scholarly journals Exercise Ameliorates Spinal Cord Injury by Changing DNA Methylation

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 143
Author(s):  
Ganchimeg Davaa ◽  
Jin Young Hong ◽  
Tae Uk Kim ◽  
Seong Jae Lee ◽  
Seo Young Kim ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Cortex ◽  
Functional Recovery ◽  
Treadmill Exercise ◽  
Exercise Group ◽  
Control Group ◽  
Epigenetic Changes ◽  
Cord Injury ◽  
The Brain

Exercise training is a traditional method to maximize remaining function in patients with spinal cord injury (SCI), but the exact mechanism by which exercise promotes recovery after SCI has not been identified; whether exercise truly has a beneficial effect on SCI also remains unclear. Previously, we showed that epigenetic changes in the brain motor cortex occur after SCI and that a treatment leading to epigenetic modulation effectively promotes functional recovery after SCI. We aimed to determine how exercise induces functional improvement in rats subjected to SCI and whether epigenetic changes are engaged in the effects of exercise. A spinal cord contusion model was established in rats, which were then subjected to treadmill exercise for 12 weeks. We found that the size of the lesion cavity and the number of macrophages were decreased more in the exercise group than in the control group after 12 weeks of injury. Immunofluorescence and DNA dot blot analysis revealed that levels of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in the brain motor cortex were increased after exercise. Accordingly, the expression of ten-eleven translocation (Tet) family members (Tet1, Tet2, and Tet3) in the brain motor cortex also elevated. However, no macrophage polarization was induced by exercise. Locomotor function, including Basso, Beattie, and Bresnahan (BBB) and ladder scores, also improved in the exercise group compared to the control group. We concluded that treadmill exercise facilitates functional recovery in rats with SCI, and mechanistically epigenetic changes in the brain motor cortex may contribute to exercise-induced improvements.

Transplantation of Neural Stem/Progenitor Cells at Different Locations in Mice with Spinal Cord Injury

2014 ◽  
Vol 23 (11) ◽  
pp. 1451-1464 ◽  
Author(s):  
Hiroki Iwai ◽  
Satoshi Nori ◽  
Soraya Nishimura ◽  
Akimasa Yasuda ◽  
Morito Takano ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Progenitor Cells ◽  
Functional Recovery ◽  
Control Group ◽  
Cord Injury ◽  
Neural Stem Progenitor Cells ◽  
Neurotropic Factor ◽  
Transplantation Site

Transplantation of neural stem/progenitor cells (NS/PCs) promotes functional recovery after spinal cord injury (SCI); however, few studies have examined the optimal site of NS/PC transplantation in the spinal cord. The purpose of this study was to determine the optimal transplantation site of NS/PCs for the treatment of SCI. Wild-type mice were generated with contusive SCI at the T10 level, and NS/PCs were derived from fetal transgenic mice. These NS/PCs ubiquitously expressed ffLuc-cp156 protein (Venus and luciferase fusion protein) and so could be detected by in vivo bioluminescence imaging 9 days postinjury. NS/PCs (low: 250,000 cells per mouse; high: 1 million cells per mouse) were grafted into the spinal cord at the lesion epicenter (E) or at rostral and caudal (RC) sites. Phosphate-buffered saline was injected into E as a control. Motor functional recovery was better in each of the transplantation groups (E-Low, E-High, RC-Low, and RC-High) than in the control group. The photon counts of the grafted NS/PCs were similar in each of the four transplantation groups, suggesting that the survival of NS/PCs was fairly uniform when more than a certain threshold number of cells were transplanted. Quantitative RT-PCR analyses demonstrated that brain-derived neurotropic factor expression was higher in the RC segment than in the E segment, and this may underlie why NS/PCs more readily differentiated into neurons than into astrocytes in the RC group. The location of the transplantation site did not affect the area of spared fibers, angiogenesis, or the expression of any other mediators. These findings indicated that the microenvironments of the E and RC sites are able to support NS/PCs transplanted during the subacute phase of SCI similarly. Optimally, a certain threshold number of NS/PCs should be grafted into the E segment to avoid damaging sites adjacent to the lesion during the injection procedure.

scholarly journals Ascorbic Acid Promotes Functional Restoration after Spinal Cord Injury Partly by Epigenetic Modulation

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1310 ◽  
Author(s):  
Jin Young Hong ◽  
Ganchimeg Davaa ◽  
Hyunjin Yoo ◽  
Kwonho Hong ◽  
Jung Keun Hyun
Keyword(s):  
Spinal Cord ◽  
Dna Methylation ◽  
Spinal Cord Injury ◽  
Ascorbic Acid ◽  
Motor Cortex ◽  
Functional Restoration ◽  
Mrna Levels ◽  
Cord Injury ◽  
Epigenetic Modulation ◽  
The Brain

Axonal regeneration after spinal cord injury (SCI) is difficult to achieve, and no fundamental treatment can be applied in clinical settings. DNA methylation has been suggested to play a role in regeneration capacity and neuronal growth after SCI by controlling the expression of regeneration-associated genes (RAGs). The aim of this study was to examine changes in neuronal DNA methylation status after SCI and to determine whether modulation of DNA methylation with ascorbic acid can enhance neuronal regeneration or functional restoration after SCI. Changes in epigenetic marks (5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC)); the expression of Ten-eleven translocation (Tet) family genes; and the expression of genes related to inflammation, regeneration, and degeneration in the brain motor cortex were determined following SCI. The 5hmC level within the brain was increased after SCI, especially in the acute and subacute stages, and the mRNA levels of Tet gene family members (Tet1, Tet2, and Tet3) were also increased. Administration of ascorbic acid (100 mg/kg) to SCI rats enhanced 5hmC levels; increased the expression of the Tet1, Tet2, and Tet3 genes within the brain motor cortex; promoted axonal sprouting within the lesion cavity of the spinal cord; and enhanced recovery of locomotor function until 12 weeks. In conclusion, we found that epigenetic status in the brain motor cortex is changed after SCI and that epigenetic modulation using ascorbic acid may contribute to functional recovery after SCI.

scholarly journals Intravascular innate immune cells reprogrammed via intravenous nanoparticles to promote functional recovery after spinal cord injury

2019 ◽  
Vol 116 (30) ◽  
pp. 14947-14954 ◽  
Author(s):  
Jonghyuck Park ◽  
Yining Zhang ◽  
Eiji Saito ◽  
Steve J. Gurczynski ◽  
Bethany B. Moore ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Immune Cells ◽  
Macrophage Polarization ◽  
Innate Immune ◽  
Control Group ◽  
Innate Immune Cells ◽  
Benefit Ratio ◽  
Cord Injury

Traumatic primary spinal cord injury (SCI) results in paralysis below the level of injury and is associated with infiltration of hematogenous innate immune cells into the injured cord. Methylprednisolone has been applied to reduce inflammation following SCI, yet was discontinued due to an unfavorable risk-benefit ratio associated with off-target effects. In this study, i.v. administered poly(lactide-coglycolide) nanoparticles were internalized by circulating monocytes and neutrophils, reprogramming these cells based on their physicochemical properties and not by an active pharmaceutical ingredient, to exhibit altered biodistribution, gene expression, and function. Approximately 80% of nanoparticle-positive immune cells were observed within the injury, and, additionally, the overall accumulation of innate immune cells at the injury was reduced 4-fold, coinciding with down-regulated expression of proinflammatory factors and increased expression of antiinflammatory and proregenerative genes. Furthermore, nanoparticle administration induced macrophage polarization toward proregenerative phenotypes at the injury and markedly reduced both fibrotic and gliotic scarring 3-fold. Moreover, nanoparticle administration with the implanted multichannel bridge led to increased numbers of regenerating axons, increased myelination with about 40% of axons myelinated, and an enhanced locomotor function (score of 6 versus 3 for control group). These data demonstrate that nanoparticles provide a platform that limits acute inflammation and tissue destruction, at a favorable risk-benefit ratio, leading to a proregenerative microenvironment that supports regeneration and functional recovery. These particles may have applications to trauma and potentially other inflammatory diseases.

scholarly journals hiPSC-derived NSCs effectively promote the functional recovery of acute spinal cord injury in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Desheng Kong ◽  
Baofeng Feng ◽  
Asiamah Ernest Amponsah ◽  
Jingjing He ◽  
Ruiyun Guo ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Morphological Changes ◽  
Embryonic Stem ◽  
Control Group ◽  
Common Disease ◽  
Mice Model ◽  
Cord Injury

Abstract Background Spinal cord injury (SCI) is a common disease that results in motor and sensory disorders and even lifelong paralysis. The transplantation of stem cells, such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), or subsequently generated stem/progenitor cells, is predicted to be a promising treatment for SCI. In this study, we aimed to investigate effect of human iPSC-derived neural stem cells (hiPSC-NSCs) and umbilical cord-derived MSCs (huMSCs) in a mouse model of acute SCI. Methods Acute SCI mice model were established and were randomly treated as phosphate-buffered saline (PBS) (control group), repaired with 1 × 105 hiPSC-NSCs (NSC group), and 1 × 105 huMSCs (MSC group), respectively, in a total of 54 mice (n = 18 each). Hind limb motor function was evaluated in open-field tests using the Basso Mouse Scale (BMS) at days post-operation (dpo) 1, 3, 5, and 7 after spinal cord injury, and weekly thereafter. Spinal cord and serum samples were harvested at dpo 7, 14, and 21. Haematoxylin-eosin (H&E) staining and Masson staining were used to evaluate the morphological changes and fibrosis area. The differentiation of the transplanted cells in vivo was evaluated with immunohistochemical staining. Results The hiPSC-NSC-treated group presented a significantly smaller glial fibrillary acidic protein (GFAP) positive area than MSC-treated mice at all time points. Additionally, MSC-transplanted mice had a similar GFAP+ area to mice receiving PBS. At dpo 14, the immunostained hiPSC-NSCs were positive for SRY-related high-mobility-group (HMG)-box protein-2 (SOX2). Furthermore, the transplanted hiPSC-NSCs differentiated into GFAP-positive astrocytes and beta-III tubulin-positive neurons, whereas the transplanted huMSCs differentiated into GFAP-positive astrocytes. In addition, hiPSC-NSC transplantation reduced fibrosis formation and the inflammation level. Compared with the control or huMSC transplanted group, the group with transplantation of hiPSC-NSCs exhibited significantly improved behaviours, particularly limb coordination. Conclusions HiPSC-NSCs promote functional recovery in mice with acute SCI by replacing missing neurons and attenuating fibrosis, glial scar formation, and inflammation. Graphical abstract

scholarly journals Trunk sensory and motor cortex is preferentially integrated with hindlimb sensory information that supports trunk stabilization

2020 ◽  
Author(s):  
Bharadwaj Nandakumar ◽  
Gary H. Blumenthal ◽  
Francois Philippe Pauzin ◽  
Karen A. Moxon
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Cortex ◽  
Postural Control ◽  
Functional Recovery ◽  
Sensorimotor Integration ◽  
Cortical Reorganization ◽  
Sensory Cortex ◽  
Proprioceptive Information ◽  
Cord Injury

AbstractSensorimotor integration in the trunk system has been poorly studied despite its importance for examining functional recovery after neurological injury or disease. Here, we mapped the relationship between thoracic dorsal root ganglia and trunk sensory cortex (S1) to create a detailed map of the extent and internal organization of trunk primary sensory cortex, and trunk primary motor cortex (M1) and showed that both cortices are somatotopically complex structures that are larger than previously described. Surprisingly, projections from trunk S1 to trunk M1 were not anatomically organized. We found relatively weak sensorimotor integration between trunk M1 and S1 and between trunk M1 and forelimb S1 compared to extensive integration between trunk M1 and hindlimb S1 and M1. This strong trunk/hindlimb connection was identified for high intensity stimuli that activated proprioceptive pathways. To assess the implication of this integration, the responses in sensorimotor cortex were examined during a postural control task and supported sensorimotor integration between hindlimb sensory and lower trunk motor cortex. Together, these data suggest that trunk M1 is guided predominately by hindlimb proprioceptive information that reached the cortex directly via the thalamus. This unique sensorimotor integration suggests an essential role for the trunk system in postural control, and its consideration could be important for understanding studies regarding recovery of function after spinal cord injury.SignificanceThis work identifies extensive sensorimotor integration between trunk and hindlimb cortices, demonstrating that sensorimotor integration is an operational mode of the trunk cortex in intact animals. The functional role of this integration was demonstrated for postural control when the animal was subjected to lateral tilts. Furthermore, these results provide insight into cortical reorganization after spinal cord injury making clear that sensorimotor integration after SCI is an attempt to restore sensorimotor integration that existed in the intact system. These results could be used to tailor rehabilitative strategies to optimize sensorimotor integration for functional recovery.

scholarly journals Transneuronal delivery of hyper-interleukin-6 enables functional recovery after severe spinal cord injury in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marco Leibinger ◽  
Charlotte Zeitler ◽  
Philipp Gobrecht ◽  
Anastasia Andreadaki ◽  
Günter Gisselmann ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Brain Stem ◽  
Functional Recovery ◽  
Cortical Neurons ◽  
Locomotor Recovery ◽  
Stat3 Signaling ◽  
Cord Injury ◽  
Severed Axons ◽  
The Brain

AbstractSpinal cord injury (SCI) often causes severe and permanent disabilities due to the regenerative failure of severed axons. Here we report significant locomotor recovery of both hindlimbs after a complete spinal cord crush. This is achieved by the unilateral transduction of cortical motoneurons with an AAV expressing hyper-IL-6 (hIL-6), a potent designer cytokine stimulating JAK/STAT3 signaling and axon regeneration. We find collaterals of these AAV-transduced motoneurons projecting to serotonergic neurons in both sides of the raphe nuclei. Hence, the transduction of cortical neurons facilitates the axonal transport and release of hIL-6 at innervated neurons in the brain stem. Therefore, this transneuronal delivery of hIL-6 promotes the regeneration of corticospinal and raphespinal fibers after injury, with the latter being essential for hIL-6-induced functional recovery. Thus, transneuronal delivery enables regenerative stimulation of neurons in the deep brain stem that are otherwise challenging to access, yet highly relevant for functional recovery after SCI.

scholarly journals Afferent input and sensory function after human spinal cord injury

2018 ◽  
Vol 119 (1) ◽  
pp. 134-144 ◽  
Author(s):  
Recep A. Ozdemir ◽  
Monica A. Perez
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Cortex ◽  
Primary Motor Cortex ◽  
Afferent Input ◽  
Sensory Function ◽  
Severity Of Injury ◽  
Cord Injury ◽  
Afferent Inputs ◽  
The Brain

Spinal cord injury (SCI) often disrupts the integrity of afferent (sensory) axons projecting through the spinal cord dorsal columns to the brain. Examinations of ascending sensory tracts, therefore, are critical for monitoring the extent of SCI and recovery processes. In this review, we discuss the most common electrophysiological techniques used to assess transmission of afferent inputs to the primary motor cortex (i.e., afferent input-induced facilitation and inhibition) and the somatosensory cortex [i.e., somatosensory evoked potentials (SSEPs), dermatomal SSEPs, and electrical perceptual thresholds] following human SCI. We discuss how afferent input modulates corticospinal excitability by involving cortical and spinal mechanisms depending on the timing of the effects, which need to be considered separately for upper and lower limb muscles. We argue that the time of arrival of afferent input onto the sensory and motor cortex is critical to consider in plasticity-induced protocols in humans with SCI. We also discuss how current sensory exams have been used to detect differences between control and SCI participants but might be less optimal to characterize the level and severity of injury. There is a need to conduct some of these electrophysiological examinations during functionally relevant behaviors to understand the contribution of impaired afferent inputs to the control, or lack of control, of movement. Thus the effects of transmission of afferent inputs to the brain need to be considered on multiple functions following human SCI.

scholarly journals HiPSC-Derived NSCs Effectively Promote The Functional Recovery of Acute Spinal Cord Injury in Mice

2020 ◽  
Author(s):  
Desheng Kong ◽  
Baofeng Feng ◽  
Asiamah Ernest Amponsah ◽  
Jingjing He ◽  
Ruiyun Guo ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Morphological Changes ◽  
Embryonic Stem ◽  
Control Group ◽  
Common Disease ◽  
Mice Model ◽  
Cord Injury

Abstract Background: Spinal cord injury (SCI) is a common disease that results in motor and sensory disorders and even lifelong paralysis. The transplantation of stem cells, such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), or subsequently generated stem/progenitor cells, is predicted to be a promising treatment for SCI. In this study, we aimed to investigate effect of human iPSC-derived neural stem cells (hiPSC-NSCs) and umbilical cord-derived MSCs (huMSCs) in a mouse model of acute SCI. Methods: Acute SCI mice model were established and were randomly treated as PBS (control group), repaired with 1×105 hiPSC-NSCs (NSC group), and 1×105 huMSCs (MSC group), respectively, in a total of 54 mice (n = 18 each). Hind limb motor function was evaluated in open-field tests using the Basso Mouse Scale (BMS) at days post-operation (dpo) 1, 3, 5 and 7 after spinal cord injury, and weekly thereafter. Spinal cord and serum samples were harvested at dpo 7, 14 and 21. HE staining and Masson staining were used to evaluate the morphological changes and fibrosis area. The differentiation of the transplanted cells in vivo was evaluated with immunohistochemical staining. Results: The hiPSC-NSC-treated group presented a significantly smaller GFAP+ area than MSC-treated mice at all time points. Additionally, MSC-transplanted mice had a similar GFAP+ area to mice receiving PBS. At dpo14, the immunostained hiPSC-NSCs were positive for SOX2. Furthermore, the transplanted hiPSC-NSCs differentiated into glial fibrillary acidic protein (GFAP)-positive astrocytes and beta-III tubulin-positive neurons, whereas the transplanted huMSCs differentiated into GFAP-positive astrocytes. In addition, hiPSC-NSC transplantation reduced fibrosis formation and the inflammation level. Compared with the control or huMSC transplanted group, the group with transplantation of hiPSC-NSCs exhibited significantly improved behaviours, particularly limb coordination. Conclusions: HiPSC-NSCs promote functional recovery in mice with acute SCI by replacing missing neurons and attenuating fibrosis, glial scar formation, and inflammation.

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