Spinal cord repair: advances in biology and technology

Nature Medicine, Journal Year: 2019, Volume and Issue: 25(6), P. 898 - 908

Published: June 1, 2019

Language: Английский

---

The translational landscape in spinal cord injury: focus on neuroplasticity and regeneration

Nature Reviews Neurology, Journal Year: 2019, Volume and Issue: 15(12), P. 732 - 745

Published: Nov. 14, 2019

Language: Английский

---

The gut metabolite indole-3 propionate promotes nerve regeneration and repair

Nature, Journal Year: 2022, Volume and Issue: 607(7919), P. 585 - 592

Published: June 22, 2022

Language: Английский

---

The neurons that restore walking after paralysis

Nature, Journal Year: 2022, Volume and Issue: 611(7936), P. 540 - 547

Published: Nov. 9, 2022

Abstract A spinal cord injury interrupts pathways from the brain and brainstem that project to lumbar cord, leading paralysis. Here we show spatiotemporal epidural electrical stimulation (EES) of 1–3 applied during neurorehabilitation 4,5 (EES REHAB ) restored walking in nine individuals with chronic injury. This recovery involved a reduction neuronal activity humans walking. We hypothesized this unexpected reflects activity-dependent selection specific subpopulations become essential for patient walk after To identify these putative neurons, modelled technological therapeutic features underlying EES mice. single-nucleus RNA sequencing 6–9 spatial transcriptomics 10,11 cords mice chart spatially resolved molecular atlas then employed cell type 12,13 prioritization neurons single population excitatory interneurons nested within intermediate laminae emerged. Although are not required before injury, demonstrate they following Augmenting phenocopied enabled by , whereas ablating them prevented occurs spontaneously moderate thus identified recovery-organizing subpopulation is necessary sufficient regain Moreover, our methodology establishes framework using cartography produce complex behaviours.

Language: Английский

---

Therapeutic repair for spinal cord injury: combinatory approaches to address a multifaceted problem

EMBO Molecular Medicine, Journal Year: 2020, Volume and Issue: 12(3)

Published: Feb. 24, 2020

Review24 February 2020Open Access Therapeutic repair for spinal cord injury: combinatory approaches to address a multifaceted problem Jarred M Griffin Corresponding Author [email protected] orcid.org/0000-0002-3013-8057 Laboratory Axonal Growth and Regeneration, German Centre Neurodegenerative Diseases (DZNE), Bonn, Germany Search more papers by this author Frank Bradke orcid.org/0000-0002-0345-3772 Information *,1 1Laboratory *Corresponding author. Tel: +49 228 43302-590; E-mail: 43302-591; EMBO Mol Med (2020)12:e11505https://doi.org/10.15252/emmm.201911505 See the Glossary abbreviations used in article. PDFDownload PDF of article text main figures. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract The recent years saw advent promising preclinical strategies that combat devastating effects injury (SCI) are progressing towards clinical trials. However, individually, these treatments produce only modest levels recovery animal models SCI could hamper their implementation into therapeutic injured humans. Combinational have demonstrated greater beneficial outcomes than individual components alone addressing multiple aspects pathology. Clinical trial designs future will eventually also need align with notion. scenario become increasingly complex as happens conversations between basic researchers clinicians required ensure accurate study functional readouts. Allodynia A type neuropathic pain is result increased sensitivity otherwise innocuous stimuli Anterograde tracing This research method which trace axonal projections direction cell bodies point termination. complimentary technique known retrograde Autologous (transplant) transplant autologous if recipient serves donor Basso, Beattie Bresnahan (BBB) locomotor rating scale 21-point behavioural analysis assess limb motor skills over wide range severities Chondroitin sulphate proteoglycans (CSPGs) Components extracellular matrix composed protein core covalently linked chondroitin glycosaminoglycan sidechains. CSPGs inhibit axon regeneration Chondroitinase ABC (ChABC) bacterial enzyme degrades Conditioning lesion These involve lesioning peripheral branch adult sensory dorsal root ganglion neurons prior central lesion. increases regenerative capacity DRG Contusion An caused blunt trauma Corticospinal tract (CST) One most important descending tracts. It controls primary activity from cortex Dorsal (DRG) cluster nerve. pseudo-unipolar Excitotoxicity pathological process damaged or killed through overstimulation excitatory neurotransmitter receptors Functional electrical stimulation (FES) FES involves electrophysiological nerves muscle cone Is large actin supported extension at tip developing regenerating neurite/axon Induced pluripotent stem cells (iPSCs) Are generated directly expression specific transcription factors Kinematic measuring movement (kinematic) quantities describe motion Myelin-associated inhibitors CNS myelin be growth regeneration. three classic myelin-associated Nogo-A, glycoprotein oligodendrocyte Neuroplasticity Refers adaptive changes neurological function. can anatomical physiological Neuroprotection relative preservation neural tissue during ongoing secondary damage Neurorehabilitation Physical therapy aims aid nervous system and/or improve compensatory functions Neurotrophins family regulatory mediate survival, differentiation Phase I includes small number human participants determine safety new drug invasive medical device; allows determination dosage toxicity limits II larger intended evaluate efficacy treatment; side monitored Propriospinal neuron contained entirely within interconnect various Reticulospinal descends reticular formation primarily responsible locomotion postural control Retraction bulb Dystrophic structures hallmark failed response Transection surgical created fine transverse cut Introduction Through silver staining neurons, Ramon y Cajal discovered (PNS) regenerate after injury, contrasting minor (Ramon Cajal, 1928). then prompted question: Do (CNS) lack intrinsic capability there extrinsic influence dichotomous observation? In actuality, both come play when tasked axotomy. Several families molecules present (ECM) prevent including (CSPGs), molecules, ephrins semaphorins (Miranda et al, 1999; Chen 2000; Willson 2002; Silver Miller, 2004; Geoffroy Zheng, 2014; Worzfeld Offermanns, 2014). Yet even provided growth-permissive environment, feebly compared immature counterparts, indicating they limiting (Hilton Bradke, 2017). On brighter nearly 100 on Cajal's statement "in centres, nerve paths something fixed, ended, immutable; everything may die, nothing regenerated" (Ramon-Cueto 1998), we now know not true. Many groups reported experimental following variety (Thuret 2006). While certainly feat, many problematic translation. For those are, it becoming apparent singular won't facilitate successful Conversely, likely require combination treatment problems SCI. attempts been made, varying degrees success, combine replacement, removal inhibitory supplying neurotrophic factors, manipulation pro-regenerative neuronal signalling pathways neurorehabilitation. review provide an update interventions focus attempted approaches, how improved road induces processes. first leads death CNS, astrocytes, microglia, oligodendrocytes endothelial cells. particular, long interruption ascending transmit information brain rest body. Secondary vascular changes, acute signalling, neuroinflammation, excitotoxicity, demyelination, degeneration, astrogliosis ECM remodelling exacerbates initial pathology 2017; Bradbury Burnside, 2019). unfolds temporal cascade biological processes last months (Buss Norenberg Donnelly Popovich, 2008). Some degree spontaneous observed lesser extent humans (Curt 2008; Hilton 2016). endogenous mechanisms remains incomplete (Fawcett 2007; Courtine Based pathologies SCI, identified several targets development potential interventions. referred "7 R's" (Fig 1). Figure 1. seven injuryA horizontal plane view region thoracic depicting some features immediate continued alongside disruption fibres. Seven SCI: neuroprotective limit resulting spared tissue; cellular transplants replace lost trophic environments; such allow enhanced growth; targeting neuron-intrinsic enhance directed resupply support; remyelination demyelinated axons conduction. Finally, rehabilitation function circuit strengthens connections. Download figure PowerPoint Reduction (neuroprotection). 2. Replacement damage. 3. Removal molecules. 4. Regeneration reparative responses. 5. Resupply support survival direct growth. 6. Remyelination regenerated, replaced (demyelinated) axons. 7. Rehabilitation induce neuroplasticity shape We discuss respective sections. Reduction: neuroprotection Substantial efforts made Pharmacological agents suppress immune key involved inflammation were major applied patients. include non-steroidal anti-inflammatory drugs (NSAIDs), minocycline, cyclosporine corticosteroid methylprednisolone (Badhiwala 2018). use controversial since trials revealed no effect lead complications (Bowers Preclinically, indomethacin (an NSAID) led sparing slight (Simpson 1991), while minocycline reduced well outcome cervical rats (Stirling 2004). reassessment suggested harmful phase did report (Guven Casha 2012). Similar conflicting results suppressant (Chen Since neuroinflammation has detrimental effects, broad-spectrum suppression efficacious. achieved preventing glutamate excitotoxicity blockade NMDA magnesium (Ditor 2007) gacyclidine (Feldblum 2000), tetrodotoxin-sensitive sodium channels using riluzole (Satkunendrarajah 2016), apoptosis erythropoietin (Baptiste Fehlings, 2006), inhibition connexin hemichannels mimetic peptide (Mao 2017), mild moderate hypothermia (Dietrich 2009) 2006; Thuret discrete manipulations prove benefit broad approaches. Regardless, translate clinic. Stroke similar neuropathology huge efforts, particularly 1990s, develop stroke. attempts, 1,000 agents, leading 200 trials, resulted (Minnerup Worryingly, assessing reflect trend. Overall, progression often stalled, conferred understood. Improvements our understanding underpin benefits better inform application. Replacement: transplantation Cell aim replacing historic origins stretching back experiments conducted laboratory 1998). seminal works Anders Björklund colleagues showed foetal promote types Huntington's Parkinson's disease (Bjorklund Lindvall, 2000). discovery graft integration host (Bregman 1993). Likewise, Richard, David Aguayo grafts permissive conduit (Richardson 1980, 1984; Aguayo, 1981; Benfey 1982), thoroughly studied (Cote 2011a). studies critical evidence capable regenerating. propriospinal appears sprouts non-injured (Friedman 1985). Despite findings, few PNGs correlate reason remaining challenge PNS fail extend beyond distal graft–host interface where encounter environment CNS. example, improvements primates hemisection PNG (Levi 2002). Cell-based transplantations largely superseded reasons: injected fill site, less cause further graft, genetically modified ex vivo secrete (Assinck behind confers multifactorial. replacement cells, promoting synapse formation, myelination newly formed transplantation, mesenchymal (MSCs), progenitor (NPCs), Schwann olfactory ensheathing (OECs) induced (iPSCs; Assinck Each advantages disadvantages one another. MSCs NPCs typically harvested embryonic tissue, differentiate glia vitro (Liu Billon Neurons obtained survive integrate rat (Deshpande Whether occurs clear circumstances considering early investigations majority transplanted remain progenitor-like glial (Vallieres Sawchenko, 2003; Karimi-Abdolrezaee generally accepted do form (Lu NPCs, other hand, recently shown "hundreds thousands cord" (Rosenzweig 2018), regenerated appropriate domains NPC (Dulin Furthermore, host–graft synaptic network patterns paralleling normal (preprint: Ceto Aside confer substrates whereby grow (Hofstetter Lu Ankeny Injured transplant, mediated secretion itself 2003). grafts, terminate border (Ruff 2012; final consideration via paracrine actions. modulation neuroinflammatory contribute (Kokaia OECs terminally differentiated, myelinating found system, respectively. Like studies, structural (Bunge Pearse, Barnett Riddell, 2007). rodents reduce cavitation became myelinated evidenced electrophysiologically active (Xu 1995b, 1997; Pinzon 2001; Takami MSC transplants, leave distally reinnervate tissue. Recovery was (Takami 2002) but all publications (Pearse 2004a). observations witnessed OECs. After injection unilateral site corticospinal rodents, anterograde lesioned hindlimb CST extensive (Li 1997). Later, intervention respiratory climbing ability later challenged whether Other veterinary robust 1998; Li Jeffery 2005; Toft potentiated delivered together. co-delivery two potentiates long-distance around guidance what either iPSCs circumvent ethical issues associated use. (Nagoshi Okano, unclear meaningful supportive role. As case issue risk tumorigenicity. Though promisingly, marmosets, iPSC-NPCs subacute predominantly differentiated without tumorigenicity promoted regrowth angiogenesis, preserved area (Kobayashi strategy decrease addition gamma-secretase inhibitors, removes tumour-initiating promotes chronic phases (Okubo 2016, efficacious mechanisms. Considering limitations listed above, much experimentation. full any synergistic therapies. Removal: inhibiting synthesis, enzymatic degradation, antibody neutralisation pharmacological effector (Bradbury Burnside al., xylosyltransferase-1 (XT-1) crucial biosynthesis (GAG) chains CPSGs. XT-1 DNA catalytic degradation mRNA strongly CSPG-GAGs allowed microtransplanted ganglions (DRGs) column (Grimpe Silver, study, mRNA-mediated knockdown transection significantly proteoglycan length density (Hurtado replicated model contusion serotonergic innervation caudal correlated reduction errors ladder test (Oudega Enzymatic modification commonly chondroitinase (ChABC). Derived bacteria Proteus vulgaris, catalyses glycosidic bonds CS-GAGs CSPGs, liberating them CSPG (Prabhakar 2005a, 2005b). Intrathecal infusion ChABC 10 days C4 crush degraded CST-axonal scores tests Using immunohistochemical markers neuroplasticity, sprouting intact systems relay networks (Barritt delivery independent laboratories Carter, 2011). positive confirmed animals. cats hemisection, skilled kinematic measurements (Tester Howland, Importantly, dogs, seemingly modest, yet forelimb–hindlimb coordination bladder compliance long-term adverse (Hu average group differences small, 10% treated dogs recovered ambulation represent estimate "true" population heterogeneous sample size 60 (Moon Bradbury, Cervical rhesus monkeys intrathecal administration 4 weeks synapses hand vehicle-treated controls. Increasing long-lasting effects. single phrenic pool complete hemidiaphragm paralysis patterned 1.5 (Warren such, unmasking develops rapid near lifetime rats. continuous production ChABC. reason, mammalian-compatible gene engineered modifying N-glycosylation sites eukaryotic (Muir 2010). avoids repeated addresses possible risks recognition enzyme. Lentiviral vector (LV) achieve "mammalianised" (mChABC) contused large-scale (Bartus Recently, findings restoration upper developed (James 2015). immune-evasive, doxycycline Tet-on inducible LV-mChABC enabled (Burnside Such regulatable approach viable candidate There proteins affect composition therapeutically harnessed. metalloproteinases (MMPs), disintegrin metalloproteases (ADAMs) metalloproteinase thrombospondin motifs (ADAMTSs; Troeberg Nagase, MMPs, ADAMs ADAMTSs implicated role degrading knockout MMP-9 mice worsened deficit traumatic (Wang particular interest display CSPG-specific substrate recognition. ADAMTS4 intrathecally significant improvement score comparable (Tauchi More recently, astrocyte-selective AAV-ADAMTS4 decreased size, regeneration, inputs BBB error (Griffin 2020). Given profile AAV viruses (Hudry Vandenberghe, 2019), potentially safer alternative LV-ChABC therapy. Ultimately, proven consistently advantageous decades anticipate next steps taken translation CSPG-targeting Independent anti-Nogo-A antibodies GrandPre non-human primates, therapies regain (Freund 2009). Interestingly, effective enhancing (Zhao 2013). Nogo soluble Nogo-66 receptor (NgR (310) ecto-FC) complexes Nogo-A. NgR ecto-FC enhances raphespinal fibres bridge bridgi

Language: Английский

---

Regulation of axonal regeneration after mammalian spinal cord injury

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(6), P. 396 - 413

Published: Jan. 5, 2023

Language: Английский

---

Recent progress and challenges in the treatment of spinal cord injury

Protein & Cell, Journal Year: 2023, Volume and Issue: 14(9), P. 635 - 652

Published: Feb. 10, 2023

Abstract Spinal cord injury (SCI) disrupts the structural and functional connectivity between higher center spinal cord, resulting in severe motor, sensory, autonomic dysfunction with a variety of complications. The pathophysiology SCI is complicated multifaceted, thus individual treatments acting on specific aspect or process are inadequate to elicit neuronal regeneration recovery after SCI. Combinatory strategies targeting multiple aspects pathology have achieved greater beneficial effects than therapy alone. Although many problems challenges remain, encouraging outcomes that been preclinical models offer promising foothold for development novel clinical treat In this review, we characterize mechanisms underlying axon adult neurons summarize recent advances facilitating following at both acute chronic stages. addition, analyze current status, remaining problems, realistic towards translation. Finally, consider future treatment provide insights into how narrow translational gap currently exists studies practice. Going forward, trials should emphasize multidisciplinary conversation cooperation identify optimal combinatorial approaches maximize therapeutic benefit humans

Language: Английский

---

Clonally expanded, targetable, natural killer-like NKG7 T cells seed the aged spinal cord to disrupt myeloid-dependent wound healing

Neuron, Journal Year: 2025, Volume and Issue: 113(5), P. 684 - 700.e8

Published: Jan. 13, 2025

Spinal cord injury (SCI) increasingly affects aged individuals, where functional impairment and mortality are highest. However, the aging-dependent mechanisms underpinning tissue damage remain elusive. Here, we find that natural killer-like T (NKLT) cells seed intact human murine spinal multiply further after injury. NKLT accumulate in via C-X-C motif chemokine receptor 6 ligand 16 signaling to clonally expand by engaging with major histocompatibility complex (MHC)-I-expressing myeloid cells. expressing killer cell granule protein 7 (Nkg7) disrupt myeloid-cell-dependent wound healing injured cord. Nkg7 deletion mice curbs degranulation normalize phenotype, thus promoting repair axonal integrity. Monoclonal antibodies neutralizing CD8+ SCI enhance neurological recovery healing. Our results unveil a reversible role for NKG7+CD8+ exacerbating damage, suggesting clinically relevant treatment SCI.

Language: Английский

---

The Struggle to Make CNS Axons Regenerate: Why Has It Been so Difficult?

Neurochemical Research, Journal Year: 2019, Volume and Issue: 45(1), P. 144 - 158

Published: Aug. 6, 2019

Axon regeneration in the CNS is inhibited by many extrinsic and intrinsic factors. Because these act parallel, no single intervention has been sufficient to enable full of damaged axons adult mammalian CNS. In external environment, NogoA CSPGs are strongly inhibitory axons. neurons lose regenerative ability as they mature: embryonic but not mature can grow for long distances when transplanted into CNS, fails with maturity vitro axotomy models. The causes this loss include partitioning axonal dendritic fields growth-related molecules directed specifically dendrites excluded from axons, changes signalling due expression localization receptors their ligands, local translation proteins cytoskeletal dynamics after injury. Also neuronal maturation come epigenetic neurons, transcription factor binding sites that drive axon genes becoming inaccessible. overall aim successful ensure right expressed arrange them be transported place neuron, including tip.

Language: Английский

---

Self-Assembling Hydrogel Structures for Neural Tissue Repair

ACS Biomaterials Science & Engineering, Journal Year: 2021, Volume and Issue: 7(9), P. 4136 - 4163

Published: March 29, 2021

Hydrogel materials have been employed as biological scaffolds for tissue regeneration across a wide range of applications. Their versatility and biomimetic properties make them an optimal choice treating the complex delicate milieu neural damage. Aside from finely tailored hydrogel properties, which aim to mimic healthy physiological tissue, minimally invasive delivery method is essential prevent off-target surgery-related complications. The specific class injectable hydrogels termed self-assembling peptides (SAPs), provide ideal combination in situ polymerization combined with biofunctionlization, tunable physicochemical high cytocompatibility. This review identifies design criteria based upon key cellular interactions extracellular matrix (ECM), emphasis on aspects that are reproducible biomaterial environment. Examples most recent SAPs modification methods presented, focus biological, mechanical, topographical cues. Furthermore, SAP electrical appropriate electrochemical cues widely discussed, light endogenous activity well clinical effectiveness stimulation treatments. Recent applications repair therapies highlighted, identifying research gaps field regeneration.

Language: Английский

---