NT3-chitosan enables de novo regeneration and functional recovery in monkeys after spinal cord injury

Spinal cord injury (SCI) often leads to permanent loss of motor, sensory, and autonomic functions. We have previously shown that neurotrophin3 (NT3)-loaded chitosan biodegradable material allowed for prolonged slow release of NT3 for 14 weeks under physiological conditions. Here we report that NT3-loaded chitosan, when inserted into a 1-cm gap of hemisectioned and excised adult rhesus monkey thoracic spinal cord, elicited robust axonal regeneration. Labeling of cortical motor neurons indicated motor axons in the corticospinal tract not only entered the injury site within the biomaterial but also grew across the 1-cm-long lesion area and into the distal spinal cord. Through a combination of magnetic resonance diffusion tensor imaging, functional MRI, electrophysiology, and kinematics-based quantitative walking behavioral analyses, we demonstrated that NT3-chitosan enabled robust neural regeneration accompanied by motor and sensory functional recovery. Given that monkeys and humans share similar genetics and physiology, our method is likely translatable to human SCI repair.

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Sonic Hedgehog modulates the inflammatory response and improves functional recovery after spinal cord injury in a thoracic contusion–compression model

European Spine Journal ◽

10.1007/s00586-021-06796-2 ◽

2021 ◽

Author(s):

Hao Zhang ◽

Alexander Younsi ◽

Guoli Zheng ◽

Mohamed Tail ◽

Anna-Kathrin Harms ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Sonic Hedgehog ◽

Functional Recovery ◽

Intrathecal Administration ◽

Neuroprotective Effects ◽

Thoracic Spinal Cord ◽

Shh Pathway ◽

Thoracic Spinal ◽

Cord Injury

Abstract Purpose The Sonic Hedgehog (Shh) pathway has been associated with a protective role after injury to the central nervous system (CNS). We, therefore, investigated the effects of intrathecal Shh-administration in the subacute phase after thoracic spinal cord injury (SCI) on secondary injury processes in rats. Methods Twenty-one Wistar rats were subjected to thoracic clip-contusion/compression SCI at T9. Animals were randomized into three treatment groups (Shh, Vehicle, Sham). Seven days after SCI, osmotic pumps were implanted for seven-day continuous intrathecal administration of Shh. Basso, Beattie and Bresnahan (BBB) score, Gridwalk test and bodyweight were weekly assessed. Animals were sacrificed six weeks after SCI and immunohistological analyses were conducted. The results were compared between groups and statistical analysis was performed (p < 0.05 was considered significant). Results The intrathecal administration of Shh led to significantly increased polarization of macrophages toward the anti-inflammatory M2-phenotype, significantly decreased T-lymphocytic invasion and significantly reduced resident microglia six weeks after the injury. Reactive astrogliosis was also significantly reduced while changes in size of the posttraumatic cyst as well as the overall macrophagic infiltration, although reduced, remained insignificant. Finally, with the administration of Shh, gain of bodyweight (216.6 ± 3.65 g vs. 230.4 ± 5.477 g; p = 0.0111) and BBB score (8.2 ± 0.2 vs. 5.9 ± 0.7 points; p = 0.0365) were significantly improved compared to untreated animals six weeks after SCI as well. Conclusion Intrathecal Shh-administration showed neuroprotective effects with attenuated neuroinflammation, reduced astrogliosis and improved functional recovery six weeks after severe contusion/compression SCI.

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B-RAFV600E Inhibitor Dabrafenib Attenuates RIPK3-Mediated Necroptosis and Promotes Functional Recovery after Spinal Cord Injury

Cells ◽

10.3390/cells8121582 ◽

2019 ◽

Vol 8 (12) ◽

pp. 1582 ◽

Cited By ~ 2

Author(s):

Takehiro Sugaya ◽

Haruo Kanno ◽

Michiharu Matsuda ◽

Kyoichi Handa ◽

Satoshi Tateda ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Functional Recovery ◽

Tissue Damage ◽

Neuroprotective Effect ◽

Neural Tissue ◽

Injured Spinal Cord ◽

Thoracic Spinal Cord ◽

Thoracic Spinal ◽

Cord Injury

The receptor-interacting protein kinase 3 (RIPK3) is a key regulator of necroptosis and is involved in various pathologies of human diseases. We previously reported that RIPK3 expression is upregulated in various neural cells at the lesions and necroptosis contributed to secondary neural tissue damage after spinal cord injury (SCI). Interestingly, recent studies have shown that the B-RAFV600E inhibitor dabrafenib has a function to selectively inhibit RIPK3 and prevents necroptosis in various disease models. In the present study, using a mouse model of thoracic spinal cord contusion injury, we demonstrate that dabrafenib administration in the acute phase significantly inhibites RIPK3-mediated necroptosis in the injured spinal cord. The administration of dabrafenib attenuated secondary neural tissue damage, such as demyelination, neuronal loss, and axonal damage, following SCI. Importantly, the neuroprotective effect of dabrafenib dramatically improved the recovery of locomotor and sensory functions after SCI. Furthermore, the electrophysiological assessment of the injured spinal cord objectively confirmed that the functional recovery was enhanced by dabrafenib. These findings suggest that the B-RAFV600E inhibitor dabrafenib attenuates RIPK3-mediated necroptosis to provide a neuroprotective effect and promotes functional recovery after SCI. The administration of dabrafenib may be a novel therapeutic strategy for treating patients with SCI in the future.

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Reduced Field of View Diffusion Tensor Imaging and Fiber Tractography of the Pediatric Cervical and Thoracic Spinal Cord Injury

Journal of Neurotrauma ◽

10.1089/neu.2017.5174 ◽

2018 ◽

Vol 35 (3) ◽

pp. 452-460 ◽

Cited By ~ 6

Author(s):

Mahdi Alizadeh ◽

Joshua Fisher ◽

Sona Saksena ◽

Yusra Sultan ◽

Chris J. Conklin ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Diffusion Tensor Imaging ◽

Diffusion Tensor ◽

Field Of View ◽

Fiber Tractography ◽

Thoracic Spinal Cord ◽

Thoracic Spinal ◽

Cord Injury

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Rolipram promotes functional recovery after contusive thoracic spinal cord injury in rats

Behavioural Brain Research ◽

10.1016/j.bbr.2012.12.056 ◽

2013 ◽

Vol 243 ◽

pp. 66-73 ◽

Cited By ~ 27

Author(s):

Luís M. Costa ◽

José E. Pereira ◽

Vítor M. Filipe ◽

Luís G. Magalhães ◽

Pedro A. Couto ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Functional Recovery ◽

Thoracic Spinal Cord ◽

Thoracic Spinal ◽

Cord Injury

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NT3-chitosan elicits robust endogenous neurogenesis to enable functional recovery after spinal cord injury

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1510194112 ◽

2015 ◽

Vol 112 (43) ◽

pp. 13354-13359 ◽

Cited By ~ 85

Author(s):

Zhaoyang Yang ◽

Aifeng Zhang ◽

Hongmei Duan ◽

Sa Zhang ◽

Peng Hao ◽

...

Keyword(s):

Neural Networks ◽

Spinal Cord ◽

Spinal Cord Injury ◽

Neural Regeneration ◽

Cns Injury ◽

Behavioral Recovery ◽

Thoracic Spinal Cord ◽

Thoracic Spinal ◽

Cord Injury ◽

Novel Strategy

Neural stem cells (NSCs) in the adult mammalian central nervous system (CNS) hold the key to neural regeneration through proper activation, differentiation, and maturation, to establish nascent neural networks, which can be integrated into damaged neural circuits to repair function. However, the CNS injury microenvironment is often inhibitory and inflammatory, limiting the ability of activated NSCs to differentiate into neurons and form nascent circuits. Here we report that neurotrophin-3 (NT3)-coupled chitosan biomaterial, when inserted into a 5-mm gap of completely transected and excised rat thoracic spinal cord, elicited robust activation of endogenous NSCs in the injured spinal cord. Through slow release of NT3, the biomaterial attracted NSCs to migrate into the lesion area, differentiate into neurons, and form functional neural networks, which interconnected severed ascending and descending axons, resulting in sensory and motor behavioral recovery. Our study suggests that enhancing endogenous neurogenesis could be a novel strategy for treatment of spinal cord injury.

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Neurological and functional recovery after thoracic spinal cord injury

Journal of Spinal Cord Medicine ◽

10.1179/2045772314y.0000000280 ◽

2014 ◽

Vol 39 (1) ◽

pp. 67-76 ◽

Cited By ~ 25

Author(s):

Brian A. Lee ◽

Benjamin E. Leiby ◽

Ralph J. Marino

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Functional Recovery ◽

Thoracic Spinal Cord ◽

Thoracic Spinal ◽

Cord Injury

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Effect of thoracic spinal cord injury on forelimb somatosensory evoked potential

Brain Research Bulletin ◽

10.1016/j.brainresbull.2021.05.005 ◽

2021 ◽

Author(s):

Angelo H. All ◽

Shiyu Luo ◽

Xiaogang Liu ◽

Hasan Al-Nashash

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Evoked Potential ◽

Somatosensory Evoked Potential ◽

Thoracic Spinal Cord ◽

Thoracic Spinal ◽

Cord Injury

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CD157 in bone marrow mesenchymal stem cells mediates mitochondrial production and transfer to improve neuronal apoptosis and functional recovery after spinal cord injury

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02305-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jing Li ◽

Heyangzi Li ◽

Simin Cai ◽

Shi Bai ◽

Huabo Cai ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Bone Marrow ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Motor Neurons ◽

Functional Recovery ◽

Mitochondrial Transfer ◽

Cord Injury ◽

Marrow Mesenchymal Stem Cells

Abstract Background Recent studies demonstrated that autologous mitochondria derived from bone marrow mesenchymal stem cells (BMSCs) might be valuable in the treatment of spinal cord injury (SCI). However, the mechanisms of mitochondrial transfer from BMSCs to injured neurons are not fully understood. Methods We modified BMSCs by CD157, a cell surface molecule as a potential regulator mitochondria transfer, then transplanted to SCI rats and co-cultured with OGD injured VSC4.1 motor neuron. We detected extracellular mitochondrial particles derived from BMSCs by transmission electron microscope and measured the CD157/cyclic ADP-ribose signaling pathway-related protein expression by immunohistochemistry and Western blotting assay. The CD157 ADPR-cyclase activity and Fluo-4 AM was used to detect the Ca2+ signal. All data were expressed as mean ± SEM. Statistical analysis was analyzed by GraphPad Prism 6 software. Unpaired t-test was used for the analysis of two groups. Multiple comparisons were evaluated by one-way ANOVA or two-way ANOVA. Results CD157 on BMSCs was upregulated when co-cultured with injured VSC4.1 motor neurons. Upregulation of CD157 on BMSCs could raise the transfer extracellular mitochondria particles to VSC4.1 motor neurons, gradually regenerate the axon of VSC4.1 motor neuron and reduce the cell apoptosis. Transplantation of CD157-modified BMSCs at the injured sites could significantly improve the functional recovery, axon regeneration, and neuron apoptosis in SCI rats. The level of Ca2+ in CD157-modified BMSCs dramatically increased when objected to high concentration cADPR, ATP content, and MMP of BMSCs also increased. Conclusion The present results suggested that CD157 can regulate the production and transfer of BMSC-derived extracellular mitochondrial particles, enriching the mechanism of the extracellular mitochondrial transfer in BMSCs transplantation and providing a novel strategy to improve the stem cell treatment on SCI.

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