Transplantation of Skin Precursor-Derived Schwann Cells Yields Better Locomotor Outcomes and Reduces Bladder Pathology in Rats with Chronic Spinal Cord Injury.
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ABSTRACT:
SUBMITTER: Assinck P
PROVIDER: S-EPMC7363874 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A gram-negative Buttiauxella gaviniae-like organism (LBV449) was isolated from a urine sample of a patient suffering from urine bladder pathology and neurological problems. The isolate was positive for adonitol fermentation and L-arginine dihydrolase and negative for melibiose and L-ornithine decarboxylase. The API 20E code was 3004113. Retrospectively, another isolate (ENT107), from a leg wound, was recovered from our collections and was shown to have similar biochemical characteristics. DNA-DNA hybridization showed 77% similarity between both strains, and strain LBV449 revealed 74% DNA-DNA similarity to the type strain of B. gaviniae. Neither 16S rRNA gene sequencing nor fatty acid analysis were useful for identification. The characteristic tRNA-PCR patterns obtained for these two clinical isolates consisted of fragments with lengths of 102.2, 105.4, 116.6, and 136.9 bp and most resembled the tRNA-PCR pattern obtained for B. gaviniae, but they lacked the B. gaviniae fragments of 88.2 and 239.5 bp. To our knowledge, no clinical cases with Buttiauxella strains have been described thus far.
| S-EPMC130887 | biostudies-literature
Project description:ObjectiveLocomotor training (LT) as a therapeutic intervention following spinal cord injury (SCI) is an effective rehabilitation strategy for improving motor outcomes, but its impact on non-locomotor functions is unknown. Given recent results of our labs' pre-clinical animal SCI LT studies and existing overlap of lumbosacral spinal circuitries controlling pelvic-visceral and locomotor functions, we addressed whether LT can improve bladder, bowel and sexual function in humans at chronic SCI time-points (> two years post-injury).Study designProspective cohort study; pilot trial with small sample size.MethodsEight SCI research participants who were undergoing 80 daily one-hour sessions of LT on a treadmill using body-weight support, or one-hour of LT and stand training on alternate days, as part of another research study conducted at the Kentucky Spinal Cord Injury Research Center, University of Louisville, were enrolled in this pilot trial. Urodynamic assessments were performed and International Data Set questionnaire forms completed for bladder, bowel and sexual functions at pre-and post-training time points. Four usual care (non-trained; regular at-home routine) research participants were also enrolled in this study and had the same assessments collected twice, at least 3 months apart.ResultsFilling cystometry documented significant increases in bladder capacity, voiding efficiency and detrusor contraction time as well as significant decreases in voiding pressure post-training relative to baseline. Questionnaires revealed a decrease in the frequency of nocturia and urinary incontinence for several research participants as well as a significant decrease in time required for defecation and a significant increase in sexual desire post-training. No significant differences were found for usual care research participants.ConclusionsThese results suggest that an appropriate level of sensory information provided to the spinal cord, generated through task-specific stepping and/or loading, can positively benefit the neural circuitries controlling urogenital and bowel functions.Trial registrationClinicalTrials.gov NCT03036527.
| S-EPMC5791974 | biostudies-literature
Project description:The early neuropathological features of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) are protein aggregates in motor neurons and microglial activation. Similar pathology characterizes Guamanian ALS/Parkinsonism dementia complex, which may be triggered by the cyanotoxin β-N-methylamino-l-alanine (BMAA). We report here the occurrence of ALS/MND-type pathological changes in vervets (Chlorocebus sabaeus; n = 8) fed oral doses of a dry powder of BMAA HCl salt (210 mg/kg/day) for 140 days. Spinal cords and brains from toxin-exposed vervets were compared to controls fed rice flour (210 mg/kg/day) and to vervets coadministered equal amounts of BMAA and l-serine (210 mg/kg/day). Immunohistochemistry and quantitative image analysis were used to examine markers of ALS/MND and glial activation. UHPLC-MS/MS was used to confirm BMAA exposures in dosed vervets. Motor neuron degeneration was demonstrated in BMAA-dosed vervets by TDP-43+ proteinopathy in anterior horn cells, by reactive astrogliosis, by activated microglia, and by damage to myelinated axons in the lateral corticospinal tracts. Vervets dosed with BMAA + l-serine displayed reduced neuropathological changes. This study demonstrates that chronic dietary exposure to BMAA causes ALS/MND-type pathological changes in the vervet and coadministration of l-serine reduces the amount of reactive gliosis and the number of protein inclusions in motor neurons.
| S-EPMC7092359 | biostudies-literature
Project description:BackgroundSpinal cord injury (SCI) presents a significant challenge for the field of neurotherapeutics. Stem cells have shown promise in replenishing the cells lost to the injury process, but the release of axon growth-inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs) by activated cells within the injury site hinders the integration of transplanted cells. We hypothesised that simultaneous application of enteric neural stem cells (ENSCs) isolated from the gastrointestinal tract, with a lentivirus (LV) containing the enzyme chondroitinase ABC (ChABC), would enhance the regenerative potential of ENSCs after transplantation into the injured spinal cord.MethodsENSCs were harvested from the GI tract of p7 rats, expanded in vitro and characterised. Adult rats bearing a contusion injury were randomly assigned to one of four groups: no treatment, LV-ChABC injection only, ENSC transplantation only or ENSC transplantation+LV-ChABC injection. After 16 weeks, rats were sacrificed and the harvested spinal cords examined for evidence of repair.ResultsENSC cultures contained a variety of neuronal subtypes suitable for replenishing cells lost through SCI. Following injury, transplanted ENSC-derived cells survived and ChABC successfully degraded CSPGs. We observed significant reductions in the injured tissue and cavity area, with the greatest improvements seen in the combined treatment group. ENSC-derived cells extended projections across the injury site into both the rostral and caudal host spinal cord, and ENSC transplantation significantly increased the number of cells extending axons across the injury site. Furthermore, the combined treatment resulted in a modest, but significant functional improvement by week 16, and we found no evidence of the spread of transplanted cells to ectopic locations or formation of tumours.ConclusionsRegenerative effects of a combined treatment with ENSCs and ChABC surpassed either treatment alone, highlighting the importance of further research into combinatorial therapies for SCI. Our work provides evidence that stem cells taken from the adult gastrointestinal tract, an easily accessible source for autologous transplantation, could be strongly considered for the repair of central nervous system disorders.
| S-EPMC7789480 | biostudies-literature
Project description:The transplantation of autologous Schwann cells (SCs) to repair the injured spinal cord is currently being evaluated in a clinical trial. In support, this study determined properties of spinal cord/SC bridge interfaces that enabled regenerated brainstem axons to cross them, possibly leading to improvement in rat hindlimb movement. Fluid bridges of SCs and Matrigel were placed in complete spinal cord transections. Compared to pregelled bridges of SCs and Matrigel, they improved regeneration of brainstem axons across the rostral interface. The regenerating brainstem axons formed synaptophysin(+) bouton-like terminals and contacted MAP2A(+) dendrites at the caudal interface. Brainstem axon regeneration was directly associated with glial fibrillary acidic protein (GFAP(+)) astrocyte processes that elongated into the SC bridge. Electron microscopy revealed that axons, SCs, and astrocytes were enclosed together within tunnels bounded by a continuous basal lamina. Neuroglycan (NG2) expression was associated with these tunnels. One week after injury, the GFAP(+) processes coexpressed nestin and brain lipid-binding protein, and the tips of GFAP(+)/NG2(+) processes extended into the bridges together with the regenerating brainstem axons. Both brainstem axon regeneration and number of GFAP(+) processes in the bridges correlated with improvement in hindlimb locomotion. Following SCI, astrocytes may enter a reactive state that prohibits axon regeneration. Elongation of astrocyte processes into SC bridges, however, and formation of NG2(+) tunnels enable brainstem axon regeneration and improvement in function. It is important for spinal cord repair to define conditions that favor elongation of astrocytes into lesions/transplants.
| S-EPMC4809058 | biostudies-literature
Project description:Spinal cord injury (SCI) can result in sensorimotor impairments or disability. Studies of the cellular response to SCI have increased our understanding of nerve regenerative failure following spinal cord trauma. Biological, engineering and rehabilitation strategies for repairing the injured spinal cord have shown impressive results in SCI models of both rodents and non-human primates. Cell transplantation, in particular, is becoming a highly promising approach due to the cells' capacity to provide multiple benefits at the molecular, cellular, and circuit levels. While various cell types have been investigated, we focus on the use of Schwann cells (SCs) to promote SCI repair in this review. Transplantation of SCs promotes functional recovery in animal models and is safe for use in humans with subacute SCI. The rationales for the therapeutic use of SCs for SCI include enhancement of axon regeneration, remyelination of newborn or sparing axons, regulation of the inflammatory response, and maintenance of the survival of damaged tissue. However, little is known about the molecular mechanisms by which transplanted SCs exert a reparative effect on SCI. Moreover, SC-based therapeutic strategies face considerable challenges in preclinical studies. These issues must be clarified to make SC transplantation a feasible clinical option. In this review, we summarize the recent advances in SC transplantation for SCI, and highlight proposed mechanisms and challenges of SC-mediated therapy. The sparse information available on SC clinical application in patients with SCI is also discussed.
| S-EPMC8891437 | biostudies-literature
Project description:Promoting residential cells, particularly endogenous neural stem and progenitor cells (NSPCs), for tissue regeneration represents a potential strategy for the treatment of spinal cord injury (SCI). However, adult NSPCs differentiate mainly into glial cells and contribute to glial scar formation at the site of injury. Gsx1 is known to regulate the generation of excitatory and inhibitory interneurons during embryonic development of the spinal cord. Here we show that lentivirus-mediated expression of Gsx1 increases the number of NSPCs in a mouse model of lateral hemisection SCI during the acute stage. Subsequently, Gsx1 expression increases the generation of glutamatergic and cholinergic interneurons and decreases the generation of GABAergic interneurons in the chronic stage of SCI. Importantly, Gsx1 reduces reactive astrogliosis and glial scar formation, promotes 5-HT neuronal activity, and improves the locomotor function of the injured mice. Moreover, RNA-seq analysis reveals that Gsx1-induced transcriptome regulation correlates with NSPC signaling, NSPC activation, neuronal differentiation, and inhibition of astrogliosis and scar formation. Collectively, our study provides molecular insights for Gsx1-mediated functional recovery and identifies Gsx1 gene regulation as a potential application for injuries in the spinal cord and possibly other parts of the central nervous system.
2021-05-01 | GSE171441 | GEO
Project description:Bacterial chondroitinase ABC (ChaseABC) has been used to remove the inhibitory chondroitin sulfate chains from chondroitin sulfate proteoglycans to improve regeneration after rodent spinal cord injury. We hypothesized that the mammalian enzyme arylsulfatase B (ARSB) would also enhance recovery after mouse spinal cord injury. Application of the mammalian enzyme would be an attractive alternative to ChaseABC because of its more robust chemical stability and reduced immunogenicity. A one-time injection of human ARSB into injured mouse spinal cord eliminated immunoreactivity for chondroitin sulfates within five days, and up to 9 weeks after injury. After a moderate spinal cord injury, we observed improvements of locomotor recovery assessed by the Basso Mouse Scale (BMS) in ARSB treated mice, compared to the buffer-treated control group, at 6 weeks after injection. After a severe spinal cord injury, mice injected with equivalent units of ARSB or ChaseABC improved similarly and both groups achieved significantly more locomotor recovery than the buffer-treated control mice. Serotonin and tyrosine hydroxylase immunoreactive axons were more extensively present in mouse spinal cords treated with ARSB and ChaseABC, and the immunoreactive axons penetrated further beyond the injury site in ARSB or ChaseABC treated mice than in control mice. These results indicate that mammalian ARSB improves functional recovery after CNS injury. The structural/molecular mechanisms underlying the observed functional improvement remain to be elucidated.
| S-EPMC3592852 | biostudies-literature
Project description:Neurophysiological changes that involve activity-dependent neuroplasticity mechanisms via repeated stimulation and locomotor training are not commonly employed in research even though combination of interventions is a common clinical practice. In this randomized clinical trial, we established neurophysiological changes when transcranial magnetic stimulation (TMS) of the motor cortex was paired with transcutaneous thoracolumbar spinal (transspinal) stimulation in human spinal cord injury (SCI) delivered during locomotor training. We hypothesized that TMS delivered before transspinal (TMS-transspinal) stimulation promotes functional reorganization of spinal networks during stepping. In this protocol, TMS-induced corticospinal volleys arrive at the spinal cord at a sufficient time to interact with transspinal stimulation induced depolarization of alpha motoneurons over multiple spinal segments. We further hypothesized that TMS delivered after transspinal (transspinal-TMS) stimulation induces less pronounced effects. In this protocol, transspinal stimulation is delivered at time that allows transspinal stimulation induced action potentials to arrive at the motor cortex and affect descending motor volleys at the site of their origin. Fourteen individuals with motor incomplete and complete SCI participated in at least 25 sessions. Both stimulation protocols were delivered during the stance phase of the less impaired leg. Each training session consisted of 240 paired stimuli delivered over 10-min blocks. In transspinal-TMS, the left soleus H-reflex increased during the stance-phase and the right soleus H-reflex decreased at mid-swing. In TMS-transspinal no significant changes were found. When soleus H-reflexes were grouped based on the TMS-targeted limb, transspinal-TMS and locomotor training promoted H-reflex depression at swing phase, while TMS-transspinal and locomotor training resulted in facilitation of the soleus H-reflex at stance phase of the step cycle. Furthermore, both transspinal-TMS and TMS-transspinal paired-associative stimulation (PAS) and locomotor training promoted a more physiological modulation of motor activity and thus depolarization of motoneurons during assisted stepping. Our findings support that targeted non-invasive stimulation of corticospinal and spinal neuronal pathways coupled with locomotor training produce neurophysiological changes beneficial to stepping in humans with varying deficits of sensorimotor function after SCI.
| S-EPMC8141587 | biostudies-literature
Project description:Combined interventions for neuromodulation leading to neurorecovery have gained great attention by researchers to resemble clinical rehabilitation approaches. In this randomized clinical trial, we established changes in the net output of motoneurons innervating multiple leg muscles during stepping when transcranial magnetic stimulation (TMS) of the primary motor cortex was paired with transcutaneous spinal (transspinal) stimulation over the thoracolumbar region during locomotor training. TMS was delivered before (TMS-transspinal) or after (transspinal-TMS) transspinal stimulation during the stance phase of the less impaired leg. Ten individuals with chronic incomplete or complete SCI received at least 20 sessions of training. Each session consisted of 240 paired stimuli delivered over 10-min blocks for 1 h during robotic assisted step training on a motorized treadmill. Body weight support, leg guidance force and treadmill speed were adjusted based on each subject's ability to step without knee buckling or toe dragging. Most transspinal evoked potentials (TEPs) recorded before and after each intervention from ankle and knee muscles during assisted stepping were modulated in a phase-dependent pattern. Transspinal-TMS and locomotor training affected motor neuron output of knee and ankle muscles with ankle TEPs to be modulated in a phase-dependent manner. TMS-transspinal and locomotor training increased motor neuron output for knee but not for ankle muscles. Our results support that targeted brain and spinal cord stimulation alters responsiveness of neurons over multiple spinal segments in people with chronic SCI. Noninvasive stimulation of the brain and spinal cord along with locomotor training is a novel neuromodulation method that can become a promising modality for rehabilitation in humans after SCI.
| S-EPMC9612520 | biostudies-literature