LOTUS overexpression via ex vivo gene transduction further promotes recovery of motor function following human iPSC-NS/PC transplantation for contusive spinal cord injury.
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ABSTRACT:
SUBMITTER: Ito S
PROVIDER: S-EPMC8580872 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Gliosis and fibrosis after spinal cord injury (SCI) lead to formation of a scar that is an impediment to axonal regeneration. Fibrotic scarring is characterized by the accumulation of fibronectin, collagen, and fibroblasts at the lesion site. The mechanisms regulating fibrotic scarring after SCI and its effects on axonal elongation and functional recovery are not well understood. In this study, we examined the effects of eliminating an isoform of fibronectin containing the Extra Domain A domain (FnEDA) on both fibrosis and on functional recovery after contusion SCI using male and female FnEDA-null mice. Eliminating FnEDA did not reduce the acute fibrotic response but markedly diminished chronic fibrotic scarring after SCI. Glial scarring was unchanged after SCI in FnEDA-null mice. We found that FnEDA was important for the long-term stability of the assembled fibronectin matrix during both the subacute and chronic phases of SCI. Motor functional recovery was significantly improved, and there were increased numbers of axons in the lesion site compared to wildtype mice, suggesting that the chronic fibrotic response is detrimental to recovery. Our data provide insight into the mechanisms of fibrosis after SCI and suggest that disruption of fibronectin matrix stability by targeting FnEDA represents a potential therapeutic strategy for promoting recovery after SCI.
| S-EPMC5995671 | biostudies-literature
Project description:Astrocytes and their precursors respond to spinal cord injury (SCI) by proliferating, migrating, and altering phenotype. This contributes to glial scar formation at the lesion border and gliosis in spared gray and white matter. The present study was undertaken to evaluate astrocyte changes over time and determine when and where interventions might be targeted to alter the astrocyte response. Bromodeoxyuridine (BrdU) was administered to mice 3 days after SCI, and cells expressing BrdU and the astrocyte marker, glial fibrillary acidic protein (GFAP), were counted at 3, 7, and 49 days post-injury (DPI). BrdU-labeled cells accumulated at the lesion border by 7 DPI and approximately half of these expressed GFAP. In spared white matter, the total number of BrdU+ cells decreased, while the percentage of BrdU+ cells expressing GFAP increased at 49 DPI. Phenotypic changes were examined using the progenitor marker nestin, the radial glial marker, brain lipid binding protein (BLBP), and GFAP. Nestin was upregulated by 3 DPI and declined between 7 and 49 DPI in all regions, and GFAP increased and remained above naïve levels at all timepoints. BLBP increased early and remained high along the lesion border and spared white matter, but was expressed transiently by cells lining the central canal and in a unique population of small cells found within the lesion and in gray matter rostral and caudal to the border. The results demonstrate that the astrocyte response to SCI is regionally heterogeneous, and suggests astrocyte populations that could be targeted by interventions.
| S-EPMC2867111 | biostudies-literature
Project description:Remyelination occurs after spinal cord injury (SCI) but its functional relevance is unclear. We assessed the necessity of myelin regulatory factor (Myrf) in remyelination after contusive SCI by deleting the gene from platelet-derived growth factor receptor alpha positive (PDGFRα-positive) oligodendrocyte progenitor cells (OPCs) in mice prior to SCI. While OPC proliferation and density are not altered by Myrf inducible knockout after SCI, the accumulation of new oligodendrocytes is largely prevented. This greatly inhibits myelin regeneration, resulting in a 44% reduction in myelinated axons at the lesion epicenter. However, spontaneous locomotor recovery after SCI is not altered by remyelination failure. In controls with functional MYRF, locomotor recovery precedes the onset of most oligodendrocyte myelin regeneration. Collectively, these data demonstrate that MYRF expression in PDGFRα-positive cell derived oligodendrocytes is indispensable for myelin regeneration following contusive SCI but that oligodendrocyte remyelination is not required for spontaneous recovery of stepping.
| S-EPMC6076268 | biostudies-literature
Project description:NG2(+) cells in the adult CNS are a heterogeneous population. The extent to which the subpopulation of NG2(+) cells that function as oligodendrocyte progenitor cells (OPCs) respond to spinal cord injury (SCI) and recapitulate their normal developmental progression remains unclear. We used the CNP-EGFP mouse, in which oligodendrocyte lineage cells express EGFP, to study NG2(+) cells in the normal and injured spinal cord. In white matter of uninjured mice, bipolar EGFP(+)NG2(+) cells and multipolar EGFP(neg)NG2(+) cells were identified. After SCI, EGFP(+)NG2(+) cell proliferation in residual white matter peaked at 3 days post injury (DPI) rostral to the epicenter, while EGFP(neg)NG2(+) cell proliferation peaked at 7 DPI at the epicenter. The expression of transcription factors, Olig2, Sox10, and Sox17, and the basic electrophysiological membrane parameters and potassium current phenotype of the EGFP(+)NG2(+) population after injury were consistent with those of proliferative OPCs during development. EGFP(neg)NG2(+) cells did not express transcription factors involved in oligodendrogenesis. EGFP(+)CC1(+) oligodendrocytes at 6 weeks included cells that incorporated BrdU during the peak of EGFP(+)NG2(+) cell proliferation. EGFP(neg)CC1(+) oligodendrocytes were never observed. Treatment with glial growth factor 2 and fibroblast growth factor 2 enhanced oligodendrogenesis and increased the number of EGFP(neg)NG2(+) cells. Therefore, based on EGFP and transcription factor expression, spatiotemporal proliferation patterns, and response to growth factors, two populations of NG2(+) cells can be identified that react to SCI. The EGFP(+)NG2(+) cells undergo cellular and physiological changes in response to SCI that are similar to those that occur in early postnatal NG2(+) cells during developmental oligodendrogenesis.
| S-EPMC2696059 | biostudies-literature
Project description:Spasticity is a frequent chronic complication in individuals with spinal cord injury (SCI). However, the severity of spasticity varies in patients with SCI. Therefore, an evaluation method is needed to determine the severity of spasticity. We used a contusive SCI model that is suitable for clinical translation. In this study, we examined the feasibility of the swimming test and an EMG for evaluating spasticity in a contusive SCI rat model. Sprague-Dawley rats received an injury at the 8th thoracic vertebra. Swimming tests were performed 3 to 6 weeks after SCI induction. We placed the SCI rats into spasticity-strong or spasticity-weak groups based on the frequency of spastic behavior during the swimming test. Subsequently, we recorded the Hoffman reflex (H-reflex) and examined the immunoreactivity of serotonin (5-HT) and its receptor (5-HT2A) in the spinal tissues of the SCI rats. The spasticity-strong group had significantly decreased rate-dependent depression of the H-reflex compared to the spasticity-weak group. The area of 5-HT2A receptor immunoreactivity was significantly increased in the spasticity-strong group. Thus, both electrophysiological and histological evaluations indicate that the spasticity-strong group presented with a more severe upper motor neuron syndrome. We also observed the groups in their cages for 20 hours. Our results suggest that the swimming test provides an accurate evaluation of spasticity in this contusive SCI model. We believe that the swimming test is an effective method for evaluating spastic behaviors and developing treatments targeting spasticity after SCI.
| S-EPMC5300247 | biostudies-literature
Project description:Autophagy is an essential process of cellular waist clearance that becomes altered following spinal cord injury (SCI). Details on these changes, including timing after injury, underlying mechanisms, and affected cells, remain controversial. Here we present a characterization of autophagy in the mice spinal cord before and after a contusive SCI. In the undamaged spinal cord, analysis of LC3 and Beclin 1 autophagic markers reveals important differences in basal autophagy between neurons, oligodendrocytes, and astrocytes and even within cell populations. Following moderate contusion, western blot analyses of LC3 indicates that autophagy increases to a maximum at 7 days post injury (dpi), whereas unaltered Beclin 1 expression and increase of p62 suggests a possible blockage of autophagosome clearance. Immunofluorescence analyses of LC3 and Beclin 1 provide additional details that reveal a complex, cell-specific scenario. Autophagy is first activated (1 dpi) in the severed axons, followed by a later (7 dpi) accumulation of phagophores and/or autophagosomes in the neuronal soma without signs of increased initiation. Oligodendrocytes and reactive astrocytes also accumulate phagophores and autophagosomes at 7 dpi, but whereas the accumulation in astrocytes is associated with an increased autophagy initiation, it seems to result from a blockage of the autophagic flux in oligodendrocytes. Comparison with previous studies highlights the complex and heterogeneous autophagic responses induced by the SCI, leading in many cases to contradictory results and interpretations. Future studies should consider this complexity in the design of therapeutic interventions based on the modulation of autophagy to treat SCI.
| S-EPMC6005838 | biostudies-literature
Project description:NG2 cells, also known as oligodendrocyte progenitors or polydendrocytes, are a major component of the glial scar that forms after spinal cord injury. NG2 cells react to injury by proliferating around the lesion site and differentiating into oligodendrocytes and astrocytes, but the molecular mechanism is poorly understood. In this study, we tested the role of the transcription factor STAT3, and its suppressor SOCS3, in NG2 cell proliferation and differentiation after spinal cord injury. Using knockout mice in which STAT3 or SOCS3 are genetically deleted specifically in NG2 cells, we found that deletion of STAT3 led to a reduction in oligodendrogenesis, while deletion of SOCS3 led to enhanced proliferation of NG2 cells within the glial scar after spinal cord injury. Additionally, STAT3 and SOCS3 were not required for astrogliogenesis from NG2 cells after spinal cord injury. Interestingly, genetic deletion of STAT3 and SOCS3 did not have opposing effects, suggesting that SOCS3 may have targets other than the STAT3 pathway in NG2 cells after spinal cord injury. Altogether, our data show that both STAT3 and SOCS3 play important, yet unexpected, roles in NG2 cell proliferation and differentiation after spinal cord injury.
| S-EPMC4785033 | biostudies-literature
Project description:Blocking the action of inhibitory molecules at sites of central nervous system injury has been proposed as a strategy to promote axonal regeneration and functional recovery. We have previously shown that genetic deletion or competitive antagonism of EphA4 receptor activity promotes axonal regeneration and functional recovery in a mouse model of lateral hemisection spinal cord injury. Here we have assessed the effect of blocking EphA4 activation using the competitive antagonist EphA4-Fc in a rat model of thoracic contusive spinal cord injury. Using a ledged tapered balance beam and open-field testing, we observed significant improvements in recovery of locomotor function after EphA4-Fc treatment. Consistent with functional improvement, using high-resolution ex vivo magnetic resonance imaging at 16.4T, we found that rats treated with EphA4-Fc had a significantly increased cross-sectional area of the dorsal funiculus caudal to the injury epicenter compared with controls. Our findings indicate that EphA4-Fc promotes functional recovery following contusive spinal cord injury and provides further support for the therapeutic benefit of treatment with the competitive antagonist in acute cases of spinal cord injury.
| S-EPMC3689926 | biostudies-literature
Project description:BackgroundWnt proteins are a large family of molecules that are critically involved in multiple central nervous system (CNS) developmental processes. Experimental evidences suggest a role for this family of proteins in many CNS disorders, including spinal cord injury (SCI), which is a major neuropathology owing to its high prevalence and chronic sensorimotor functional sequelae. Interestingly, most Wnt proteins and their inhibitors are expressed in the uninjured spinal cord, and their temporal expression patterns are dramatically altered after injury. However, little is known regarding the expression of their better-known receptors, the Frizzled family, after SCI. Thus, the aim of the present study was to evaluate the expression of Frizzled receptors in the damaged spinal cord.FindingsBased on the evidence that Wnts are expressed in the spinal cord and are transcriptionally regulated by SCI in adulthood, we analysed the spatio-temporal mRNA and protein expression patterns of Frizzled receptors after contusive SCI using quantitative RT-PCR and single and double immunohistochemistry, respectively. Our results show that almost all of the 10 known Frizzled receptors were expressed in specific spatial patterns in the uninjured spinal cords. Moreover, the Frizzled mRNAs and proteins were expressed after SCI, although their expression patterns were altered during the temporal progression of SCI. Finally, analysis of cellular Frizzled 5 expression pattern by double immunohistochemistry showed that, in the uninjured spinal cord, this receptor was expressed in neurons, oligodendrocytes, astrocytes, microglia and NG2(+) glial precursors. After injury, Frizzled 5 was not only still expressed in oligodendrocytes, astrocytes and NG2(+) glial precursors but also in axons at all evaluated time points. Moreover, Frizzled 5 was expressed in reactive microglia/macrophages from 3 to 14 days post-injury.ConclusionsOur data suggest the involvement of Frizzled receptors in physiological spinal cord function and in the cellular and molecular events that characterise its neuropathology.
| S-EPMC3519492 | biostudies-literature
Project description:Spinal locomotor circuitry is comprised of rhythm generating centers, one for each limb, that are interconnected by local and long-distance propriospinal neurons thought to carry temporal information necessary for interlimb coordination and gait control. We showed previously that conditional silencing of the long ascending propriospinal neurons (LAPNs) that project from the lumbar to the cervical rhythmogenic centers (L1/L2 to C6), disrupts right-left alternation of both the forelimbs and hindlimbs without significantly disrupting other fundamental aspects of interlimb and speed-dependent coordination (Pocratsky et al., 2020). Subsequently, we showed that silencing the LAPNs after a moderate thoracic contusive spinal cord injury (SCI) resulted in better recovered locomotor function (Shepard et al., 2021). In this research advance, we focus on the descending equivalent to the LAPNs, the long descending propriospinal neurons (LDPNs) that have cell bodies at C6 and terminals at L2. We found that conditional silencing of the LDPNs in the intact adult rat resulted in a disrupted alternation of each limb pair (forelimbs and hindlimbs) and after a thoracic contusion SCI significantly improved locomotor function. These observations lead us to speculate that the LAPNs and LDPNs have similar roles in the exchange of temporal information between the cervical and lumbar rhythm generating centers, but that the partial disruption of the pathway after SCI limits the independent function of the lumbar circuitry. Silencing the LAPNs or LDPNs effectively permits or frees-up the lumbar circuitry to function independently.
| S-EPMC10776087 | biostudies-literature