-organic framework (CD-MOF). The epidural microneedle patch boasts high drug loading capacity, the ability to penetrate the dura, and controlled release. When loaded with methylprednisolone sodium succinate (MPSS), it effectively reduces inflammation and improves neurological function after spinal cord injury. Therefore, it is a novel and promising drug platform for the treatment of spinal cord diseases in a clinical setting.

Simultaneous Presentation of Dexamethasone and Nerve Growth Factor via Layered Carbon Nanotubes and Polypyrrole to Interface Neural Cells.

The implantation of neural electrodes usually induces acute and chronic inflammation, which can result in the formation of glial scars encapsulating the implanted electrodes and the loss of neurons near the active electrode sites. Local presentation of anti-inflammatory drugs or neural protective factors has been evidenced as an effective strategy to modulate inflammatory responses and promote electrode-neuron integration. Here, a novel delivery system for the simultaneous presentation of both anti-inflammatory drugs (dexamethasone, Dex) and nerve-growth-promoting factors (nerve growth factor, NGF) from the electrode sites was developed via layer-structured carbon nanotubes and conductive polymers. The modified electrodes exhibited higher charge storage capacitance and lower electrochemical impedance compared to unmodified electrodes and electrodes coated with polypyrrole/Dex. Dex released from the functional coating under controlled electrochemical stimulation was able to inhibit the lipopolysaccharide-induced secretion or mRNA transcription of inflammatory cytokines, including nitric oxide, TNF-α, and IL-6 in RAW264.7 cells, and control the activation of cultured astrocytes. In addition, the functional coatings did not show a toxic effect on PC12 cells and primary neural cells but exhibited promoted activities on the adhesion, growth, and neurite extension of neural cells.

Stub1 ameliorates ER stress-induced neural cell apoptosis and promotes locomotor recovery through restoring autophagy flux after spinal cord injury

Endoplasmic reticulum (ER) stress-induced apoptosis and autophagy flux blockade significantly contribute to neuronal pathology of spinal cord injury (SCI). Yet, the molecular interplay between these two distinctive pathways in mediating the pathology of SCI remains largely unexplored. Currently, we aimed at exploring the crucial role of Stub1 in maintaining ER homeostasis and regulating autophagic flux after SCI. Our results demonstrate that Stub1 reduces ER stress induced neuronal apoptosis, promotes axonal regeneration, inhibits glial scar formation and fosters functional recovery by restoring autophagic flux following SCI. Stub1 enhances autophagic flux following SCI by alleviating the permeabilization of lysosomal membrane through activating TFEB. Importantly, we showed that Stub1 promotes the activation of TFEB by targeting HDAC2 for ubiquitination and degradation. Furthermore, the neuroprotective effect of Stub1 on SCI was abrogated by chloroquine administration, underscoring the essential role of Stub1-mediated enhancement of autophagic flux in its protective effects against SCI. Collectively, our data highlights the vital role of Stub1 in regulating ER stress and autophagy flux after SCI, and propose its potential as a promising target for neuroprotective interventions in SCI.

Black phosphorus nanosheets enhance differentiation of neural progenitor cells for improved treatment in spinal cord injury

Stem cell transplantation holds great potential as a treatment option for nerve damage diseases. However, the therapeutic effects are significantly impeded by low survival rate and uncontrolled differentiation of stem cells. In this study, black phosphorus nanosheets (BPNs), which are biodegradable inorganic nanomaterials, are first revealed with remarkable abilities to regulate cellular redox homeostasis, enhance transplant survival rate of stem cells, and facilitate neural differentiation of neural progenitor cells (NPCs). These effects of BPNs are proved to be associated with the activation of nuclear factor erythroid 2-like 2 (Nrf2) pathways in NPCs. In vivo, BPNs-treated NPCs could effectively inhibit inflammatory response and neuronal apoptosis in the mice with spinal cord injury (SCI). In addition, BPNs-treated NPCs more effectively reduce glial scar formation and promote axon regeneration compared with natural NPCs in SCI site. These findings collectively support the therapeutic potentials of BPNs for advanced stem cell transplantation and neural tissue engineering in the future.

Dual-targeting AAV9P1-mediated neuronal reprogramming in a mouse model of traumatic brain injury.

Traumatic brain injury results in neuronal loss and glial scar formation. Replenishing neurons and eliminating the consequences of glial scar formation are essential for treating traumatic brain injury. Neuronal reprogramming is a promising strategy to convert glial scars to neural tissue. However, previous studies have reported inconsistent results. In this study, an AAV9P1 vector incorporating an astrocyte-targeting P1 peptide and glial fibrillary acidic protein promoter was used to achieve dual-targeting of astrocytes and the glial scar while minimizing off-target effects. The results demonstrate that AAV9P1 provides high selectivity of astrocytes and reactive astrocytes. Moreover, neuronal reprogramming was induced by downregulating the polypyrimidine tract-binding protein 1 gene via systemic administration of AAV9P1 in a mouse model of traumatic brain injury. In summary, this approach provides an improved gene delivery vehicle to study neuronal programming and evidence of its applications for traumatic brain injury.

Macrophages play a leading role in determining the direction of astrocytic migration in spinal cord injury via ADP-P2Y1R axis

After spinal cord injury (SCI), inflammatory cells such as macrophages infiltrate the injured area, and astrocytes migrate, forming a glial scar around macrophages. The glial scar inhibits axonal regeneration, resulting in significant permanent disability. However, the mechanism through which glial scar-forming astrocytes migrate to the injury site has not been clarified. Here we show that migrating macrophages attract reactive astrocytes toward the center of the lesion after SCI. Chimeric mice with bone marrow lacking IRF8, which controls macrophage centripetal migration after SCI, showed widely scattered macrophages in the injured spinal cord with the formation of a huge glial scar around the macrophages. To determine whether astrocytes or macrophages play a leading role in determining the directions of migration, we generated chimeric mice with reactive astrocyte-specific Socs3−/− mice, which showed enhanced astrocyte migration, and bone marrow from IRF8−/− mice. In this mouse model, macrophages were widely scattered, and a huge glial scar was formed around the macrophages as in wild-type mice that were transplanted with IRF8−/− bone marrow. In addition, we revealed that macrophage-secreted ATP-derived ADP attracts astrocytes via the P2Y1 receptor. Our findings revealed a mechanism through which migrating macrophages attract astrocytes and affect the pathophysiology and outcome after SCI.

Curcumin-Containing polyphosphazene nanodrug for Anti-Inflammation and nerve regeneration to improve functional recovery after spinal cord injury

The microenvironment of excessive inflammation and the activation of apoptotic signals are primary barriers to neurological recovery following spinal cord injury (SCI). Thus, long-lasting anti-inflammation has become an effective strategy to navigate SCI. Herein, a curcumin (CUR)-containing nanosystem (FCTHPC) with high drug loading efficiency was reported via assembling hydrophobic CUR into cross-linked polyphosphazene (PPZ), and simultaneous loading and coordinating with porous bimetallic polymers for greatly enhanced the water-solubility and biocompatibility of CUR. The nanosystem is noncytotoxic when directing its biological activities. By inhibiting the expression of pro-inflammatory factors (IL-1β, TNF-α and IL-6) and apoptotic proteins (C-caspase-3 and Bax/Bcl-2), which may be accomplished by activating the Wnt/β-catenin pathway, the versatile FCTHPC can significantly alleviate the damage to tissues and cells caused by inflammation and apoptosis in the early stage of SCI. In addition, the long-term in vivo studies had demonstrated that FCTHPC could effectively inhibit the formation of glial scars, and simultaneously promote nerve regeneration and myelination, leading to significant recovery of spinal cord function. This study emphasises the promise of the biocompatible CUR-based nanosystem and provides a fresh approach to effectively treat SCI.

Astrocytes in ischemic stroke: Crosstalk in central nervous system and therapeutic potential.

In the central nervous system (CNS), a large group of glial cells called astrocytes play important roles in both physiological and disease conditions. Astrocytes participate in the formation of neurovascular units and interact closely with other cells of the CNS, such as microglia and neurons. Stroke is a global disease with high mortality and disability rate, most of which are ischemic stroke. Significant strides in understanding astrocytes have been made over the past few decades. Astrocytes respond strongly to ischemic stroke through a process known as activation or reactivity. Given the important role played by reactive astrocytes (RAs) in different spatial and temporal aspects of ischemic stroke, there is a growing interest in the potential therapeutic role of astrocytes. Currently, interventions targeting astrocytes, such as mediating astrocyte polarization, reducing edema, regulating glial scar formation, and reprogramming astrocytes, have been proven in modulating the progression of ischemic stroke. The aforementioned potential interventions on astrocytes and the crosstalk between astrocytes and other cells of the CNS will be summarized in this review.