Spinal Cord Injury Repair Strategies Research Articles

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.

Kdm6a-CNN1 axis orchestrates epigenetic control of trauma-induced spinal cord microvascular endothelial cell senescence to balance neuroinflammation for improved neurological repair

Cellular senescence assumes pivotal roles in various diseases through the secretion of proinflammatory factors. Despite extensive investigations into vascular senescence associated with aging and degenerative diseases, the molecular mechanisms governing microvascular endothelial cell senescence induced by traumatic stress, particularly its involvement in senescence-induced inflammation, remain insufficiently elucidated. In this study, we present a comprehensive demonstration and characterization of microvascular endothelial cell senescence induced by spinal cord injury (SCI). Lysine demethylase 6A (Kdm6a), commonly known as UTX, emerges as a crucial regulator of cell senescence in injured spinal cord microvascular endothelial cells (SCMECs). Upregulation of UTX induces senescence in SCMECs, leading to an amplified release of proinflammatory factors, specifically the senescence-associated secretory phenotype (SASP) components, thereby modulating the inflammatory microenvironment. Conversely, the deletion of UTX in endothelial cells shields SCMECs against senescence, mitigates the release of proinflammatory SASP factors, and promotes neurological functional recovery after SCI. UTX forms an epigenetic regulatory axis by binding to calponin 1 (CNN1), orchestrating trauma-induced SCMECs senescence and SASP secretion, thereby influencing neuroinflammation and neurological functional repair. Furthermore, local delivery of a senolytic drug reduces senescent SCMECs and suppresses proinflammatory SASP secretion, reinstating a local regenerative microenvironment and enhancing functional repair after SCI. In conclusion, targeting the UTX-CNN1 epigenetic axis to prevent trauma-induced SCMECs senescence holds the potential to inhibit SASP secretion, alleviate neuroinflammation, and provide a novel treatment strategy for SCI repair.

Injectable polyvinylpyrrolidone/tannic acid multifunctional hydrogel coating with excellent self-healing and adhesive properties for application in tissue engineering

Hydrogels can simulate the physiological environment of soft tissues, showing great promise in spinal cord injury (SCI) repair. Nevertheless, hydrogels for effective SCI repair have limitations such as their inability to effectively contact with irregular cavities and structural damage caused by long-term physical movement. In this study, a unique and facile hydrogel with injectable, electroconductive, self-healing, and adhesive properties was synthesized by introducing tannic acid (TA) and polyvinylpyrrolidone (PVP)-stabilized polypyrrole (PPy) nanoparticles. Fe(III) ion-triggered in situ polymerization of pyrrole, and the dispersibility of PPy was significantly improved utilizing the stabilizing effect of PVP. The P@Py/TA had excellent injectable, self-healing, and cytocompatibility properties. Meanwhile, the hydrogel coating exhibited robust self-adhesion to different substrates. The P@Py/TA provided a suitable microenvironment for axon regeneration, effective angiogenesis, and immune-regulated function. This facilitated functional recovery from traumatic SCI. The multifunctional conductive P@Py/TA hydrogel scaffold provides a new strategy for SCI repair and has potential applications in other fields of bionic skin and multi-functional coatings.

Local delivery of EGFR+NSCs-derived exosomes promotes neural regeneration post spinal cord injury via miR-34a-5p/HDAC6 pathway

Spinal cord injury (SCI) causes severe axon damage, usually leading to permanent paraparesis, which still lacks effective regenerative therapy. Recent studies have suggested that exosomes derived from neural stem cells (NSCs) may hold promise as attractive candidates for SCI treatment. Epidermal Growth Factor Receptor positive NSC (EGFR+NSC) is a subpopulation of endogenous NSCs, showing strong regenerative capability in central nervous system disease. In the current study, we isolated exosomes from the EGFR+NSCs (EGFR+NSCs-Exos) and discovered that local delivery of EGFR+NSCs-Exos can effectively promote neurite regrowth in the injury site of spinal cord-injured mice and improve their neurological function recovery. Using the miRNA-seq, we firstly characterized the microRNAs (miRNAs) cargo of EGFR+NSCs-Exos and identified miR-34a-5p which was highly enriched in EGFR+NSCs derived exosomes. We further interpreted that exosomal miR-34a-5p could be transferred to neurons and inhibit the HDAC6 expression by directly binding to its mRNA, contributing to microtubule stabilization and autophagy induction for aiding SCI repair. Overall, our research demonstrated a novel therapeutic approach to improving neurological functional recovery by using exosomes secreted from a subpopulation of endogenous NSCs and providing a precise cell-free treatment strategy for SCI repair.

Engineered human spinal cord-like tissues with dorsal and ventral neuronal progenitors for spinal cord injury repair in rats and monkeys.

Transplanting human neural progenitor cells is a promising method of replenishing the lost neurons after spinal cord injury (SCI), but differentiating neural progenitor cells into the diverse types of mature functional spinal cord neurons in vivo is challenging. In this study, engineered human embryonic spinal cord-like tissues with dorsal and ventral neuronal characters (DV-SC) were generated by inducing human neural progenitor cells (hscNPCs) to differentiate into various types of dorsal and ventral neuronal cells on collagen scaffold in vitro. Transplantation of DV-SC into complete SCI models in rats and monkeys showed better therapeutic effects than undifferentiated hscNPCs, including pronounced cell survival and maturation. DV-SC formed a targeted connection with the host's ascending and descending axons, partially restored interrupted neural circuits, and improved motor evoked potentials and the hindlimb function of animals with SCI. This suggests that the transplantation of pre-differentiated hscNPCs with spinal cord dorsal and ventral neuronal characteristics could be a promising strategy for SCI repair.

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.

Berberine-loaded MSC-derived sEVs encapsulated in injectable GelMA hydrogel for spinal cord injury repair

After spinal cord injury (SCI), local inflammatory response and fibrous scar formation severely hinder nerve regeneration. Berberine (Ber) has a powerful regulatory effect on the local microenvironment, but its limited solubility and permeability through the blood–brain barrier severely limit its systemic efficacy. Human umbilical cord mesenchymal stem cells (hUC-MSCs)-derived small extracellular vesicles (sEVs) are natural nanocarriers with high cargo loading capacity, and can cross the blood–brain barrier. Most importantly, sEVs can improve drug solubility and drug utilization. Therefore, they can overcome many defects of Ber application. This experiment aimed to design a Ber-carrying hUC-MSCs-derived sEVs and GelMA hydrogel. Ber was loaded into sEVs (sEVs-Ber) by ultrasonic co-incubation with a drug loading capacity (LC) of 15.07%. The unhindered release of up to 80% of sEVs-Ber from GelMA hydrogel was accomplished for up to 14 days. And they could be directly absorbed by local cells of injury, allowing for direct local delivery of the drug and enhancing its efficacy. The experimental results confirmed injecting GelMA-sEVs-Ber into spinal cord defects could exert anti-inflammatory effects by regulating the expression of inflammatory factors. It also demonstrated the anti-fibrotic effect of Ber in SCI for the first time. The modulatory effects of sEVs and Ber on the local microenvironment significantly promoted nerve regeneration and recovery of motor function in post-SCI rats. These results demonstrated that the GelMA-sEVs-Ber dual carrier system is a promising therapeutic strategy for SCI repair.

An In Situ Assembled Trapping Gel Repairs Spinal Cord Injury by Capturing Glutamate and Free Calcium Ions.

Spinal cord injury (SCI) can lead to devastating autonomic dysfunction. One of the most challenging issues for functional repair in SCI is the secondary damage caused by the increased release of glutamate and free Ca2+ from injured cells. Here, an in situ assembled trapping gel (PF-SA-GAD) is developed to sweep glutamate and Ca2+ , promoting SCI repair. The hydrogel solution is a mixture of recombinant glutamate decarboxylase 67 (rGAD67) protein, sodium alginate (SA), and pluronic F-127 (PF-127). After intrathecal administration, temperature-sensitive PF-127 promoted in situ gelation. Glutamate (Glu) is captured and decarboxylated by rGAD67 into γ-aminobutyric acid (GABA). SA reacted with the free Ca2+ to generate gellable calcium alginate. Thereby, this in situ trapping gel retarded secondary neuron injury caused by Glu and free Ca2+ during SCI. In rat models of SCI, PF-SA-GAD reduces the lesion volume and inflammatory response after SCI, restores the motor function of rats with SCI. Together, the in situ assembled trapping gel is a long-term effective and minimally invasive sweeper for the direct elimination of glutamate and Ca2+ from injury lesions and can be a novel strategy for SCI repair by preventing secondary injury.

An Electroconductive Hydrogel Scaffold with Injectability and Biodegradability to Manipulate Neural Stem Cells for Enhancing Spinal Cord Injury Repair

Spinal cord injury (SCI) generally leads to long-term functional deficits and is difficult to repair spontaneously. Many biological scaffold materials and stem cell treatment strategies have been explored, but very little research focused on the method of combining exogenous neural stem cells (NSCs) with a biodegradable conductive hydrogel scaffold. Here, a NSC loaded conductive hydrogel scaffold (named ICH/NSCs) was assembled by amino-modified gelatin (NH2-Gelatin) and aniline tetramer grafted oxidized hyaluronic acid (AT-OHA). Desirably, the well-conducting ICH/NSCs can be simply injected into the target site of SCI for establishing a good electrical signal pathway of cells, and the proper degradation cycle facilitates new nerve growth. In vitro experiments indicated that the inherent electroactive microenvironment of the hydrogel could better manipulate the differentiation of NSCs into neurons and inhibit the formation of glial cells and scars. Collectively, the ICH/NSC scaffold has successfully stimulated the recovery of SCI and may provide a promising treatment strategy for SCI repair.

The aOECs Facilitate the Neuronal Differentiation of Neural Stem Cells in the Inflammatory Microenvironment Through Up-Regulation of Bioactive Factors and Activation of Wnt3/β-Catenin Pathway.

The therapeutic application of neural stem cells (NSCs) in the central nerve system (CNS) injury is a promising strategy for combating irreversible neuronal loss. However, a variety of obvious inflammatory responses following nerve injury rapidly create an unfavorable microenvironment for survival and neuronal differentiation of NSCs in lesion area, limiting the efficacy of NSC-based therapy for CNS injury. It remained unknown how to effectively increase the neuronal differentiation efficiency of NSCs through transplantation. Here, we demonstrated that curcumin (CCM)-activated olfactory ensheathing cells (aOECs) effectively promoted neuronal differentiation of NSCs in the activated microglial inflammatory condition, and co-transplantation of aOECs and NSCs improved neurological recovery of rats after spinal cord injury (SCI), as evidenced by higher expression levels of neuronal markers and lower expression levels of glial markers in the differentiated cells, greater number of Tuj-1-positive cells as well as higher Basso, Beattie, and Bresnahan (BBB) locomotor scale, compared to the corresponding controls. Pathologically, hematoxylin and eosin (HE) staining and immunostaining also showed that aOECs remarkably enhanced the in vivo neuronal differentiation of NSCs and migration, and nerve repair. Further analysis revealed that the underlying mechanisms of aOECs potentiating the neuronal conversion of NSCs under inflammatory environment were tightly associated with up-regulation of anti-inflammatory cytokines and neurotrophic factors in OECs, and importantly, the activation of Wnt3/β-catenin pathway was likely involved in the mechanisms underlying the observed cellular events. Therefore, this study provides a promising strategy for SCI repair by co-transplantation of aOECs and NSCs.

Thermosensitive hydrogel-mediated sphere/fiber multi-dimensional composite nanotube with controlled release of NGF for improved spinal cord injury repair

Spinal cord injury is a serious disabling disease that not only causes physical defects, but also causes psychological problems for patients. In the current study, a novel multi-dimensional functional composite nanotube was prepared by simultaneouslyriveting nerve growth factor (NGF)-loaded PLGA microspheres and tissue-engineered cells (BMSCs) into the PLA fiber nanotube by a designed thermosensitive hydrogel to improve spinal cord injury (SCI) repair. The PLGA microspheres allow the protection and long-term controlled release of NGF to guarantee enough time and drug concentration to promote the growth and differentiation of cells into axons and promote axonal regeneration. Thermosensitive hydrogels are served not only to provide a tunable physiologically simulated microenvironment, but also as scaffolds to provide a suitable matrix for cells and drugs, and PLA nanotube ensures the seal of the released NGF in the nanotube to improve its drug bioavailability, as well as the supporting and guiding of the nerve growth. The physicochemical properties of the composite nanotube are investigated and the repair efficacy is evaluated according to the functional recovery, histological, immunohistochemistry, immunofluorescence examinations as well as the westernblot analysis. The administration of the composite nanotube in the SCI rat models obviously improves the regeneration of the neuron, axon, myelin sheath, neural stem cell and nissnei body but decreases the astrocytes formation, as well as enhances the integrity of the spinal cord tissue and the recovery of locomotor functions. This present work provides a future perspective for NGF application and a potential strategy for SCI repair.

Release of O-GlcNAc transferase inhibitor promotes neuronal differentiation of neural stem cells in 3D bioprinted supramolecular hydrogel scaffold for spinal cord injury repair

Precise fabrication of biomimetic three-dimensional (3D) structure and effective neuronal differentiation under the pathological environment are the key to neural stem cell (NSC)-based spinal cord injury (SCI) therapy. In this study, we have developed a spinal cord-like bioprinted scaffold loading with OSMI-4, a small molecule O-GlcNAc transferase (OGT) inhibitor, to induce and guide the neuron differentiation of NSCs for efficient SCI repair. To achieve this, we developed a supramolecular bioink (SM bioink) consisting of methacrylated gelatin and acrylated β-cyclodextrins to load NSCs and OSMI-4. This bioink showed fast gelation and stable mechanical properties, facilitating bioprinting of functional neural scaffolds. Moreover, the weak host-guest cross-linking of the SM scaffolds significantly improved the cell-matrix interaction for the infiltration and migration of NSCs. What's more, the sustained delivery of OSMI-4 remarkably enhanced the intrinsic neuronal differentiation of the encapsulated NSCs in vitro by inhibiting Notch signaling pathway. In vivo experiment further revealed that the functional bioprinted scaffolds promoted the neuronal regeneration and axonal growth, leading to significant locomotor recovery of the SCI model rats. Together, the NSC-laden bioprinted SM scaffolds in combination with sustained release of the therapeutic agent OSMI-4 largely induced neuronal differentiation of NSCs and thus leading to efficient SCI repair. Statement of significanceEfficient neuronal differentiation of neural stem cells (NSCs) under the complex pathological microenvironment of spinal cord injury (SCI) is a major challenge of neural regeneration. By the use of a supramolecular bioink, we bioprinted a spinal cord-like scaffold loaded with NSCs and a small molecule drug OSMI-4 to significantly induce neuronal differentiation of NSCs for efficient SCI repair in vivo. The scaffolds with spinal cord-like structure can support the interaction and neuronal differentiation of NSCs by providing a dynamic matrix and a source of molecular release of OSMI-4. The influences of OSMI-4 on NSCs and its molecular mechanism were investigated for the first time in this study. Altogether, three-dimensional bioprinting fabrication of NSC- and small molecule drug-laden biomimetic construct may represent a promising therapeutic strategy for SCI repair.

Recent Advances in Cell and Functional Biomaterial Treatment for Spinal Cord Injury.

Spinal cord injury (SCI) is a devastating central nervous system disease caused by accidental events, resulting in loss of sensory and motor function. Considering the multiple effects of primary and secondary injuries after spinal cord injury, including oxidative stress, tissue apoptosis, inflammatory response, and neuronal autophagy, it is crucial to understand the underlying pathophysiological mechanisms, local microenvironment changes, and neural tissue functional recovery for preparing novel treatment strategies. Treatment based on cell transplantation has become the forefront of spinal cord injury therapy. The transplanted cells provide physical and nutritional support for the damaged tissue. At the same time, the implantation of biomaterials with specific biological functions at the site of the SCI has also been proved to improve the local inhibitory microenvironment and promote axonal regeneration, etc. The combined transplantation of cells and functional biomaterials for SCI treatment can result in greater neuroprotective and regenerative effects by regulating cell differentiation, enhancing cell survival, and providing physical and directional support for axon regeneration and neural circuit remodeling. This article reviews the pathophysiology of the spinal cord, changes in the microenvironment after injury, and the mechanisms and strategies for spinal cord regeneration and repair. The article will focus on summarizing and discussing the latest intervention models based on cell and functional biomaterial transplantation and the latest progress in combinational therapies in SCI repair. Finally, we propose the future prospects and challenges of current treatment regimens for SCI repair, to provide references for scientists and clinicians to seek better SCI repair strategies in the future.

Gene-Modified Stem Cells for Spinal Cord Injury: a Promising Better Alternative Therapy.

Stem cell therapy holds great promise for the treatment of spinal cord injury (SCI), which can reverse neurodegeneration and promote tissue regeneration via its pluripotency and ability to secrete neurotrophic factors. Although various stem cell-based approaches have shown certain therapeutic effects when applied to the treatment of SCI, their clinical efficacies have been disappointing. Thus, it is an urgent need to further enhance the neurological benefits of stem cells through bioengineering strategies including genetic engineering. In this review, we summarize the progress of stem cell therapy for SCI and the prospect of genetically modified stem cells, focusing on the genome editing tools and functional molecules involved in SCI repair, trying to provide a deeper understanding of genetically modified stem cell therapy and more applicable clinical strategies for SCI repair.

ALG-bFGF Hydrogel Inhibiting Autophagy Contributes to Protection of Blood-Spinal Cord Barrier Integrity via PI3K/Akt/FOXO1/KLF4 Pathway After SCI.

Promoting blood–spinal cord barrier (BSCB) repair at the early stage plays a crucial role in treatment of spinal cord injury (SCI). Excessive activation of autophagy can prevent recovery of BSCB after SCI. Basic fibroblast growth factor (bFGF) has been shown to promote BSCB repair and locomotor function recovery in SCI. However, the therapeutic effect of bFGF via direct administration on SCI is limited because of its rapid degradation and dilution at injury site. Based on these considerations, controlled release of bFGF in the lesion area is becoming an attractive strategy for SCI repair. At present, we have designed a sustained-release system of bFGF (called ALG-bFGF) using sodium alginate hydrogel, which is able to load large amounts of bFGF and suitable for in situ administration of bFGF in vivo. Here, traumatic SCI mice models and oxygen glucose deprivation (OGD)–stimulated human brain microvascular endothelial cells were performed to explore the effects and the underlying mechanisms of ALG-bFGF in promoting SCI repair. After a single in situ injection of ALG-bFGF hydrogel into the injured spinal cord, sustained release of bFGF from ALG hydrogel distinctly prevented BSCB destruction and improved motor functional recovery in mice after SCI, which showed better therapeutic effect than those in mice treated with bFGF solution or ALG. Evidences have demonstrated that autophagy is involved in maintaining BSCB integrity and functional restoration in animals after SCI. In this study, SCI/OGD exposure–induced significant upregulations of autophagy activation-related proteins (Beclin1, ATG5, LC3II/I) were distinctly decreased by ALG-bFGF hydrogel near the baseline and not less than it both in vivo and in vitro, and this inhibitory effect contributed to prevent BSCB destruction. Finally, PI3K inhibitor LY294002 and KLF4 inhibitor NSC-664704 were applied to further explore the underlying mechanism by which ALG-bFGF attenuated autophagy activation to alleviate BSCB destruction after SCI. The results further indicated that ALG-bFGF hydrogel maintaining BSCB integrity by inhibiting autophagy activation was regulated by PI3K/Akt/FOXO1/KLF4 pathway. In summary, our current study revealed a novel mechanism by which ALG-bFGF hydrogel improves BSCB and motor function recovery after SCI, providing an effective therapeutic strategy for SCI repair.

Exosomes‐Loaded Electroconductive Hydrogel Synergistically Promotes Tissue Repair after Spinal Cord Injury via Immunoregulation and Enhancement of Myelinated Axon Growth

Electroconductive hydrogels are very attractive candidates for accelerated spinal cord injury (SCI) repair because they match the electrical and mechanical properties of neural tissue. However, electroconductive hydrogel implantation can potentially aggravate inflammation, and hinder its repair efficacy. Bone marrow stem cell‐derived exosomes (BMSC‐exosomes) have shown immunomodulatory and tissue regeneration effects, therefore, neural tissue‐like electroconductive hydrogels loaded with BMSC‐exosomes are developed for the synergistic treatment of SCI. These exosomes‐loaded electroconductive hydrogels modulate microglial M2 polarization via the NF‐κB pathway, and synergistically enhance neuronal and oligodendrocyte differentiation of neural stem cells (NSCs) while inhibiting astrocyte differentiation, and also increase axon outgrowth via the PTEN/PI3K/AKT/mTOR pathway. Furthermore, exosomes combined electroconductive hydrogels significantly decrease the number of CD68‐positive microglia, enhance local NSCs recruitment, and promote neuronal and axonal regeneration, resulting in significant functional recovery at the early stage in an SCI mouse model. Hence, the findings of this study demonstrate that the combination of electroconductive hydrogels and BMSC‐exosomes is a promising therapeutic strategy for SCI repair.

Neuregulin-1 converts reactive astrocytes toward oligodendrocyte lineage cells via upregulating the PI3K-AKT-mTOR pathway to repair spinal cord injury

Axonal demyelination is a consistent pathological characteristic of Spinal cord injury (SCI). Promoting differentiation of oligodendrocytes is of importance for remyelination. Conversion of reactive astrocytes with stem cell potential to oligodendrocytes is proposed as an innovative strategy for SCI repair. Neuregulin-1 (Nrg1) plays an essential role in the differentiation of oligodendrocytes. Therefore, it's a potential treatment for demyelination in SCI that using Nrg1 to drive reactive astrocytes toward oligodendrocyte lineage cells. In this study, tumor necrosis factor-α (TNF-α) was used to induce dedifferentiation of primary rat spinal cord astrocytes into reactive astrocytes and Nrg1 was used to induce astrocytes in vitro and in vivo. The results showed that astrocytes treated with TNF-α expressed immaturity markers CD44 and Musashi1 at mRNA and protein levels, indicating that TNF-α induced the stem cell state of astrocytes. Nrg1 induced reactive astrocytes to express oligodendrocyte markers PDGFR-α and O4 at mRNA and protein levels, indicating that Nrg1 directly converts reactive astrocytes toward oligodendrocyte lineage cells. Moreover, upregulation of PI3K-AKT-mTOR signaling activation in response to Nrg1 was observed. In rats with SCI, intrathecal treatment with Nrg1 converted reactive astrocytes to oligodendrocyte lineage cells, inhibited astrogliosis, promoted remyelination, protected axons and eventually improved BBB score. All the biological effects of Nrg1 were significantly reversed by the co-administration of Nrg1 and ErbB inhibitor, suggesting that Nrg1 functioned through the receptor ErbB. Our findings indicate that Nrg1 is sufficient to trans-differentiate reactive astrocytes to oligodendrocytes via the PI3K-AKT-mTOR signaling pathway and repair SCI. Delivery of Nrg1 for the remyelination processes could be a promising strategy for spinal cord repair.

Thermosensitive heparin-poloxamer hydrogel encapsulated bFGF and NGF to treat spinal cord injury.

The application of growth factors (GFs) for treating chronic spinal cord injury (SCI) has been shown to promote axonal regeneration and functional recovery. However, direct administration of GFs is limited by their rapid degradation and dilution at the injured sites. Moreover, SCI recovery is a multifactorial process that requires multiple GFs to participate in tissue regeneration. Based on these facts, controlled delivery of multiple growth factors (GFs) to lesion areas is becoming an attractive strategy for repairing SCI. Presently, we developed a GFs‐based delivery system (called GFs‐HP) that consisted of basic fibroblast growth factor (bFGF), nerve growth factor (NGF) and heparin‐poloxamer (HP) hydrogel through self‐assembly mode. This GFs‐HP was a kind of thermosensitive hydrogel that was suitable for orthotopic administration in vivo. Meanwhile, a 3D porous structure of this hydrogel is commonly used to load large amounts of GFs. After single injection of GFs‐HP into the lesioned spinal cord, the sustained release of NGF and bFGF from HP could significantly improve neuronal survival, axon regeneration, reactive astrogliosis suppression and locomotor recovery, when compared with the treatment of free GFs or HP. Moreover, we also revealed that these neuroprotective and neuroregenerative effects of GFs‐HP were likely through activating the phosphatidylinositol 3 kinase and protein kinase B (PI3K/Akt) and mitogen‐activated protein kinase/extracellular signal‐regulated kinase (MAPK/ERK) signalling pathways. Overall, our work will provide an effective therapeutic strategy for SCI repair.

Functional Multichannel Poly(Propylene Fumarate)-Collagen Scaffold with Collagen-Binding Neurotrophic Factor 3 Promotes Neural Regeneration After Transected Spinal Cord Injury.

Many factors contribute to the poor axonal regrowth and ineffective functional recovery after spinal cord injury (SCI). Biomaterials have been used for SCI repair by promoting bridge formation and reconnecting the neural tissue at the lesion site. The mechanical properties of biomaterials are critical for successful design to ensure the stable support as soon as possible when compressed by the surrounding spine and musculature. Poly(propylene fumarate) (PPF) scaffolds with high mechanical strength have been shown to provide firm spatial maintenance and to promote repair of tissue defects. A multichannel PPF scaffold is combined with collagen biomaterial to build a novel biocompatible delivery system coated with neurotrophin-3 containing an engineered collagen-binding domain (CBD-NT3). The parallel-aligned multichannel structure of PPF scaffolds guide the direction of neural tissue regeneration across the lesion site and promote reestablishment of bridge connectivity. The combinatorial treatment consisting of PPF and collagen loaded with CBD-NT3 improves the inhibitory microenvironment, facilitates axonal and neuronal regeneration, survival of various types of functional neurons and remyelination and synapse formation of regenerated axons following SCI. This novel treatment strategy for SCI repair effectively promotes neural tissue regeneration after transected spinal injury by providing a regrowth-supportive microenvironment and eventually induces functional improvement.

Transplantation of Pro-Oligodendroblasts, Preconditioned by LPS-Stimulated Microglia, Promotes Recovery After Acute Contusive Spinal Cord Injury.

Spinal cord injury (SCI) is a significant clinical challenge, and to date no effective treatment is available. Oligodendrocyte progenitor cell (OPC) transplantation has been a promising strategy for SCI repair. However, the poor posttransplantation survival and deficiency in differentiation into myelinating oligodendrocytes (OLs) are two major challenges that limit the use of OPCs as donor cells. Here we report the generation of an OL lineage population [i.e., pro-oligodendroblasts (proOLs)] that is relatively more mature than OPCs for transplantation after SCI. We found that proOLs responded to lipopolysaccharide (LPS)-stimulated microglia conditioned medium (L+M) by preserving toll-like receptor 4 (TLR4) expression, improving cell viability, and enhancing the expression of a myelinating OL marker myelin basic protein (MBP), compared to other OL lineage cells exposed to either LPS-stimulated (L+M) or nonstimulated microglia conditioned medium (LM). When L+M-stimulated proOLs were intrathecally delivered through a lumbar puncture after a T10 thoracic contusive SCI, they promoted behavioral recovery, as assessed by the BassoBeattieBresnahan (BBB) locomotor rating scale, stride length, and slips on the grid tests. Histologically, transplantation of L+M proOLs caused a considerable increase in intralesional axon numbers and myelination, and less accumulation of invading macrophages when compared with the vehicle control or OPC transplantation. Thus, transplantation of proOLs, preconditioned by L+M, may offer a better therapeutic potential for SCI than OPCs since the former may have initiated the differentiation process toward OLs prior to transplantation.