Complete Spinal Cord Transection Research Articles

Developing preclinical dog models for reconstructive severed spinal cord continuity via spinal cord fusion technique

BackgroundSpinal cord injury (SCI) is a severe impairment of the central nervous system, leading to motor, sensory, and autonomic dysfunction. The present study investigates the efficacy of the polyethylene glycol (PEG)-mediated spinal cord fusion (SCF) techniques, demonstrating efficacious in various animal models with complete spinal cord transection at the T10 level. This research focuses on a comparative analysis of three SCF treatment models in beagles: spinal cord transection (SCT), vascular pedicle hemisected spinal cord transplantation (vSCT), and vascularized allograft spinal cord transplantation (vASCT) surgical model. MethodsSeven female beagles were included in the SCT surgical model, while four female dogs were enrolled in the vSCT surgical model. Additionally, twelve female dogs underwent vASCT in a paired donor-recipient setup. Three surgical model were evaluated and compared through electrophysiology, imaging and behavioral recovery. ResultsThe results showed a progressive recovery in the SCT, vSCT and vASCT surgical models, with no statistically significant differences observed in cBBB scores at both 2-month and 6-month post-operation (both P>0.05). Neuroimaging analysis across the SCT, vSCT and vASCT surgical models revealed spinal cord graft survival and fiber regrowth across transection sites at 6 months postoperatively. Also, positive MEP waveforms were recorded in all three surgical models at 6-month post-surgery. ConclusionThe study underscores the clinical relevance of PEG-mediated SCF techniques in promoting nerve fusion, repair, and motor functional recovery in SCI. SCT, vSCT, and vASCT, tailored to specific clinical characteristics, demonstrated similar effective therapeutic outcomes.

Improved Recovery of Complete Spinal Cord Transection by a Plasma-Modified Fibrillar Scaffold.

Complete spinal cord injury causes an irreversible disruption in the central nervous system, leading to motor, sensory, and autonomic function loss, and a secondary injury that constitutes a physical barrier preventing tissue repair. Tissue engineering scaffolds are presented as a permissive platform for cell migration and the reconnection of spared tissue. Iodine-doped plasma pyrrole polymer (pPPy-I), a neuroprotective material, was applied to polylactic acid (PLA) fibers and implanted in a rat complete spinal cord transection injury model to evaluate whether the resulting composite implants provided structural and functional recovery, using magnetic resonance (MR) imaging, diffusion tensor imaging and tractography, magnetic resonance spectroscopy, locomotion analysis, histology, and immunofluorescence. In vivo, MR studies evidenced a tissue response to the implant, demonstrating that the fibrillar composite scaffold moderated the structural effects of secondary damage by providing mechanical stability to the lesion core, tissue reconstruction, and significant motor recovery. Histologic analyses demonstrated that the composite scaffold provided a permissive environment for cell attachment and neural tissue guidance over the fibers, reducing cyst formation. These results supply evidence that pPPy-I enhanced the properties of PLA fibrillar scaffolds as a promising treatment for spinal cord injury recovery.

Adipose tissue derived stem cell secretome induces motor and histological gains after complete spinal cord injury in Xenopus laevis and mice

Mesenchymal stem cell-based therapies have been studied for spinal cord injury (SCI) treatment due to their paracrine action upon damaged tissues. MSCs neuroregenerative role may relate to the contents of their secretome in anti-inflammatory cytokines and growth-permissive factors. We propose using the secretome of MSCs isolated from the adipose tissue—adipose tissue-derived stem cells (ASCs) as a cell-free based therapy for SCI. In vivo studies were conducted in two SCI models, Xenopus laevis and mice, after complete spinal cord transection. Our results on both models demonstrated positive impacts of ASC secretome on their functional recovery which were correlated with histopathological markers of regeneration. Furthermore, in our mice study, secretome induced white matter preservation together with modulation of the local and peripheral inflammatory response. Altogether, these results demonstrate the neuroregenerative and potential for inflammatory modulation of ASC secretome suggesting it as a good candidate for cell-free therapeutic strategies for SCI.

PEG-chitosan (Neuro-PEG) induced restoration of motor function after complete transection of the dorsal spinal cord in swine. A pilot study

Background: Spinal cord injury (SCI) remains an unmet medical need. Recently, fusogens, such as polyethylene glycol (PEG), have been proven effective in restoring sensorimotor function after complete transection of the spinal cord at different levels and in different species. Here, we report on the use of a PEG-chitosan combo in a different animal model (swine). Methods: Five Hungarian Mangalica pigs were subjected to complete transection of the thoracic cord (T7-9). Three animals were treated with locally injected PEG-chitosan (Neuro-PEG) gel; two acted as controls. PEG-600 was also injected intra- and post-operatively intravenously. Animals were submitted to rehabilitation, including electrical myostimulation. Results were assessed after 60 days using the Individual Limb Motor Score, the Porcine Thoracic Spinal Cord Injured Behavioral Scale, and the modified motor Basso, Beattie, and Bresnahan scale; sensory and sphincter functions were also assessed. Animals underwent in vivo spinal cord tracing with DiI. Immunofluorescence histology included NF-200, DAPI, and a fluorochrome-conjugated secondary antibody. Results: Starting on postoperative day (POD) 2, neuro-PEG-treated animals evinced the first signs of recovery, and on POD 60, they could all support their weight and were mobile. Controls never recovered any useful function. Fluorescence microscopy in the experimental group revealed axons passing through the site of injury, while degenerative post-traumatic changes were noted in controls. Conclusion: Neuro-PEG affords sensorimotor recovery after complete spinal cord transection. This opens the door to human experimentation, including trials of spinal cord transplantation.

Chitosan/PEG-mediated spinal cord fusion after complete dorsal transection in rabbits – functional results at 30 days

Background: The aim was to study functional recovery in experimental animals (rabbits) with transected spinal cords treated with a combination of photo-cross-linked chitosan in a homogeneous mixture with polyethylene glycol (PEG-chitosan). Methods: 20 rabbits (n = 10 experimental and n = 10 controls) were submitted to complete spinal cord transection at T9. The experimental group received an intraoperative injection of PEG-chitosan. Neurological recovery was assessed using the modified Basso, Beattie, and Bresnahan scale. Results: In the experimental group, partial recovery of movements, sensory function, and sphincter control were all observed by postoperative day 30. Paraplegia and anesthesia persisted in the control group; 4 controls died versus none in the test group. Conclusion: PEG-chitosan is a candidate for neurological restoration after spinal paralysis.

Functional Hydrogel Co-Remolding Migration and Differentiation Microenvironment for Severe Spinal Cord Injury Repair.

Spinal cord injury (SCI) activates nestin+ neural stem cells (NSCs), which can be regarded as potential seed cells for neuronal regeneration. However, the lesion microenvironment seriously hinders the migration of the nestin+ cells to the lesion epicenter and their differentiation into neurons to rebuild neural circuits. In this study, a photosensitive hydrogel scaffold is prepared as drug delivery carrier. Genetically engineered SDF1α and NT3 are designed and the scaffold is binary modified to reshape the lesion microenvironment. The binary modified scaffold can effectively induce the migration and neuronal differentiation of nestin+ NSCs in vitro. When implanted into a rat complete SCI model, many of the SCI-activated nestin+ cells migrate into the lesion site and give rise to neurons in short-term. Meanwhile, long-term repair results also show that implantation of the binary modified scaffold can effectively promote the maturation, functionalization and synaptic network reconstruction of neurons in the lesion site. In addition, animals treated with binary scaffold also showed better improvement in motor functions. The therapeutic strategy based on remolding the migration and neuronal differentiation lesion microenvironment provides a new insight into SCI repair by targeting activated nestin+ cells, which exhibits excellent clinical transformation prospects.

Anti-Siglec-15 Antibody Prevents Marked Bone Loss after Acute Spinal Cord Injury-Induced Immobilization in Rats.

Rapid and extensive sublesional bone loss after spinal cord injury (SCI) is a difficult medical problem that has been refractory to available interventions except the antiresorptive agent denosumab (DMAB). While DMAB has shown some efficacy in inhibiting bone loss, its concurrent inhibition of bone formation limits its use. Sialic acid-binding immunoglobulin-like lectin (Siglec)-15 is expressed on the cell surface of mature osteoclasts. Anti-Siglec-15 antibody (Ab) has been shown to inhibit osteoclast maturation and bone resorption while maintaining osteoblast activity, which is distinct from current antiresorptive agents that inhibit the activity of both osteoclasts and osteoblasts. The goal of the present study is to test a Siglec-15 Ab (NP159) as a new treatment option to prevent bone loss in an acute SCI model. To this end, 4-month-old male Wistar rats underwent complete spinal cord transection and were treated with either vehicle or NP159 at 20 mg/kg once every 2 weeks for 8 weeks. SCI results in significant decreases in bone mineral density (BMD, -18.7%), trabecular bone volume (-43.1%), trabecular connectivity (-59.7%), and bone stiffness (-76.3%) at the distal femur. Treatment with NP159 almost completely prevents the aforementioned deterioration of bone after SCI. Blood and histomorphometric analyses revealed that NP159 is able to greatly inhibit bone resorption while maintaining bone formation after acute SCI. In ex vivo cultures of bone marrow cells, NP159 reduces osteoclastogenesis while increasing osteoblastogenesis. In summary, treatment with NP159 almost fully prevents sublesional loss of BMD and metaphysis trabecular bone volume and preserves bone strength in a rat model of acute SCI. Because of its unique ability to reduce osteoclastogenesis and bone resorption while promoting osteoblastogenesis to maintain bone formation, Siglec-15 Ab may hold greater promise as a therapeutic agent, compared with the exclusively antiresorptive or anabolic agents that are currently used, in mitigating the striking bone loss that occurs after SCI or other conditions associated with severe immobilization. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Spinal Cord Injury and Assays for Regeneration.

Due to their renowned regenerative capacity, adult zebrafish are a premier vertebrate model to interrogate mechanisms of innate spinal cord regeneration. Following complete transection to their spinal cord, zebrafish extend glial and axonal bridges across severed tissue, regenerate neurons proximal to the lesion, and regain swim capacity within 8weeks of injury. Here, we describe methods to perform complete spinal cord transections and to assess functional and cellular recovery during regeneration. For spinal cord injury, a complete transection is performed 4mm caudal to the brainstem. Swim endurance is quantified as a central readout of functional spinal cord repair. For swim endurance, zebrafish are subjected to a constantly increasing water current velocity until exhaustion, and time at exhaustion is reported. To assess cellular regeneration, histological examination is performed to analyze the extents of glial and axonal bridging across the lesion.

Regenerative medicine strategies for chronic complete spinal cord injury.

Spinal cord injury is a condition in which the parenchyma of the spinal cord is damaged by trauma or various diseases. While rapid progress has been made in regenerative medicine for spinal cord injury that was previously untreatable, most research in this field has focused on the early phase of incomplete injury. However, the majority of patients have chronic severe injuries; therefore, treatments for these situations are of fundamental importance. The reason why the treatment of complete spinal cord injury has not been studied is that, unlike in the early stage of incomplete spinal cord injury, there are various inhibitors of neural regeneration. Thus, we assumed that it is difficult to address all conditions with a single treatment in chronic complete spinal cord injury and that a combination of several treatments is essential to target severe pathologies. First, we established a combination therapy of cell transplantation and drug-releasing scaffolds, which contributes to functional recovery after chronic complete transection spinal cord injury, but we found that functional recovery was limited and still needs further investigation. Here, for the further development of the treatment of chronic complete spinal cord injury, we review the necessary approaches to the different pathologies based on our findings and the many studies that have been accumulated to date and discuss, with reference to the literature, which combination of treatments is most effective in achieving functional recovery.

Thecal sac ligation in the setting of thoracic spondyloptosis with complete cord transection.

Traumatic spondyloptosis (TS) with complete spinal cord transection and unrepairable durotomy is particularly rare and can lead to a difficult-to-manage cerebrospinal fluid (CSF) leak. We performed a systematic review of the literature on TS and discuss the management strategies and outcomes of TS with cord transection and significant dural tear. We also report a novel case of a 26-year-old female who presented with thoracic TS with complete spinal cord transection and unrepairable durotomy with high-flow CSF leak. Of 93 articles that resulted in the search query, 13 described cases of TS with complete cord transection. The approach to dural repair was only described in 8 (n = 20) of the 13 articles. The dura was not repaired in two (20%) of the cases. Ligation of the proximal end of the dural defect was done in 15 (75%) of the cases, all at the same institution. One (5%) case report describes ligation of the distal end; one (5%) case describes the repair of the dura with duraplasty; and another (5%) case describes repair using muscle graft to partially reconstruct the defect. Suture ligation of the thecal sac in the setting of traumatic complete spinal cord transection with significant dural disruption has been described in the international literature and is a safe and successful technique to prevent complications associated with persisting high-flow CSF leakage. To the best of our knowledge, this is the first report of thecal sac ligation of the proximal end of the defect from the United States.

Effect of GR205171 on autonomic dysreflexia induced by colorectal distension in spinal cord injured rats.

Preclinical pharmacology. To determine whether blocking substance P signaling attenuates the hypertension and bradycardia evoked by colorectal distension (CRD) in spinal cord injured (SCI) rats. University laboratory in Pennsylvania, U.S.A. Tachykinin NK1 receptor antagonists were administered 30 min prior to CRD three weeks after complete spinal cord transection at the 4th thoracic (T4) level. The dose range, route of administration, and pretreatment time was based on published data demonstrating occupancy of brain NK1 receptors in rodents. Subcutaneous (SC) administration of 10-30 mg/kg GR205171 ((2S,3S)-N-[[2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]methyl]-2-phenylpiperidin-3-amine dihydrochloride) reduced CRD-induced hypertension and bradycardia by 55 and 49%, respectively, compared with pretreatment values. There was no effect of GR205171 on resting blood pressure or heart rate. In contrast, the same dose range of CP-99,994 ((2S,3S)-N-[(2-methoxyphenyl)methyl]-2-phenyl-3-piperidinamine dihydrochloride) had no effect on CRD-induced cardiovascular responses. The effective dose range of GR205171 to alleviate autonomic dysreflexia is consistent with the blockade of NK1 receptors on pelvic sensory afferents in the lumbosacral spinal cord, which may in turn prevent the over-excitation of sympathetic preganglionic neurons (SPNs) that regulate blood pressure and heart rate. The findings provide preclinical support for the utility of NK1 receptor antagonists to treat autonomic dysreflexia in people with SCI. The difference in the effects of the two NK1 receptor antagonists may reflect the ~200-fold lower affinity of CP-99,994 than GR205171 for the rat NK1 receptor.

Regenerative Potential of Injured Spinal Cord in the Light of Epigenetic Regulation and Modulation.

A spinal cord injury is a form of physical harm imposed on the spinal cord that causes disability and, in many cases, leads to permanent mammalian paralysis, which causes a disastrous global issue. Because of its non-regenerative aspect, restoring the spinal cord's role remains one of the most daunting tasks. By comparison, the remarkable regenerative ability of some regeneration-competent species, such as some Urodeles (Axolotl), Xenopus, and some teleost fishes, enables maximum functional recovery, even after complete spinal cord transection. During the last two decades of intensive research, significant progress has been made in understanding both regenerative cells' origins and the molecular signaling mechanisms underlying the regeneration and reconstruction of damaged spinal cords in regenerating organisms and mammals, respectively. Epigenetic control has gradually moved into the center stage of this research field, which has been helped by comprehensive work demonstrating that DNA methylation, histone modifications, and microRNAs are important for the regeneration of the spinal cord. In this review, we concentrate primarily on providing a comparison of the epigenetic mechanisms in spinal cord injuries between non-regenerating and regenerating species. In addition, we further discuss the epigenetic mediators that underlie the development of a regeneration-permissive environment following injury in regeneration-competent animals and how such mediators may be implicated in optimizing treatment outcomes for spinal cord injurie in higher-order mammals. Finally, we briefly discuss the role of extracellular vesicles (EVs) in the context of spinal cord injury and their potential as targets for therapeutic intervention.

The therapeutic mechanism of transcranial iTBS on nerve regeneration and functional recovery in rats with complete spinal cord transection.

After spinal cord transection injury, the inflammatory microenvironment formed at the injury site, and the cascade of effects generated by secondary injury, results in limited regeneration of injured axons and the apoptosis of neurons in the sensorimotor cortex (SMC). It is crucial to reverse these adverse processes for the recovery of voluntary movement. The mechanism of transcranial intermittent theta-burst stimulation (iTBS) as a new non-invasive neural regulation paradigm in promoting axonal regeneration and motor function repair was explored by means of a severe spinal cord transection. Rats underwent spinal cord transection and 2 mm resection of spinal cord at T10 level. Four groups were studied: Normal (no lesion), Control (lesion with no treatment), sham iTBS (lesion and no functional treatment) and experimental, exposed to transcranial iTBS, 72 h after spinal lesion. Each rat received treatment once a day for 5 days a week; behavioral tests were administered one a week. Inflammation, neuronal apoptosis, neuroprotective effects, regeneration and synaptic plasticity after spinal cord injury (SCI) were determined by immunofluorescence staining, western blotting and mRNA sequencing. For each rat, anterograde tracings were acquired from the SMC or the long descending propriospinal neurons and tested for cortical motor evoked potentials (CMEPs). Regeneration of the corticospinal tract (CST) and 5-hydroxytryptamine (5-HT) nerve fibers were analyzed 10 weeks after SCI. When compared to the Control group, the iTBS group showed a reduced inflammatory response and reduced levels of neuronal apoptosis in the SMC when tested 2 weeks after treatment. Four weeks after SCI, the neuroimmune microenvironment at the injury site had improved in the iTBS group, and neuroprotective effects were evident, including the promotion of axonal regeneration and synaptic plasticity. After 8 weeks of iTBS treatment, there was a significant increase in CST regeneration in the region rostral to the site of injury. Furthermore, there was a significant increase in the number of 5-HT nerve fibers at the center of the injury site and the long descending propriospinal tract (LDPT) fibers in the region caudal to the site of injury. Moreover, CMEPs and hindlimb motor function were significantly improved. Neuronal activation and neural tracing further verified that iTBS had the potential to provide neuroprotective effects during the early stages of SCI and induce regeneration effects related to the descending motor pathways (CST, 5-HT and LDPT). Furthermore, our results revealed key relationships between neural pathway activation, neuroimmune regulation, neuroprotection and axonal regeneration, as well as the interaction network of key genes.

MP60-08 COMPARISON OF LOWER URINARY TRACT DYSFUNCTION AFTER SPINAL CORD INJURY (SCI) BETWEEN FEMALE AND MALE MICE

You have accessJournal of UrologyCME1 Apr 2023MP60-08 COMPARISON OF LOWER URINARY TRACT DYSFUNCTION AFTER SPINAL CORD INJURY (SCI) BETWEEN FEMALE AND MALE MICE Mamoru Hashimoto, Kang Jun Cho, Stephanie L Daugherty, PA Pittsburgh, Nobutaka Shimizu, Pradeep Tyagi, Akihide Hirayama, Hirotsugu Uemura, Jonathan M Beckel, Sergei Karnup, and Naoki Yoshimura Mamoru HashimotoMamoru Hashimoto More articles by this author , Kang Jun ChoKang Jun Cho More articles by this author , Stephanie L DaughertyStephanie L Daugherty More articles by this author , PA PittsburghPA Pittsburgh More articles by this author , Nobutaka ShimizuNobutaka Shimizu More articles by this author , Pradeep TyagiPradeep Tyagi More articles by this author , Akihide HirayamaAkihide Hirayama More articles by this author , Hirotsugu UemuraHirotsugu Uemura More articles by this author , Jonathan M BeckelJonathan M Beckel More articles by this author , Sergei KarnupSergei Karnup More articles by this author , and Naoki YoshimuraNaoki Yoshimura More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003318.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In humans, voiding occurs during synergic relaxation of the external urethral sphincter (EUS), and SCI induces detrusor-sphincter dyssynergia (DSD) shown by tonic EUS contraction during voiding. However, EUS bursting activity is known to be an important mechanism for efficient voiding in spinal intact (SI) and SCI rats while such data are less available in mice. Thus, we evaluated gender-specific EUS function during voiding in male and female mice with or without SCI. METHODS: C57BL/6N mice at 9-10-weeks old were used. SCI mice underwent complete transection of the Th8-9 spinal cord. Six weeks after SCI, cystometrograms (CMGs) and EUS- electromyography (EMG) were performed under an awake condition. Thereafter, L6-S1 dorsal root ganglia (DRG) were harvested to evaluate the transcripts of TRPV1 and Piezo2 using qPCR. RESULTS: In female SI mice, voiding occurred during an EUS relaxation period. Female SCI mice voided urine during notch like reductions in bladder pressure, which corresponded to EMG signal reduction periods during tonic EMG activity (DSD). On the other hand, male SI and SCI mice voided during EUS bursting activity characterized by alternating active and silent phases of EMG activity, with the longer active phase and low voiding efficiency in SCI vs. SI mice (Table and Figure). The mRNA levels of TRPV1 and Piezo2 in L6-S1 DRG were significantly higher in SCI male mice (n=4) and female mice (n=4) vs. SI mice (n=4). CONCLUSIONS: Lower urinary tract function during the voiding phase was different between male and female mice. Female SI mice, in which voiding occurs during EUS relaxation, and female SCI mice, which exhibit DSD with periodic EUS relaxations, seem to be more suitable for the study of SCI-induced EUS dysfunction in humans, compared to SI and SCI male mice that exhibit EUS bursting activity during voiding. Source of Funding: NIH R01DK129194 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e846 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mamoru Hashimoto More articles by this author Kang Jun Cho More articles by this author Stephanie L Daugherty More articles by this author PA Pittsburgh More articles by this author Nobutaka Shimizu More articles by this author Pradeep Tyagi More articles by this author Akihide Hirayama More articles by this author Hirotsugu Uemura More articles by this author Jonathan M Beckel More articles by this author Sergei Karnup More articles by this author Naoki Yoshimura More articles by this author Expand All Advertisement PDF downloadLoading ...

Upregulated 5-HT1A Receptors Regulate Lower Urinary Tract Function in Rats after Complete Spinal Cord Injury.

Spinal cord injury (SCI) above the lumbosacral level often leads to dysfunction of the lower urinary tract (LUT) including detrusor hyper-reflexia, wherein bladder compliance is low, baseline pressures are increased, and filling is accompanied by numerous non-voiding contractions (NVCs) referred to as neurogenic detrusor overactivity. Here, we investigate the expression levels of the serotonin 1A (5-HT1A) receptor in segments both rostral and caudal to the injured site, as well as the effects on micturition of blocking 5-HT1A receptor using pharmacological interventions in spinally intact rats or T8 complete SCI rats. The activities of detrusor and external urethral sphincter (EUS) were assessed with the rats in a conscious condition. Adult female rats were divided into two groups: (1) sham control (T8 laminectomy only) and (2) T8 complete spinal cord transection. The observation period was 2 months after the original SCI. In Western blot analyses, we identified significant upregulation of the 5-HT1A receptor in the T10-L2 and L6/S1 segments after chronic complete SCI. In pharmacological studies, a dose-response study of the 5-HT1A receptor antagonist, WAY100635, indicated alterations in detrusor and EUS activities in spinally intact rats. Interestingly, blocking the 5-HT1A receptor alone resulted in inhibitory effects on NVCs with a reduced number and decreased amplitude, but in an increased interval between NVCs in SCI rats. In addition, the duration of EUS bursting was also significantly increased by WAY100635. These inhibitory effects of WAY100635 on NVCs were diminished by subsequent application of a beta-adrenergic blocker (propranolol). The reduction of NVCs observed by WAY100635 may be the result of blocking the constitutive activities of the 5-HT1A receptor but activating the beta-adrenergic sympathetic pathway, which in turn relaxes bladder activity. Together, the neuroplasticity of the 5-HT1A receptor can be a potential therapeutic target for treatment of bladder dysfunction after SCI.

Adult spinal cord tissue transplantation combined with local tacrolimus sustained‐release collagen hydrogel promotes complete spinal cord injury repair

The strategy of replacing a completely damaged spinal cord with allogenic adult spinal cord tissues (aSCs) can potentially repair complete spinal cord injury (SCI) in combination with immunosuppressive drugs, such as tacrolimus (Tac), which suppress transplant rejection and improve graft survival. However, daily systemic administration of immunosuppressive agents may cause harsh side effects. Herein, a localized, sustained Tac-release collagen hydrogel (Col/Tac) was developed to maximize the immune regulatory efficacy but minimize the side effects of Tac after aSC transplantation in complete SCI recipients. Thoracic aSCs of rat donors were transplanted into the complete thoracic spinal cord transection rat recipients, after which Col/Tac hydrogel was implanted. The Tac-encapsulated collagen hydrogel exhibited suitable mechanical properties and long-term sustained Tac release behaviour. After Col/Tac hydrogel implantation in SCI rats with aSC transplantation, the recipients' survival rate significantly improved and the side effects on tissues were reduced compared with those with conventional Tac medication. Moreover, treatment with the Col/Tac hydrogel exhibited similarly reduced immune rejection levels by regulating immune responses and promoted neurogenesis compared to daily Tac injections, and thus improved functional restoration. Localized delivery of immunosuppressive agents by the Col/Tac hydrogel may be a promising strategy for overcoming immune rejection of transplants, with significant potential for clinical application in the future.

Dr. Xiao-Ming Xu: A True Gentleman and Scholar in the Field of Spinal Cord Injury and Schwann Cell Biology.

Dr. Xiao-Ming Xu: A True Gentleman and Scholar in the Field of Spinal Cord Injury and Schwann Cell Biology.

Experimental study on the repair of spinal cord injury by conducting hydrogel loaded with tetramethylpyrazine sustained-release microparticles

To investigate the neuroprotective effect of conducting hydrogel loaded with tetramethylpyrazine sustained-release microparticles (hereinafter referred to as "TGTP hydrogel") on spinal cord injury rats. Forty-eight adult female Sprague Dawley rats were randomly divided into 4 groups: sham operation group (group A), model group (group B), conductive hydrogel group (group C), and TGTP hydrogel group (group D), with 12 rats in each group. Only laminectomy was performed in group A, and complete spinal cord transection was performed in groups B, C, and D. Basso-Bettie-Bresnahan (BBB) score was used to evaluate the recovery of hind limb motor function of each group before modeling and at 1, 3, 7, 14, and 28 days after modeling, respectively. At 28 days after modeling, the rats were sacrificed for luxol fast blue (LFB) staining to detect myelin regeneration. Nissl staining was used to detect the survival of neurons. Immunohistochemical staining was used to evaluate the expression of inflammation-related factors [nuclear factor кB (NF-кB), tumor necrosis factor α (TNF-α), and interleukin 10 (IL-10)]. Immunofluorescence staining and Western blot were used to evaluate the expression of neurofilament 200 (NF200). BBB scores of group A were significantly better than those of the other three groups at all time points after modeling (P<0.05); at 14 and 28 days after modeling, there was no significant difference in BBB scores between groups C and D (P>0.05), but the BBB score of group D was significantly better than that of group B (P<0.05). LFB staining and Nissl staining showed that the structure of neurons and myelin in group A was intact, and the myelin integrity and survival number of neurons in group D were significantly better than those in groups B and C. Immunohistochemical staining showed that the absorbency (A) value of NF-кB and TNF-α in group A were significantly lower than those in groups B and C (P<0.05), the A value of IL-10 was significantly higher than that in the other three groups (P<0.05); the A value of NF-κB in group D was significantly lower than that in groups B and C, the A value of TNF-α in group D was significantly lower than that in group B, while the A value of IL-10 in group D was significantly higher than that in group B (P<0.05). Immunofluorescence staining showed that the structure of neurons and nerve fibers in group A was clear and the fluorescence intensity was high. The fluorescence intensity of NF200 in group D was higher than that in groups B and C, and some nerve fibers could be seen. Western blot analysis showed that the relative expression of NF200 in group A was the highest, and the relative expression of NF200 in group D was significantly higher than that in groups B and C (P<0.05). The TGTP hydrogel can effectively promote the recovery of motor function in rats with spinal cord injury, and its mechanism may be related to the regulation of inflammatory response.

Recovery of spinal cord functions after experimental complete crossection under the effect of chitosan polymeric compounds

To study clinical and functional recovery in experimental animals with transected spinal cord after management with photo-cross-linked chitosan in a homogeneous mixture with polyethylene glycol. We studied 20 rabbits with a model of complete spinal cord transection at the level of Th9. There were control and experimental groups (n=10; n=10). In the experimental group, we intraoperatively injected photo-cross-linked chitosan in a homogeneous mixture with polyethylene glycol. Neurological status was assessed using the modified Basso Beattie Bresnahan scale. Histological examination was performed after removing the animals from the experiment. In the experimental group, significant regression of neurological disorders was accompanied by partial recovery of movements, sensitivity and control of pelvic functions by the 30th day of the experiment. There was no mortality in the experimental group. Paraplegia and anesthesia persisted in the control group while mortality was 40% (n=4). Histological analysis in the main group revealed axonal «bridges» in the area of injury and spread of DiI dye through this area. These phenomena confirm the positive effect of chitosan and polyethylene glycol on functional recovery after experimental spinal cord injury. These data are consistent with histological findings.

Myostatin is a negative regulator of adult neurogenesis after spinal cord injury in zebrafish.

Intrinsic and extrinsic inhibition of neuronal regeneration obstruct spinal cord (SC) repair in mammals. In contrast, adult zebrafish achieve functional recovery after complete SC transection. While studies of innate SC regeneration have focused on axon regrowth as a primary repair mechanism, how local adult neurogenesis affects functional recovery is unknown. Here, we uncover dynamic expression of zebrafish myostatin b (mstnb) in a niche of dorsal SC progenitors after injury. mstnb mutants show impaired functional recovery, normal glial and axonal bridging across the lesion, and an increase in the profiles of newborn neurons. Molecularly, neuron differentiation genes are upregulated, while the neural stem cell maintenance gene fgf1b is downregulated in mstnb mutants. Finally, we show that human fibroblast growth factor 1 (FGF1) treatment rescues the molecular and cellular phenotypes of mstnb mutants. These studies uncover unanticipated neurogenic functions for mstnb and establish the importance of local adult neurogenesis for innate SC repair.