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Understanding Spinal Cord Injury and Repair: From Molecules to Neurocircuits...
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Understanding Spinal Cord Injury and Repair: From Molecules to Neurocircuits and Multimodal Prostheses

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: 31 January 2025 | Viewed by 10898

Special Issue Editor

Dr. Yang D. Teng

E-Mail Website
Guest Editor
Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA, USA
Interests: spinal cord injury; stem cell biology; regenerative medicine; neuroscience; traumatic brain injury; neural oncology; neurodegeneration

Special Issue Information

Dear Colleagues,

Each year, there are ~250,000 to ~500,000 clinical encounters of spinal cord injury (SCI) worldwide. Among them, the majority are traumatic, and more frequently affect young adults and the elderly. The rest of the cases consist of non-traumatic SCI. SCI often results in severe and lifelong disabilities such as sensorimotor deficits, autonomic abnormalities including cardiorespiratory disorders, and other serious complications (e.g., lower urinary tract malfunction, neuropathic pain, gastrointestinal dysfunction, osteoporosis, sexuality and reproduction health issues, and depression). A young age at injury and a large degree of functional loss produce a long-term high fiscal burden that is placed on the individual, their family, and society. Moreover, the daily life challenges for people living with SCI can never be assigned a monetary value. The need for a cure is obvious, but effective therapy for SCI has, to date, remained an unmet medical demand.

Encouragingly, impactful progress has been made since the 1990s in basic science research, translational studies, and clinical investigations of SCI. These endeavors aim to identify molecules and cell organelles as key players of post-SCI pathophysiology, neuroprotection, neurite regrowth, neuroplasticity, and neuroimmune modulation; attain stem cell biology insights to empower regenerative and recovery therapy development; unlock spinal cord neurocircuits for functional reinstatement; and establish the next generation of prostheses for functional rehabilitation. Further, a newly established cross-disciplinary research approach has enabled the field to decipher novel therapeutic targets, develop innovative theoretical frameworks, and formulate multimodal regiments to augment clinical efficacy.

In this Special Issue, we invite laboratory researchers, physician scientists, and academic physicians with expertise in SCI-related molecular and cellular biology, neurobiology, pathophysiology, bioengineering, biomechanics, the brain–computer–spinal cord interface, multiple assistive and robotic devices, pathology, neurology, neurosurgery, pain management, rehabilitation, and neuro-oncology to contribute original research articles, reviews, and communication articles on the aforementioned aspects concerning the current advancements in understanding SCI and neural repair. We particularly welcome papers that will shed mechanistic light at the molecular, cellular, neurocircuit, neuromusculoskeletal, or system biology level with strong translational potentials.

Dr. Yang D. Teng
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Published Papers (7 papers)

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Research

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15 pages, 3344 KiB  
Article
Ketone Esters Partially and Selectively Rescue Mitochondrial Bioenergetics After Acute Cervical Spinal Cord Injury in Rats: A Time-Course
by Oscar Seira, HyoJoon (David) Park, Jie Liu, Michelle Poovathukaran, Kieran Clarke, Robert Boushel and Wolfram Tetzlaff
Cells 2024, 13(21), 1746; https://doi.org/10.3390/cells13211746 - 22 Oct 2024
Viewed by 583
Abstract
Spinal cord injury (SCI) pathology and pathophysiology can be attributed to both primary physical injury and secondary injury cascades. Secondary injury cascades involve dysregulated metabolism and energetic deficits directly linked to compromised mitochondrial bioenergetics. Rescuing mitochondrial function and reducing oxidative stress are associated [...] Read more.
Spinal cord injury (SCI) pathology and pathophysiology can be attributed to both primary physical injury and secondary injury cascades. Secondary injury cascades involve dysregulated metabolism and energetic deficits directly linked to compromised mitochondrial bioenergetics. Rescuing mitochondrial function and reducing oxidative stress are associated with neuroprotection. In this regard, ketosis after traumatic brain injury (TBI), or after SCI, improves secondary neuropathology by decreasing oxidative stress, increasing antioxidants, reducing inflammation, and improving mitochondrial bioenergetics. Here, we follow up on our previous study and have used an exogenous ketone monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE), as an alternative to a ketogenic diet, focusing on mitochondrial function between 1 and 14 days after injury. Starting 3 h following a cervical level 5 (C5) hemi-contusion injury, animals were fed either a standard control diet (SD) or a ketone ester diet (KED) combined with KE administered orally (OKE). We found that mitochondrial function was reduced after SCI at all times post-SCI, accompanied by reduced expression of most of the components of the electron transport chain (ETC). The KE rescued some of the bioenergetic parameters 1 day after SCI when D-β-Hydroxybutyrate (BHB) concentrations were ~2 mM. Still, most of the beneficial effects were observed 14 days after injury, with BHB concentrations reaching values of 4–6 mM. To our knowledge, this is the first report to show the beneficial effects of KE in rescuing mitochondrial function after SCI and demonstrates the suitability of KE in ameliorating the metabolic dysregulation that occurs after traumatic SCI without requiring a restrictive dietary regime. Full article
(This article belongs to the Special Issue Understanding Spinal Cord Injury and Repair: From Molecules to Neurocircuits and Multimodal Prostheses)
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28 pages, 9988 KiB  
Article
Concurrent Oncolysis and Neurolesion Repair by Dual Gene-Engineered hNSCs in an Experimental Model of Intraspinal Cord Glioblastoma
by Xiang Zeng, Alexander E. Ropper, Zaid Aljuboori, Dou Yu, Theodore W. Teng, Serdar Kabatas, Esteban Usuga, Jamie E. Anderson and Yang D. Teng
Cells 2024, 13(18), 1522; https://doi.org/10.3390/cells13181522 - 11 Sep 2024
Viewed by 702
Abstract
Intramedullary spinal cord glioblastoma (ISCG) is lethal due to lack of effective treatment. We previously established a rat C6-ISCG model and the antitumor effect of F3.CD-TK, an hNSC line expressing CD and TK, via producing cytocidal 5FU and GCV-TP. However, the neurotherapeutic potential [...] Read more.
Intramedullary spinal cord glioblastoma (ISCG) is lethal due to lack of effective treatment. We previously established a rat C6-ISCG model and the antitumor effect of F3.CD-TK, an hNSC line expressing CD and TK, via producing cytocidal 5FU and GCV-TP. However, the neurotherapeutic potential of this hNSC approach has remained uninvestigated. Here for the first time, cultured F3.CD-TK cells were found to have a markedly higher oncolytic effect, which was GJIC-dependent, and BDNF expression but less VEGF secretion than F3.CD. In Rowett athymic rats, F3.CD-TK (1.5 × 106 cells/10 µL × 2), injected near C6-ISCG (G55 seeding 7 days earlier: 10 K/each) and followed by q.d. (×5/each repeat; i.p.) of 5FC (500 mg/kg/5 mL/day) and GCV (25 mg/kg/1 mL/day), robustly mitigated cardiorespiratory, locomotor, and sensory deficits to improve neurofunction and overall survival compared to animals receiving either F3.CD or F3.CD-TK+F3.CD debris formula. The F3.CD-TK regimen exerted greater tumor penetration and neural inflammation/immune modulation, reshaped C6-ISCG topology to increase the tumor’s surface area/volume ratio to spare/repair host axons (e.g., vGlut1+ neurites), and had higher post-prodrug donor self-clearance. The multimodal data and mechanistic leads from this proof-of-principle study suggest that the overall stronger anti-ISCG benefit of our hNSC-based GDEPT is derived from its concurrent oncolytic and neurotherapeutic effects. Full article
(This article belongs to the Special Issue Understanding Spinal Cord Injury and Repair: From Molecules to Neurocircuits and Multimodal Prostheses)
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30 pages, 7178 KiB  
Article
T12-L3 Nerve Transfer-Induced Locomotor Recovery in Rats with Thoracolumbar Contusion: Essential Roles of Sensory Input Rerouting and Central Neuroplasticity
by Dou Yu, Xiang Zeng, Zaid S. Aljuboori, Rachel Dennison, Liquan Wu, Jamie A. Anderson and Yang D. Teng
Cells 2023, 12(24), 2804; https://doi.org/10.3390/cells12242804 - 8 Dec 2023
Cited by 1 | Viewed by 1755
Abstract
Locomotor recovery after spinal cord injury (SCI) remains an unmet challenge. Nerve transfer (NT), the connection of a functional/expendable peripheral nerve to a paralyzed nerve root, has long been clinically applied, aiming to restore motor control. However, outcomes have been inconsistent, suggesting that [...] Read more.
Locomotor recovery after spinal cord injury (SCI) remains an unmet challenge. Nerve transfer (NT), the connection of a functional/expendable peripheral nerve to a paralyzed nerve root, has long been clinically applied, aiming to restore motor control. However, outcomes have been inconsistent, suggesting that NT-induced neurological reinstatement may require activation of mechanisms beyond motor axon reinnervation (our hypothesis). We previously reported that to enhance rat locomotion following T13-L1 hemisection, T12-L3 NT must be performed within timeframes optimal for sensory nerve regrowth. Here, T12-L3 NT was performed for adult female rats with subacute (7–9 days) or chronic (8 weeks) mild (SCImi: 10 g × 12.5 mm) or moderate (SCImo: 10 g × 25 mm) T13-L1 thoracolumbar contusion. For chronic injuries, T11-12 implantation of adult hMSCs (1-week before NT), post-NT intramuscular delivery of FGF2, and environmentally enriched/enlarged (EEE) housing were provided. NT, not control procedures, qualitatively improved locomotion in both SCImi groups and animals with subacute SCImo. However, delayed NT did not produce neurological scale upgrading conversion for SCImo rats. Ablation of the T12 ventral/motor or dorsal/sensory root determined that the T12-L3 sensory input played a key role in hindlimb reanimation. Pharmacological, electrophysiological, and trans-synaptic tracing assays revealed that NT strengthened integrity of the propriospinal network, serotonergic neuromodulation, and the neuromuscular junction. Besides key outcomes of thoracolumbar contusion modeling, the data provides the first evidence that mixed NT-induced locomotor efficacy may rely pivotally on sensory rerouting and pro-repair neuroplasticity to reactivate neurocircuits/central pattern generators. The finding describes a novel neurobiology mechanism underlying NT, which can be targeted for development of innovative neurotization therapies. Full article
(This article belongs to the Special Issue Understanding Spinal Cord Injury and Repair: From Molecules to Neurocircuits and Multimodal Prostheses)
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Review

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17 pages, 2133 KiB  
Review
Novel Technologies to Address the Lower Motor Neuron Injury and Augment Reconstruction in Spinal Cord Injury
by Stanley F. Bazarek, Matthias J. Krenn, Sameer B. Shah, Ross M. Mandeville and Justin M. Brown
Cells 2024, 13(14), 1231; https://doi.org/10.3390/cells13141231 - 22 Jul 2024
Viewed by 1627
Abstract
Lower motor neuron (LMN) damage results in denervation of the associated muscle targets and is a significant yet under-appreciated component of spinal cord injury (SCI). Denervated muscle undergoes a progressive degeneration and fibro-fatty infiltration that eventually renders the muscle non-viable unless reinnervated within [...] Read more.
Lower motor neuron (LMN) damage results in denervation of the associated muscle targets and is a significant yet under-appreciated component of spinal cord injury (SCI). Denervated muscle undergoes a progressive degeneration and fibro-fatty infiltration that eventually renders the muscle non-viable unless reinnervated within a limited time window. The distal nerve deprived of axons also undergoes degeneration and fibrosis making it less receptive to axons. In this review, we describe the LMN injury associated with SCI and its clinical consequences. The process of degeneration of the muscle and nerve is broken down into the primary components of the neuromuscular circuit and reviewed, including the nerve and Schwann cells, the neuromuscular junction, and the muscle. Finally, we discuss three promising strategies to reverse denervation atrophy. These include providing surrogate axons from local sources; introducing stem cell-derived spinal motor neurons into the nerve to provide the missing axons; and finally, instituting a training program of high-energy electrical stimulation to directly rehabilitate these muscles. Successful interventions for denervation atrophy would significantly expand reconstructive options for cervical SCI and could be transformative for the predominantly LMN injuries of the conus medullaris and cauda equina. Full article
(This article belongs to the Special Issue Understanding Spinal Cord Injury and Repair: From Molecules to Neurocircuits and Multimodal Prostheses)
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29 pages, 1804 KiB  
Review
Molars to Medicine: A Focused Review on the Pre-Clinical Investigation and Treatment of Secondary Degeneration following Spinal Cord Injury Using Dental Stem Cells
by Sandra Jenkner, Jillian Mary Clark, Stan Gronthos and Ryan Louis O’Hare Doig
Cells 2024, 13(10), 817; https://doi.org/10.3390/cells13100817 - 10 May 2024
Viewed by 1215
Abstract
Spinal cord injury (SCI) can result in the permanent loss of mobility, sensation, and autonomic function. Secondary degeneration after SCI both initiates and propagates a hostile microenvironment that is resistant to natural repair mechanisms. Consequently, exogenous stem cells have been investigated as a [...] Read more.
Spinal cord injury (SCI) can result in the permanent loss of mobility, sensation, and autonomic function. Secondary degeneration after SCI both initiates and propagates a hostile microenvironment that is resistant to natural repair mechanisms. Consequently, exogenous stem cells have been investigated as a potential therapy for repairing and recovering damaged cells after SCI and other CNS disorders. This focused review highlights the contributions of mesenchymal (MSCs) and dental stem cells (DSCs) in attenuating various secondary injury sequelae through paracrine and cell-to-cell communication mechanisms following SCI and other types of neurotrauma. These mechanistic events include vascular dysfunction, oxidative stress, excitotoxicity, apoptosis and cell loss, neuroinflammation, and structural deficits. The review of studies that directly compare MSC and DSC capabilities also reveals the superior capabilities of DSC in reducing the effects of secondary injury and promoting a favorable microenvironment conducive to repair and regeneration. This review concludes with a discussion of the current limitations and proposes improvements in the future assessment of stem cell therapy through the reporting of the effects of DSC viability and DSC efficacy in attenuating secondary damage after SCI. Full article
(This article belongs to the Special Issue Understanding Spinal Cord Injury and Repair: From Molecules to Neurocircuits and Multimodal Prostheses)
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16 pages, 351 KiB  
Review
The Translation of Nanomedicines in the Contexts of Spinal Cord Injury and Repair
by Wenqian Wang, Joel Yong, Paul Marciano, Ryan O’Hare Doig, Guangzhao Mao and Jillian Clark
Cells 2024, 13(7), 569; https://doi.org/10.3390/cells13070569 - 24 Mar 2024
Viewed by 2501
Abstract
Purpose of this review: Manipulating or re-engineering the damaged human spinal cord to achieve neuro-recovery is one of the foremost challenges of modern science. Addressing the restricted permission of neural cells and topographically organised neural tissue for self-renewal and spontaneous regeneration, respectively, is [...] Read more.
Purpose of this review: Manipulating or re-engineering the damaged human spinal cord to achieve neuro-recovery is one of the foremost challenges of modern science. Addressing the restricted permission of neural cells and topographically organised neural tissue for self-renewal and spontaneous regeneration, respectively, is not straightforward, as exemplified by rare instances of translational success. This review assembles an understanding of advances in nanomedicine for spinal cord injury (SCI) and related clinical indications of relevance to attempts to design, engineer, and target nanotechnologies to multiple molecular networks. Recent findings: Recent research provides a new understanding of the health benefits and regulatory landscape of nanomedicines based on a background of advances in mRNA-based nanocarrier vaccines and quantum dot-based optical imaging. In relation to spinal cord pathology, the extant literature details promising advances in nanoneuropharmacology and regenerative medicine that inform the present understanding of the nanoparticle (NP) biocompatibility–neurotoxicity relationship. In this review, the conceptual bases of nanotechnology and nanomaterial chemistry covering organic and inorganic particles of sizes generally less than 100 nm in diameter will be addressed. Regarding the centrally active nanotechnologies selected for this review, attention is paid to NP physico-chemistry, functionalisation, delivery, biocompatibility, biodistribution, toxicology, and key molecular targets and biological effects intrinsic to and beyond the spinal cord parenchyma. Summary: The advance of nanotechnologies for the treatment of refractory spinal cord pathologies requires an in-depth understanding of neurobiological and topographical principles and a consideration of additional complexities involving the research’s translational and regulatory landscapes. Full article
(This article belongs to the Special Issue Understanding Spinal Cord Injury and Repair: From Molecules to Neurocircuits and Multimodal Prostheses)
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28 pages, 1030 KiB  
Review
Do Pharmacological Treatments Act in Collaboration with Rehabilitation in Spinal Cord Injury Treatment? A Review of Preclinical Studies
by Syoichi Tashiro, Shinsuke Shibata, Narihito Nagoshi, Liang Zhang, Shin Yamada, Tetsuya Tsuji, Masaya Nakamura and Hideyuki Okano
Cells 2024, 13(5), 412; https://doi.org/10.3390/cells13050412 - 27 Feb 2024
Cited by 1 | Viewed by 1522
Abstract
There is no choice other than rehabilitation as a practical medical treatment to restore impairments or improve activities after acute treatment in people with spinal cord injury (SCI); however, the effect is unremarkable. Therefore, researchers have been seeking effective pharmacological treatments. These will, [...] Read more.
There is no choice other than rehabilitation as a practical medical treatment to restore impairments or improve activities after acute treatment in people with spinal cord injury (SCI); however, the effect is unremarkable. Therefore, researchers have been seeking effective pharmacological treatments. These will, hopefully, exert a greater effect when combined with rehabilitation. However, no review has specifically summarized the combinatorial effects of rehabilitation with various medical agents. In the current review, which included 43 articles, we summarized the combinatorial effects according to the properties of the medical agents, namely neuromodulation, neurotrophic factors, counteraction to inhibitory factors, and others. The recovery processes promoted by rehabilitation include the regeneration of tracts, neuroprotection, scar tissue reorganization, plasticity of spinal circuits, microenvironmental change in the spinal cord, and enforcement of the musculoskeletal system, which are additive, complementary, or even synergistic with medication in many cases. However, there are some cases that lack interaction or even demonstrate competition between medication and rehabilitation. A large fraction of the combinatorial mechanisms remains to be elucidated, and very few studies have investigated complex combinations of these agents or targeted chronically injured spinal cords. Full article
(This article belongs to the Special Issue Understanding Spinal Cord Injury and Repair: From Molecules to Neurocircuits and Multimodal Prostheses)
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