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Wood RL, Calvo PM, McCallum WM, English AW, Alvarez FJ. GABA and Glycine Synaptic Release on Axotomized Motoneuron Cell Bodies Promotes Motor Axon Regeneration. Eur J Neurosci 2025; 61:e70045. [PMID: 40068993 DOI: 10.1111/ejn.70045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 02/12/2025] [Accepted: 02/19/2025] [Indexed: 03/15/2025]
Abstract
Motor axon regeneration after traumatic nerve injuries is a slow process that adversely influences patient outcomes because muscle reinnervation delays result in irreversible muscle atrophy and suboptimal axon regeneration. This advocates for investigating methods to accelerate motor axon growth. Electrical nerve stimulation and exercise both enhance motor axon regeneration in rodents and patients, but these interventions cannot always be easily implemented. A roadblock to uncover novel therapeutic approaches based on the effects of activity is the lack of understanding of the synaptic drives responsible for activity-mediated facilitation of axon regeneration. We hypothesized that the relevant excitatory inputs facilitating axon regrowth originate in GABA/glycine synapses, which become depolarizing after downregulation of the potassium chloride cotransporter 2 in motoneurons following axotomy. To test this, we injected tetanus toxin (TeTx) into the tibialis anterior (TA) muscle of mice to block the release of GABA/glycine specifically onto TA motoneurons. Thereafter, we axotomized all sciatic motoneurons by nerve crush and analyzed the time courses of muscle reinnervation in TeTx-treated (TA) and untreated (lateral gastrocnemius [LG]) motoneurons. Muscle reinnervation was slower in TA motoneurons with blocked GABA/glycine synapses, as measured by recovery of M responses and anatomical reinnervation of neuromuscular junctions. Post hoc immunohistochemistry confirmed the removal of the vesicle-associated membrane proteins 1 and 2 by TeTx activity, specifically from inhibitory synapses. These proteins are necessary for the exocytotic release of neurotransmitters. Therefore, we conclude that GABA/glycine neurotransmission on regenerating motoneurons facilitates axon growth and muscle reinnervation, and we discuss possible interventions to modulate these inputs on regenerating motoneurons.
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Affiliation(s)
- Ryan L Wood
- Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Paula M Calvo
- Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - William M McCallum
- Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Arthur W English
- Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Francisco J Alvarez
- Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, USA
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2
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Shamsnia HS, Peyrovinasab A, Amirlou D, Sirouskabiri S, Rostamian F, Basiri N, Shalmani LM, Hashemi M, Hushmandi K, Abdolghaffari AH. BDNF-TrkB Signaling Pathway in Spinal Cord Injury: Insights and Implications. Mol Neurobiol 2025; 62:1904-1944. [PMID: 39046702 DOI: 10.1007/s12035-024-04381-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 07/18/2024] [Indexed: 07/25/2024]
Abstract
Spinal cord injury (SCI) is a neurodegenerative disorder that has critical impact on patient's life expectance and life span, and this disorder also leads to negative socioeconomic features. SCI is defined as a firm collision to the spinal cord which leads to the fracture and the dislocation of vertebrae. The current available treatment is surgery. However, it cannot fully treat SCI, and many consequences remain after the surgery. Accordingly, finding new therapeutics is critical. BDNF-TrkB signaling is a vital signaling in neuronal differentiation, survival, overgrowth, synaptic plasticity, etc. Hence, many studies evaluate its impact on various neurodegenerative disorders. There are several studies evaluating this signaling in SCI, and they show promising outcomes. It was shown that various exercises, chemical interventions, etc. had significant positive impact on SCI by affecting BDNF-TrkB signaling pathway. This study aims to accumulate and evaluate these data and inspect whether this signaling is effective or not.
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Affiliation(s)
- Hedieh Sadat Shamsnia
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, No. 99, Yakhchal, Gholhak, Shariati St, P. O. Box: 19419-33111, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Amirreza Peyrovinasab
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, No. 99, Yakhchal, Gholhak, Shariati St, P. O. Box: 19419-33111, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Dorsa Amirlou
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, No. 99, Yakhchal, Gholhak, Shariati St, P. O. Box: 19419-33111, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Shirin Sirouskabiri
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, No. 99, Yakhchal, Gholhak, Shariati St, P. O. Box: 19419-33111, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Fatemeh Rostamian
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, No. 99, Yakhchal, Gholhak, Shariati St, P. O. Box: 19419-33111, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nasim Basiri
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, No. 99, Yakhchal, Gholhak, Shariati St, P. O. Box: 19419-33111, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Leila Mohaghegh Shalmani
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, No. 99, Yakhchal, Gholhak, Shariati St, P. O. Box: 19419-33111, Tehran, Iran.
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
| | - Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | | | - Amir Hossein Abdolghaffari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, No. 99, Yakhchal, Gholhak, Shariati St, P. O. Box: 19419-33111, Tehran, Iran.
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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Urbin MA. Adaptation in the spinal cord after stroke: Implications for restoring cortical control over the final common pathway. J Physiol 2025; 603:685-721. [PMID: 38787922 DOI: 10.1113/jp285563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 04/29/2024] [Indexed: 05/26/2024] Open
Abstract
Control of voluntary movement is predicated on integration between circuits in the brain and spinal cord. Although damage is often restricted to supraspinal or spinal circuits in cases of neurological injury, both spinal motor neurons and axons linking these cells to the cortical origins of descending motor commands begin showing changes soon after the brain is injured by stroke. The concept of 'transneuronal degeneration' is not new and has been documented in histological, imaging and electrophysiological studies dating back over a century. Taken together, evidence from these studies comports more with a system attempting to survive rather than one passively surrendering to degeneration. There tends to be at least some preservation of fibres at the brainstem origin and along the spinal course of the descending white matter tracts, even in severe cases. Myelin-associated proteins are observed in the spinal cord years after stroke onset. Spinal motor neurons remain morphometrically unaltered. Skeletal muscle fibres once innervated by neurons that lose their source of trophic input receive collaterals from adjacent neurons, causing spinal motor units to consolidate and increase in size. Although some level of excitability within the distributed brain network mediating voluntary movement is needed to facilitate recovery, minimal structural connectivity between cortical and spinal motor neurons can support meaningful distal limb function. Restoring access to the final common pathway via the descending input that remains in the spinal cord therefore represents a viable target for directed plasticity, particularly in light of recent advances in rehabilitation medicine.
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Affiliation(s)
- Michael A Urbin
- Human Engineering Research Laboratories, VA RR&D Center of Excellence, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA
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Fregnan F, Muratori L, Crosio A, Zen F, Fiori C, Tonazzini I, Gambarotta G, Martinelli A, Meziere J, Raimondo S, Manfredi M, Scaccini L, Geuna S, Porpiglia F. A novel rat model for studying bilateral cavernous nerve damage in vivo: exploring the potential of chitosan-blended membranes for nerve regeneration post-radical prostatectomy. Minerva Urol Nephrol 2025; 77:91-110. [PMID: 40183186 DOI: 10.23736/s2724-6051.25.06169-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
Abstract
BACKGROUND The primary treatment for localized prostate cancer involves radical prostatectomy (RP) often resulting in iatrogenic damage to the periprostatic neurovascular bundles (NVB), leading to erectile dysfunction. The current study devised an experimental model involving bilateral cavernous nerve (CN) lesions in rats to replicate nerve damage close to the injury of the NVB in humans following radical prostatectomy. METHODS Fifteen adult male Wistar rats were divided as follows: control rats without surgery (CTRL group); rats underwent bilateral resection of 2 mm of CN repaired with a glycerol-blended chitosan membranes (CS-MEM group); rats underwent a total resection of both CN and major pelvic ganglion (RES group). Two months after surgery, membranes with regenerated nerves were analyzed morphologically, and for gene and protein expression for the evaluation of nerve regeneration and vascularization. Rat penises were assessed for smooth muscle content, morphology, and tissue arrangement. Primary sensory neuron cultures and DRG explants were cultured on micro-grooved chitosan-blended membranes, to evaluate axonal orientation on different topographies. RESULTS Regenerated nerve fibers and newly formed vessels colonized the whole CS-membrane. The regenerative process was also confirmed by gene and protein expression analyses. The target organ exhibited remodeling of smooth muscle tissue around sinusoidal spaces, indicating potential restoration of cavernous tissue. The quantitative analyses of α-actin smooth muscle (α-SMA) expression in CS-MEM groups displayed α-SMA protein signals comparable to controls. In-vitro experiments on micro-patterned membranes displayed oriented axonal growth, showing valuable insights into the ways in which topographical features can be considered for a more effective performance in vivo. CONCLUSIONS Chitosan-blended membranes promote nerve fiber regeneration in an in-vivo model of nerve lesion that resembles the damage to the NVB occurring in men after radical prostatectomy. These results highlight the promising potential of this device in the clinical urological field, thus suggesting that the application of orientated micro-patterned membranes could further improve nerve regeneration.
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Affiliation(s)
- Federica Fregnan
- Department of Clinical and Biological Sciences, Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Orbassano, Turin, Italy
| | - Luisa Muratori
- Department of Clinical and Biological Sciences, Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Orbassano, Turin, Italy -
| | - Alessandro Crosio
- Unit of UOC Traumatology-Reconstructive Microsurgery, Department of Orthopedics and Traumatology, CTO Hospital, Turin, Italy
| | - Federica Zen
- Department of Clinical and Biological Sciences, Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Orbassano, Turin, Italy
| | - Cristian Fiori
- Division of Urology, Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Turin, Italy
| | - Ilaria Tonazzini
- NEST (National Enterprise for nanoScience and nanoTechnology), Istituto Nanoscienze-CNR and Scuola Normale Superiore, Pisa, Italy
| | - Giovanna Gambarotta
- Department of Clinical and Biological Sciences, Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Orbassano, Turin, Italy
| | - Antonello Martinelli
- Department of Clinical and Biological Sciences, Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Orbassano, Turin, Italy
| | - Juliette Meziere
- Department of Urology, Santa Croce e Carle Hospital, Cuneo, Italy
| | - Stefania Raimondo
- Department of Clinical and Biological Sciences, Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Orbassano, Turin, Italy
| | - Matteo Manfredi
- Division of Urology, Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Turin, Italy
| | - Luca Scaccini
- NEST (National Enterprise for nanoScience and nanoTechnology), Istituto Nanoscienze-CNR and Scuola Normale Superiore, Pisa, Italy
| | - Stefano Geuna
- Department of Clinical and Biological Sciences, Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Orbassano, Turin, Italy
| | - Francesco Porpiglia
- Division of Urology, Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Turin, Italy
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Ji S, Chen D, Ding F, Gu X, Xue Q, Zhou C, Cao M, Yu S. Salidroside exerts neuroprotective effects on retrograde neuronal death following neonatal axotomy via activation of PI3K/Akt pathway and deactivation of p38 MAPK pathway. Toxicol Appl Pharmacol 2025; 494:117178. [PMID: 39617258 DOI: 10.1016/j.taap.2024.117178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 11/26/2024] [Accepted: 11/26/2024] [Indexed: 12/15/2024]
Abstract
Salidroside, a glucoside of tyrosol, is a powerful active ingredient extracted from the Chinese herb medicine Rhodiola rosea L.. As a neuroprotective agent, the application of salidroside in combination with neural tissue engineering has recently attracted much attention in peripheral nerve repair and reconstruction. However, the cellular and molecular mechanisms by which salidroside promotes nerve regeneration remain to be elucidated. We aim to evaluate the long-term neuroprotective potential of salidroside in an experimental rat model of neonatal sciatic nerve crush injury, with a focus on target-deprived neuronal death and the mechanisms involved. Behavioral analysis showed that salidroside dose-dependently improved voluntary hindlimb behavior and rod rotation ability following neonatal axotomy during an 8-week observation period. According to electrophysiology, Fluoro-Gold retrograde tracing, histological and immunohistochemical analyses, salidroside significantly improved nerve regeneration and reinnervation. Nissle and TUNEL staining, as well as caspase-3 activation assay indicated a beneficial effect of salidroside on retrograde loss and apoptosis of motoneurons within 2 weeks after axotomy. qPCR, ELISA and oxidative stress experiments revealed that salidroside improved the imbalance of spinal microenvironment, including oxidative stress and down-regulation of neurotrophic factors. Western blotting analysis showed that salidroside enhanced the activation of PI3K/Akt and inhibited the p38 MAPK signaling pathway following axotomy. The oxidative stress and axonal disconnection/regeneration models of primary motoneurons in vitro further confirmed the involvement of these two pathways in the neuroprotective effects of salidroside. These data provide a theoretical basis for the application of salidroside in peripheral nerve repair and reconstruction.
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Affiliation(s)
- Shengtao Ji
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Department of Neurology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong University, Nantong, China
| | - Daiyue Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Department of Neurology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong University, Nantong, China
| | - Fei Ding
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Department of Neurology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong University, Nantong, China
| | - Xiaosong Gu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Department of Neurology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong University, Nantong, China
| | - Qiu Xue
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Department of Neurology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong University, Nantong, China; Department of General Surgery, Nantong Tumor Hospital, Nantong Fifth People's Hospital, Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Chun Zhou
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Department of Neurology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong University, Nantong, China.
| | - Maohong Cao
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Department of Neurology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong University, Nantong, China.
| | - Shu Yu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Department of Neurology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong University, Nantong, China.
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Balbinot G, Milosevic M, Morshead CM, Iwasa SN, Zariffa J, Milosevic L, Valiante TA, Hoffer JA, Popovic MR. The mechanisms of electrical neuromodulation. J Physiol 2025; 603:247-284. [PMID: 39740777 DOI: 10.1113/jp286205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Accepted: 11/20/2024] [Indexed: 01/02/2025] Open
Abstract
The central and peripheral nervous systems are specialized to conduct electrical currents that underlie behaviour. When this multidimensional electrical system is disrupted by degeneration, damage, or disuse, externally applied electrical currents may act to modulate neural structures and provide therapeutic benefit. The administration of electrical stimulation can exert precise and multi-faceted effects at cellular, circuit and systems levels to restore or enhance the functionality of the central nervous system by providing an access route to target specific cells, fibres of passage, neurotransmitter systems, and/or afferent/efferent communication to enable positive changes in behaviour. Here we examine the neural mechanisms that are thought to underlie the therapeutic effects seen with current neuromodulation technologies. To gain further insights into the mechanisms associated with electrical stimulation, we summarize recent findings from genetic dissection studies conducted in animal models. KEY POINTS: Electricity is everywhere around us and is essential for how our nerves communicate within our bodies. When nerves are damaged or not working properly, using exogenous electricity can help improve their function at distinct levels - inside individual cells, within neural circuits, and across entire systems. This method can be tailored to target specific types of cells, nerve fibres, neurotransmitters and communication pathways, offering significant therapeutic potential. This overview explains how exogenous electricity affects nerve function and its potential benefits, based on research in animal studies. Understanding these effects is important because electrical neuromodulation plays a key role in medical treatments for neurological conditions.
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Affiliation(s)
- Gustavo Balbinot
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
- Institute for Neuroscience and Neurotechnology, Simon Fraser University, Burnaby, BC, Canada
- Center for Advancing Neurotechnological Innovation to Application - CRANIA, University Health Network, Toronto, ON, Canada
| | - Matija Milosevic
- The Miami Project to Cure Paralysis, University of Miami, Miami, FL, USA
- Department of Neurological Surgery, University of Miami, Miami, FL, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL, USA
| | - Cindi M Morshead
- Center for Advancing Neurotechnological Innovation to Application - CRANIA, University Health Network, Toronto, ON, Canada
- KITE Research Institute - University Health Network, Toronto, ON, Canada
- Division of Anatomy, Department of Surgery, University of Toronto, Toronto, ON, Canada
- The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Rehabilitation Sciences Institute, University of Toronto, Toronto, ON, Canada
| | - Stephanie N Iwasa
- Center for Advancing Neurotechnological Innovation to Application - CRANIA, University Health Network, Toronto, ON, Canada
- KITE Research Institute - University Health Network, Toronto, ON, Canada
| | - Jose Zariffa
- KITE Research Institute - University Health Network, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Rehabilitation Sciences Institute, University of Toronto, Toronto, ON, Canada
- Edward S. Rogers Sr. Department of Electrical and Computer Engineering, University of Toronto, Toronto, ON, Canada
| | - Luka Milosevic
- Center for Advancing Neurotechnological Innovation to Application - CRANIA, University Health Network, Toronto, ON, Canada
- KITE Research Institute - University Health Network, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Taufik A Valiante
- Center for Advancing Neurotechnological Innovation to Application - CRANIA, University Health Network, Toronto, ON, Canada
- KITE Research Institute - University Health Network, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Edward S. Rogers Sr. Department of Electrical and Computer Engineering, University of Toronto, Toronto, ON, Canada
| | - Joaquín Andrés Hoffer
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
| | - Milos R Popovic
- Center for Advancing Neurotechnological Innovation to Application - CRANIA, University Health Network, Toronto, ON, Canada
- KITE Research Institute - University Health Network, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Rehabilitation Sciences Institute, University of Toronto, Toronto, ON, Canada
- Edward S. Rogers Sr. Department of Electrical and Computer Engineering, University of Toronto, Toronto, ON, Canada
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7
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Wood RL, Calvo PM, McCallum WM, English AW, Alvarez FJ. GABA and glycine synaptic release on axotomized motoneuron cell bodies promotes motor axon regeneration. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.18.623863. [PMID: 39605707 PMCID: PMC11601532 DOI: 10.1101/2024.11.18.623863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Motor axon regeneration after traumatic nerve injuries is a slow process that adversely influences patient outcomes because muscle reinnervation delays result in irreversible muscle atrophy and suboptimal axon regeneration. This advocates for investigating methods to accelerate motor axon growth. Electrical nerve stimulation and exercise both enhance motor axon regeneration in rodents and patients, but these interventions cannot always be easily implemented. A roadblock to uncover novel therapeutic approaches based on the effects of activity is the lack of understanding of the synaptic drives responsible for activity-mediated facilitation of axon regeneration. We hypothesized that the relevant excitatory inputs facilitating axon regrowth originate in GABA/glycine synapses which become depolarizing after downregulation of the potassium chloride cotransporter 2 in motoneurons following axotomy. To test this, we injected tetanus toxin (TeTx) in the tibialis anterior (TA) muscle of mice to block the release of GABA/glycine specifically on TA motoneurons. Thereafter, we axotomized all sciatic motoneurons by nerve crush and analyzed the time-courses of muscle reinnervation in TeTx- treated (TA) and untreated (lateral gastrocnemius, LG) motoneurons. Muscle reinnervation was slower in TA motoneurons with blocked GABA/glycine synapses, as measured by recovery of M- responses and anatomical reinnervation of neuromuscular junctions. Post-hoc immunohistochemistry confirmed the removal of the vesicular associated membrane proteins 1 and 2 by TeTx activity, specifically from inhibitory synapses. These proteins are necessary for exocytotic release of neurotransmitters. Therefore, we conclude that GABA/glycine neurotransmission on regenerating motoneurons facilitates axon growth and muscle reinnervation and discuss possible interventions to modulate these inputs on regenerating motoneurons.
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8
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Olsen TC, LaGuardia JS, Chen DR, Lebens RS, Huang KX, Milek D, Noble M, Leckenby JI. Influencing factors and repair advancements in rodent models of peripheral nerve regeneration. Regen Med 2024; 19:561-577. [PMID: 39469920 PMCID: PMC11633413 DOI: 10.1080/17460751.2024.2405318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 09/12/2024] [Indexed: 10/30/2024] Open
Abstract
Peripheral nerve injuries lead to severe functional impairments, with rodent models essential for studying regeneration. This review examines key factors affecting outcomes. Age-related declines, like reduced nerve fiber density and impaired axonal transport of vesicles, hinder recovery. Hormonal differences influence regeneration, with BDNF/trkB critical for testosterone and nerve growth factor for estrogen signaling pathways. Species and strain selection impact outcomes, with C57BL/6 mice and Sprague-Dawley rats exhibiting varying regenerative capacities. Injury models - crush for early regeneration, chronic constriction for neuropathic pain, stretch for traumatic elongation and transection for severe lacerations - provide insights into clinically relevant scenarios. Repair techniques, such as nerve grafts and conduits, show that autografts are the gold standard for gaps over 3 cm, with success influenced by graft type and diameter. Time course analysis highlights crucial early degeneration and regeneration phases within the first month, with functional recovery stabilizing by three to six months. Early intervention optimizes regeneration by reducing scar tissue formation, while later interventions focus on remyelination. Understanding these factors is vital for designing robust preclinical studies and translating research into effective clinical treatments for peripheral nerve injuries.
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Affiliation(s)
- Timothy C Olsen
- Division of Plastic & Reconstructive Surgery, University of Rochester Medical Center, 601 Elmwood Avenue Box 661Rochester, NY14642, USA
| | - Jonnby S LaGuardia
- Division of Plastic & Reconstructive Surgery, University of Rochester Medical Center, 601 Elmwood Avenue Box 661Rochester, NY14642, USA
| | - David R Chen
- University of California, 410 Charles E. Young Drive, East Los Angeles, CA90095, USA
| | - Ryan S Lebens
- University of California, 410 Charles E. Young Drive, East Los Angeles, CA90095, USA
| | - Kelly X Huang
- University of California, 410 Charles E. Young Drive, East Los Angeles, CA90095, USA
| | - David Milek
- Division of Plastic & Reconstructive Surgery, University of Rochester Medical Center, 601 Elmwood Avenue Box 661Rochester, NY14642, USA
| | - Mark Noble
- Department of Biomedical Genetics, University of Rochester Medical Center, 601 Elmwood Avenue Box 661Rochester, NY14642, USA
| | - Jonathan I Leckenby
- Division of Plastic & Reconstructive Surgery, University of Rochester Medical Center, 601 Elmwood Avenue Box 661Rochester, NY14642, USA
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Chen Y, Zheng YX, Li YZ, Jia Z, Yuan Y. GDNF facilitates cognitive function recovery following neonatal surgical-induced learning and memory impairment via activation of the RET pathway and modulation of downstream effectors PKMζ and Kalirin in rats. Brain Res Bull 2024; 217:111078. [PMID: 39270804 DOI: 10.1016/j.brainresbull.2024.111078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 09/03/2024] [Accepted: 09/10/2024] [Indexed: 09/15/2024]
Abstract
OBJECTIVE The aim of this study is to elucidate the underlying mechanism through which glial cell line-derived neurotrophic factor (GDNF) improves cognitive deficits in adults resulting from neonatal surgical interventions. METHODS Newborn Sprague-Dawley rats, regardless of gender, were randomly allocated into seven groups on postnatal day 7 as follows (n=15): (1) Control group (not subjected to anesthesia, surgery, or any pharmaceutical interventions); (2) GDNF group (received intracerebroventricular injection of GDNF); (3) Surgery group (underwent right carotid artery exposure under anesthesia with 3 % sevoflurane); (4) Surgery plus GDNF group; (5) Surgery plus GDNF and type II JAK inhibitor NVP-BBT594 (BBT594) group (administered intraperitoneal injection of BBT594); (6) BBT group; and (7) Surgery plus BBT group. Starting from postnatal day 33, all rats underwent Barnes maze and fear conditioning tests, followed by decapitation under sevoflurane anesthesia for subsequent analyses. The left hemibrains underwent Golgi staining, while the right hemibrains were used for hippocampal protein extraction to assess Protein kinase Mζ (PKMζ) and Kalirin expression through western blotting. RESULTS GDNF demonstrated a mitigating effect on spatial learning and memory impairment, as well as context-related fear memory impairment, reductions in dendritic total lengths, and spinal density within the hippocampus induced by surgical intervention. Notably, all of these ameliorative effects of GDNF were reversed upon administration of the RET inhibitor BBT594. Additionally, GDNF alleviated the downregulation of protein expression of PKMζ and Kalirin in the hippocampus of rats subjected to surgery, subsequently reversed by BBT594. CONCLUSION The effective impact of GDNF on learning and memory impairment caused by surgical intervention appears to be mediated through the RET pathway. Moreover, GDNF may exert its influence by upregulating the expression of PKMζ and Kalirin, consequently enhancing the development of dendrites and dendritic spines.
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Affiliation(s)
- Yi Chen
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Yu-Xin Zheng
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Yi-Ze Li
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Zhen Jia
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yuan Yuan
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, China
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10
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Masri JE, Afyouni A, Ghazi M, Hamideh K, Moubayed I, Jurjus A, Haidar H, Petrosyan R, Salameh P, Hosseini H. Stem cell transplantation in cerebrovascular accidents: A global bibliometric analysis (2000-2023). World J Stem Cells 2024; 16:832-841. [PMID: 39351261 PMCID: PMC11438731 DOI: 10.4252/wjsc.v16.i9.832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 08/01/2024] [Accepted: 09/18/2024] [Indexed: 09/24/2024] Open
Abstract
BACKGROUND Cerebrovascular accident (CVA) is a major global contributor to death and disability. As part of its medical management, researchers have recognized the importance of promising neuroprotective strategies, where stem cell transplantation (SCT) is thought to confer advantages via trophic and neuroprotective effects. AIM To evaluate the current state of research on SCT in patients with CVA, assess key trends and highlight literature gaps. METHODS PubMed was screened for SCT in CVA-related articles in October 2023, for each country during the period between 2000 and 2023. Using the World Bank data, total population and gross domestic product were collected for comparison. VOSviewer_1.6.19 was used to create the VOS figure using the results of the same query. Graphs and tables were obtained using Microsoft Office Excel. RESULTS A total of 6923 studies were identified on SCT in CVA, making 0.03% of all published studies worldwide. Approximately, 68% were conducted in high-income countries, with a significant focus on mesenchymal stem cells. The journal "Stroke" featured the largest share of these articles, with mesenchymal SCT having the highest rate of inclusion, followed by hematopoietic SCT. Over time, there has been a noticeable shift from in vitro studies, which assess stem cell proliferation and neurogenesis, to in vivo studies aimed at evaluating efficacy and safety. Additionally, the number of reviews increased along this approach. CONCLUSION This bibliometric analysis provides a comprehensive guide for physicians and researchers in the field through an objective overview of research activity, and highlights both current trends and gaps. Having a potential therapeutic role in CVA, more research is needed in the future to focus on different aspects of SCT, aiming to reach a better treatment strategy and improve life quality in patients.
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Affiliation(s)
- Jad El Masri
- École Doctorale Sciences de la Vie et de la Santé, Université Paris-Est Créteil, Créteil 94010, France
- INSERM U955-E01, Institut Mondor de Recherche Biomédicale, Université Paris-Est Créteil, Créteil 94000, France
- Faculty of Medical Sciences, Lebanese University, Beirut 1533, Lebanon
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon
| | - Ahmad Afyouni
- Faculty of Medical Sciences, Lebanese University, Beirut 1533, Lebanon
| | - Maya Ghazi
- Faculty of Medical Sciences, Lebanese University, Beirut 1533, Lebanon
- Department of Neurology, Faculty of Medicine, Lebanese American University, Beirut 1102, Lebanon
| | - Karim Hamideh
- Faculty of Medical Sciences, Lebanese University, Beirut 1533, Lebanon
| | - Israe Moubayed
- Faculty of Medical Sciences, Lebanese University, Beirut 1533, Lebanon
| | - Abdo Jurjus
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon.
| | - Hanine Haidar
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon
| | - Ruzanna Petrosyan
- Department of Pathology, Faculty of Medicine, Lebanese American University, Beirut 1102, Lebanon
| | - Pascale Salameh
- Faculty of Pharmacy, Lebanese University, Beirut 1102, Lebanon
- Faculty of Medicine, Lebanese American University, Beirut 1102, Lebanon
- Department of Primary Care and Population Health, University of Nicosia Medical School, Nicosia 2408, Cyprus
- Institut National de Santé Publique d'Épidémiologie Clinique et de Toxicologie-Liban, Beirut 1103, Lebanon
| | - Hassan Hosseini
- INSERM U955-E01, Institut Mondor de Recherche Biomédicale, Université Paris-Est Créteil, Créteil 94000, France
- Department of Neurology, Henri Mondor Hospital, AP-HP, Créteil 94000, France
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11
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Wang J, Hu Y, Xue Y, Wang K, Mao D, Pan XY, Rui Y. PMMA-induced biofilm promotes Schwann cells migration and proliferation mediated by EGF/Tnc/FN1 to improve sciatic nerve defect. Heliyon 2024; 10:e37231. [PMID: 39296039 PMCID: PMC11409128 DOI: 10.1016/j.heliyon.2024.e37231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 08/14/2024] [Accepted: 08/29/2024] [Indexed: 09/21/2024] Open
Abstract
Objective The purpose of this study is to investigate the role of PMMA-induced biofilm in nerve regeneration compared with silicone-induced biofilm involved in the mechanism. Methods PMMA or silicon rods were placed next to the sciatic nerve to induce a biological membrane which was assayed by PCR, Western blot, immunohistochemistry, immunofluorescence and proteomics. A 10 mm sciatic nerve gaps were repaired with the autologous nerve wrapped in an induced biological membrane. The repair effects were observed through general observation, functional evaluation of nerve regeneration, ultrasound examination, neural electrophysiology, the wet weight ratio of bilateral pretibial muscle and histological evaluation. Cell proliferation and migration of Schwann cells co-cultured with EGF-treated fibroblasts combined with siRNA were investigated. Results The results indicated that expression of GDNF, NGF and VEGF along with neovascularization was similar in the silicone and PMMA group and as the highest at 6 weeks after operation. Nerve injury repair mediated by toluidine blue and S100β/NF200 expression, the sensory and motor function evaluation, ultrasound, target organ muscle wet-weight ratio, percentage of collagen fiber, electromyography and histochemical staining were not different between the two groups and better than blank group. EGF-treated fibroblasts promoted proliferation and migration may be Tnc expression dependently. Conclusion Our study suggested that PMMA similar to silicon induced biofilm may promote autogenous nerve transplantation to repair nerve defects through EGF/Tnc/FN1 to increase Schwann cells proliferation and migration.
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Affiliation(s)
- Jun Wang
- Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215000, China
- Department of Orthopedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu, 214000, China
| | - YuXuan Hu
- Department of Orthopedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu, 214000, China
| | - Yuan Xue
- Department of Orthopedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu, 214000, China
| | - Kai Wang
- Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215000, China
| | - Dong Mao
- Orthopaedic Institute, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu, 214000, China
| | - Xiao-Yun Pan
- Orthopaedic Institute, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu, 214000, China
| | - YongJun Rui
- Department of Orthopedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu, 214000, China
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12
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Crabtree JR, Mulenga CM, Tran K, Feinberg K, Santerre JP, Borschel GH. Biohacking Nerve Repair: Novel Biomaterials, Local Drug Delivery, Electrical Stimulation, and Allografts to Aid Surgical Repair. Bioengineering (Basel) 2024; 11:776. [PMID: 39199733 PMCID: PMC11352148 DOI: 10.3390/bioengineering11080776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/15/2024] [Accepted: 07/26/2024] [Indexed: 09/01/2024] Open
Abstract
The regenerative capacity of the peripheral nervous system is limited, and peripheral nerve injuries often result in incomplete healing and poor outcomes even after repair. Transection injuries that induce a nerve gap necessitate microsurgical intervention; however, even the current gold standard of repair, autologous nerve graft, frequently results in poor functional recovery. Several interventions have been developed to augment the surgical repair of peripheral nerves, and the application of functional biomaterials, local delivery of bioactive substances, electrical stimulation, and allografts are among the most promising approaches to enhance innate healing across a nerve gap. Biocompatible polymers with optimized degradation rates, topographic features, and other functions provided by their composition have been incorporated into novel nerve conduits (NCs). Many of these allow for the delivery of drugs, neurotrophic factors, and whole cells locally to nerve repair sites, mitigating adverse effects that limit their systemic use. The electrical stimulation of repaired nerves in the perioperative period has shown benefits to healing and recovery in human trials, and novel biomaterials to enhance these effects show promise in preclinical models. The use of acellular nerve allografts (ANAs) circumvents the morbidity of donor nerve harvest necessitated by the use of autografts, and improvements in tissue-processing techniques may allow for more readily available and cost-effective options. Each of these interventions aid in neural regeneration after repair when applied independently, and their differing forms, benefits, and methods of application present ample opportunity for synergistic effects when applied in combination.
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Affiliation(s)
- Jordan R. Crabtree
- Division of Plastic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Chilando M. Mulenga
- Division of Plastic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Khoa Tran
- Division of Plastic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Konstantin Feinberg
- Division of Plastic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - J. Paul Santerre
- Institute of Biomedical Engineering, University of Toronto, 164 College St Room 407, Toronto, ON M5S 3G9, Canada
| | - Gregory H. Borschel
- Division of Plastic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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13
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Stassart RM, Gomez-Sanchez JA, Lloyd AC. Schwann Cells as Orchestrators of Nerve Repair: Implications for Tissue Regeneration and Pathologies. Cold Spring Harb Perspect Biol 2024; 16:a041363. [PMID: 38199866 PMCID: PMC11146315 DOI: 10.1101/cshperspect.a041363] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2024]
Abstract
Peripheral nerves exist in a stable state in adulthood providing a rapid bidirectional signaling system to control tissue structure and function. However, following injury, peripheral nerves can regenerate much more effectively than those of the central nervous system (CNS). This multicellular process is coordinated by peripheral glia, in particular Schwann cells, which have multiple roles in stimulating and nurturing the regrowth of damaged axons back to their targets. Aside from the repair of damaged nerves themselves, nerve regenerative processes have been linked to the repair of other tissues and de novo innervation appears important in establishing an environment conducive for the development and spread of tumors. In contrast, defects in these processes are linked to neuropathies, aging, and pain. In this review, we focus on the role of peripheral glia, especially Schwann cells, in multiple aspects of nerve regeneration and discuss how these findings may be relevant for pathologies associated with these processes.
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Affiliation(s)
- Ruth M Stassart
- Paul-Flechsig-Institute of Neuropathology, University Clinic Leipzig, Leipzig 04103, Germany
| | - Jose A Gomez-Sanchez
- Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante 03010, Spain
- Instituto de Neurociencias CSIC-UMH, Sant Joan de Alicante 03550, Spain
| | - Alison C Lloyd
- UCL Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, United Kingdom
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14
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Wang X, Pang Q, Hu J, Luo B, Lu Y, Sun X, Meng S, Jiang Q. Cognitive decline in Sprague-Dawley rats induced by neuroplasticity changes after occlusal support loss. CNS Neurosci Ther 2024; 30:e14750. [PMID: 38898731 PMCID: PMC11187409 DOI: 10.1111/cns.14750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 02/28/2024] [Accepted: 04/20/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND Tooth loss is closely related to cognitive impairment, especially affecting cognitive functions involving hippocampus. The most well-known function of the hippocampus is learning and memory, and the mechanism behind is neuroplasticity, which strongly depends on the level of brain-derived neurotrophic factor (BDNF). While research has delved into the possible mechanisms behind the loss of teeth leading to cognitive dysfunction, there are few studies on the plasticity of sensory neural pathway after tooth loss, and the changes in related indicators of synaptic plasticity still need to be further explored. METHODS In this study, the bilateral maxillary molars were extracted in Sprague-Dawley rats of two age ranges (young and middle age) to establish occlusal support loss model; then, the spatial cognition was tested by Morris Water Maze (MWM). Quantitative real-time PCR (qPCR) and Western Blotting (WB) were used to detect BDNF, AKT, and functional proteins (viz., PSD95 and NMDAR) of hippocampal synapses. Golgi staining was used to observe changes in ascending nerve pathway. IF was used to confirm the location of BDNF and AKT expressed in hippocampus. RESULTS MWM showed that the spatial cognitive level of rats dropped after occlusal support loss. qPCR, WB, and IF suggested that the BDNF/AKT pathway was down-regulated in the hippocampus. Golgi staining showed the neurons of ascending sensory pathway decreased in numbers. CONCLUSION Occlusal support loss caused plastic changes in ascending nerve pathway and induced cognitive impairment in rats by down-regulating BDNF and synaptic plasticity.
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Affiliation(s)
- Xiaoyu Wang
- School of StomatologyCapital Medical UniversityBeijingChina
| | - Qian Pang
- Department of Prosthodontics, Beijing Stomatological HospitalCapital Medical UniversityBeijingChina
| | - Jiangqi Hu
- Department of Prosthodontics, Beijing Stomatological HospitalCapital Medical UniversityBeijingChina
| | - Bin Luo
- Department of Prosthodontics, Beijing Stomatological HospitalCapital Medical UniversityBeijingChina
| | - Yunping Lu
- Department of Prosthodontics, Beijing Stomatological HospitalCapital Medical UniversityBeijingChina
| | - Xu Sun
- School of StomatologyCapital Medical UniversityBeijingChina
| | - Shixiang Meng
- School of StomatologyCapital Medical UniversityBeijingChina
| | - Qingsong Jiang
- Department of Prosthodontics, Beijing Stomatological HospitalCapital Medical UniversityBeijingChina
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15
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Hernandez-Morato I, Koss S, Honzel E, Pitman MJ. Netrin-1 as A neural guidance protein in development and reinnervation of the larynx. Ann Anat 2024; 254:152247. [PMID: 38458575 DOI: 10.1016/j.aanat.2024.152247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 02/01/2024] [Accepted: 03/05/2024] [Indexed: 03/10/2024]
Abstract
Neural guidance proteins participate in motor neuron migration, axonal projection, and muscle fiber innervation during development. One of the guidance proteins that participates in axonal pathfinding is Netrin-1. Despite the well-known role of Netrin-1 in embryogenesis of central nervous tissue, it is still unclear how the expression of this guidance protein contributes to primary innervation of the periphery, as well as reinnervation. This is especially true in the larynx where Netrin-1 is upregulated within the intrinsic laryngeal muscles after nerve injury and where blocking of Netrin-1 alters the pattern of reinnervation of the intrinsic laryngeal muscles. Despite this consistent finding, it is unknown how Netrin-1 expression contributes to guidance of the axons towards the larynx. Improved knowledge of Netrin-1's role in nerve regeneration and reinnervation post-injury in comparison to its role in primary innervation during embryological development, may provide insights in the search for therapeutics to treat nerve injury. This paper reviews the known functions of Netrin-1 during the formation of the central nervous system and during cranial nerve primary innervation. It also describes the role of Netrin-1 in the formation of the larynx and during recurrent laryngeal reinnervation following nerve injury in the adult.
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Affiliation(s)
- Ignacio Hernandez-Morato
- Department of Otolaryngology-Head & Neck Surgery, The Center for Voice and Swallowing, Columbia University College of Physicians and Surgeons, New York, NY, United States; Department of Anatomy and Embryology, School of Medicine, Complutense University of Madrid, Madrid, Madrid, Spain.
| | - Shira Koss
- ENT Associates of Nassau County, Levittown, NY, United States
| | - Emily Honzel
- Department of Otolaryngology-Head & Neck Surgery, The Center for Voice and Swallowing, Columbia University College of Physicians and Surgeons, New York, NY, United States
| | - Michael J Pitman
- Department of Otolaryngology-Head & Neck Surgery, The Center for Voice and Swallowing, Columbia University College of Physicians and Surgeons, New York, NY, United States
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16
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Kamal N, Abdallah MS, Abdel Wahed E, Sabri NA, Fahmy SF. Evaluation of the Effect of Loratadine versus Diosmin/Hesperidin Combination on Vinca Alkaloids-Induced Neuropathy: A Randomized Controlled Clinical Trial. Pharmaceuticals (Basel) 2024; 17:609. [PMID: 38794179 PMCID: PMC11124025 DOI: 10.3390/ph17050609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 05/01/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024] Open
Abstract
Neurological injury is a crucial problem that interferes with the therapeutic use of vinca alkaloids as well as the quality of patient life. This study was conducted to assess the impact of using loratadine or diosmin/hesperidin on neuropathy induced by vinca alkaloids. Patients were randomized into one of three groups as follows: group 1 was the control group, group 2 received 450 mg diosmin and 50 mg hesperidin combination orally twice daily, and group 3 received loratadine 10 mg orally once daily. Subjective scores (numeric pain rating scale, douleur neuropathique 4, and functional assessment of cancer therapy/gynecologic oncology group-neurotoxicity (FACT/GOG-Ntx) scores), neuroinflammation biomarkers, adverse drug effects, quality of life, and response to chemotherapy were compared among the three groups. Both diosmin/hesperidin and loratadine improved the results of the neurotoxicity subscale in the FACT/GOG-Ntx score (p < 0.001, p < 0.01 respectively) and ameliorated the upsurge in neuroinflammation serum biomarkers. They also reduced the incidence and timing of paresthesia (p = 0.001 and p < 0.001, respectively) and dysuria occurrence (p = 0.042). Both loratadine and diosmin/hesperidin attenuated the intensity of acute neuropathy triggered by vinca alkaloids. Furthermore, they did not increase the frequency of adverse effects or interfere with the treatment response.
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Affiliation(s)
- Noha Kamal
- Clinical Pharmacy Department, Faculty of Pharmacy, University of Sadat City (USC), Sadat City 32897, Egypt;
| | - Mahmoud S. Abdallah
- Clinical Pharmacy Department, Faculty of Pharmacy, University of Sadat City (USC), Sadat City 32897, Egypt;
- Department of PharmD, Faculty of Pharmacy, Jadara University, Irbid 21110, Jordan
| | - Essam Abdel Wahed
- Hematology and Bone Marrow Transplantation Unit, Internal Medicine Department, Faculty of Medicine, Ain Shams University, Cairo 11591, Egypt;
| | - Nagwa A. Sabri
- Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, African Union Organization Street, Cairo 11566, Egypt; (N.A.S.); (S.F.F.)
| | - Sarah Farid Fahmy
- Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, African Union Organization Street, Cairo 11566, Egypt; (N.A.S.); (S.F.F.)
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17
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Jorge KTDOS, Braga MP, Cazzaniga RA, Santos CNO, Teixeira MM, Gomes KB, de Jesus AMR, Soriani FM. The role of neurotrophin polymorphisms and susceptibility to neural damage in leprosy. Int J Infect Dis 2024; 142:106946. [PMID: 38278287 DOI: 10.1016/j.ijid.2024.01.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 12/20/2023] [Accepted: 01/21/2024] [Indexed: 01/28/2024] Open
Abstract
OBJECTIVES Mycobacterium leprae is able to infect Schwann cells leading to neural damage. Neurotrophins are involved in nervous system plasticity and impact neural integrity during diseases. Investigate the association between single nucleotide polymorphisms in neurotrophin genes and leprosy phenotypes, especially neural damage. DESIGN We selected single nucleotide polymorphisms in neurotrophins or their receptors genes associated with neural disorders: rs6265 and rs11030099 of brain-derived neurotrophic factor (BDNF), rs6330 of BDNF, rs6332 in NT3 and rs2072446 of P75NTR. The association of genetic frequencies with leprosy phenotypes was investigated in a case-control study. RESULTS An association of the BDNF single nucleotide polymorphism rs11030099 with the number of affected nerves was demonstrated. The "AA+AC" genotypes were demonstrated to be protective against nerve impairment. However, this variation does not affect BDNF serum levels. BDNF is an important factor for myelination of Schwann cells and polymorphisms in this gene can be associated with leprosy outcome. Moreover, rs11030099 is located in the binding region for micro-RNA (miRNA) 26a that could be involved in control of BDNF expression. We demonstrated different expression levels of this miRNA in polar forms of leprosy. CONCLUSION Our findings demonstrate for the first time an association between the polymorphism rs11030099 in the BDNF gene and neural commitment in leprosy and may indicate a possible role of miRNA-26a acting synergistically to these genetic variants in neural damage development.
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Affiliation(s)
| | - Marina Pimenta Braga
- Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | | | - Mauro Martins Teixeira
- Laboratory of Immunopharmacology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Karina Braga Gomes
- Department of Clinical and Toxicological Analyzes - Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | - Frederico Marianetti Soriani
- Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
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Zhang X, Duan X, Liu X. The role of kinases in peripheral nerve regeneration: mechanisms and implications. Front Neurol 2024; 15:1340845. [PMID: 38689881 PMCID: PMC11058862 DOI: 10.3389/fneur.2024.1340845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 04/02/2024] [Indexed: 05/02/2024] Open
Abstract
Peripheral nerve injury disease is a prevalent traumatic condition in current medical practice. Despite the present treatment approaches, encompassing surgical sutures, autologous nerve or allograft nerve transplantation, tissue engineering techniques, and others, an effective clinical treatment method still needs to be discovered. Exploring novel treatment methods to improve peripheral nerve regeneration requires more effort in investigating the cellular and molecular mechanisms involved. Many factors are associated with the regeneration of injured peripheral nerves, including the cross-sectional area of the injured nerve, the length of the nerve gap defect, and various cellular and molecular factors such as Schwann cells, inflammation factors, kinases, and growth factors. As crucial mediators of cellular communication, kinases exert regulatory control over numerous signaling cascades, thereby participating in various vital biological processes, including peripheral nerve regeneration after nerve injury. In this review, we examined diverse kinase classifications, distinct nerve injury types, and the intricate mechanisms involved in peripheral nerve regeneration. Then we stressed the significance of kinases in regulating autophagy, inflammatory response, apoptosis, cell cycle, oxidative processes, and other aspects in establishing conductive microenvironments for nerve tissue regeneration. Finally, we briefly discussed the functional roles of kinases in different types of cells involved in peripheral nerve regeneration.
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Affiliation(s)
- Xu Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, School of Life Science, Nantong Laboratory of Development and Diseases, Medical College, Clinical Medical Research Center, Affiliated Wuxi Clinical College of Nantong University, Nantong University, Nantong, China
- Clinical Medical Research Center, Wuxi No. 2 People's Hospital, Jiangnan University Medical Center, Wuxi, China
| | - Xuchu Duan
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, School of Life Science, Nantong Laboratory of Development and Diseases, Medical College, Clinical Medical Research Center, Affiliated Wuxi Clinical College of Nantong University, Nantong University, Nantong, China
| | - Xiaoyu Liu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, School of Life Science, Nantong Laboratory of Development and Diseases, Medical College, Clinical Medical Research Center, Affiliated Wuxi Clinical College of Nantong University, Nantong University, Nantong, China
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Kim NY, Choi YY, Kim TH, Ha JH, Kim TH, Kang T, Chung BG. Synergistic Effect of Electrical and Biochemical Stimulation on Human iPSC-Derived Neural Differentiation in a Microfluidic Electrode Array Chip. ACS APPLIED MATERIALS & INTERFACES 2024; 16:15730-15740. [PMID: 38527279 DOI: 10.1021/acsami.3c17108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/27/2024]
Abstract
Neural differentiation is crucial for advancing our understanding of the nervous system and developing treatments for neurological disorders. The advanced methods and the ability to manipulate the alignment, proliferation, and differentiation of stem cells are essential for studying neuronal development and synaptic interactions. However, the utilization of human induced pluripotent stem cells (iPSCs) for disease modeling of neurodegenerative conditions may be constrained by the prolonged duration and uncontrolled cell differentiation required for functional neural cell differentiation. Here, we developed a microfluidic chip to enhance the differentiation and maturation of specific neural lineages by placing aligned microelectrodes on the glass surface to regulate the neural differentiation of human iPSCs. The utilization of electrical stimulation (ES) in conjunction with neurotrophic factors (NF) significantly enhanced the efficiency in generating functional neurons from human iPSCs. We also observed that the simultaneous application of NF and ES to human iPSCs promoted their differentiation and maturation into functional neurons while increasing synaptic interactions. Our research demonstrated the effect of combining NF and ES on human iPSC-derived neural differentiation.
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Affiliation(s)
- Na Yeon Kim
- Department of Biomedical Engineering, Sogang University, Seoul 04107, Korea
| | - Yoon Young Choi
- Institute of Integrated Biotechnology, Sogang University, Seoul 04107, Korea
| | - Tae Hyeon Kim
- Department of Mechanical Engineering, Sogang University, Seoul 04107, Korea
| | - Jang Ho Ha
- Department of Mechanical Engineering, Sogang University, Seoul 04107, Korea
| | - Tae-Hyung Kim
- School of Integrative Engineering, Chung-Ang University, Seoul 06974, Korea
| | - Taewook Kang
- Institute of Integrated Biotechnology, Sogang University, Seoul 04107, Korea
- Department of Chemical and Biomolecular Engineering, Sogang University, Seoul 04107, Korea
| | - Bong Geun Chung
- Department of Biomedical Engineering, Sogang University, Seoul 04107, Korea
- Institute of Integrated Biotechnology, Sogang University, Seoul 04107, Korea
- Department of Mechanical Engineering, Sogang University, Seoul 04107, Korea
- Institute of Smart Biosensor, Sogang University, Seoul 04107, Korea
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20
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Llorián-Salvador M, Cabeza-Fernández S, Gomez-Sanchez JA, de la Fuente AG. Glial cell alterations in diabetes-induced neurodegeneration. Cell Mol Life Sci 2024; 81:47. [PMID: 38236305 PMCID: PMC10796438 DOI: 10.1007/s00018-023-05024-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 10/09/2023] [Accepted: 10/29/2023] [Indexed: 01/19/2024]
Abstract
Type 2 diabetes mellitus is a global epidemic that due to its increasing prevalence worldwide will likely become the most common debilitating health condition. Even if diabetes is primarily a metabolic disorder, it is now well established that key aspects of the pathogenesis of diabetes are associated with nervous system alterations, including deleterious chronic inflammation of neural tissues, referred here as neuroinflammation, along with different detrimental glial cell responses to stress conditions and neurodegenerative features. Moreover, diabetes resembles accelerated aging, further increasing the risk of developing age-linked neurodegenerative disorders. As such, the most common and disabling diabetic comorbidities, namely diabetic retinopathy, peripheral neuropathy, and cognitive decline, are intimately associated with neurodegeneration. As described in aging and other neurological disorders, glial cell alterations such as microglial, astrocyte, and Müller cell increased reactivity and dysfunctionality, myelin loss and Schwann cell alterations have been broadly described in diabetes in both human and animal models, where they are key contributors to chronic noxious inflammation of neural tissues within the PNS and CNS. In this review, we aim to describe in-depth the common and unique aspects underlying glial cell changes observed across the three main diabetic complications, with the goal of uncovering shared glial cells alterations and common pathological mechanisms that will enable the discovery of potential targets to limit neuroinflammation and prevent neurodegeneration in all three diabetic complications. Diabetes and its complications are already a public health concern due to its rapidly increasing incidence, and thus its health and economic impact. Hence, understanding the key role that glial cells play in the pathogenesis underlying peripheral neuropathy, retinopathy, and cognitive decline in diabetes will provide us with novel therapeutic approaches to tackle diabetic-associated neurodegeneration.
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Affiliation(s)
- María Llorián-Salvador
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK.
| | - Sonia Cabeza-Fernández
- Institute for Health and Biomedical Research of Alicante (ISABIAL), Alicante, Spain
- Institute of Neuroscience CSIC-UMH, San Juan de Alicante, Spain
| | - Jose A Gomez-Sanchez
- Institute for Health and Biomedical Research of Alicante (ISABIAL), Alicante, Spain
- Institute of Neuroscience CSIC-UMH, San Juan de Alicante, Spain
| | - Alerie G de la Fuente
- Institute for Health and Biomedical Research of Alicante (ISABIAL), Alicante, Spain.
- Institute of Neuroscience CSIC-UMH, San Juan de Alicante, Spain.
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21
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Gordon T. Brief Electrical Stimulation Promotes Recovery after Surgical Repair of Injured Peripheral Nerves. Int J Mol Sci 2024; 25:665. [PMID: 38203836 PMCID: PMC10779324 DOI: 10.3390/ijms25010665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 12/07/2023] [Accepted: 12/08/2023] [Indexed: 01/12/2024] Open
Abstract
Injured peripheral nerves regenerate their axons in contrast to those in the central nervous system. Yet, functional recovery after surgical repair is often disappointing. The basis for poor recovery is progressive deterioration with time and distance of the growth capacity of the neurons that lose their contact with targets (chronic axotomy) and the growth support of the chronically denervated Schwann cells (SC) in the distal nerve stumps. Nonetheless, chronically denervated atrophic muscle retains the capacity for reinnervation. Declining electrical activity of motoneurons accompanies the progressive fall in axotomized neuronal and denervated SC expression of regeneration-associated-genes and declining regenerative success. Reduced motoneuronal activity is due to the withdrawal of synaptic contacts from the soma. Exogenous neurotrophic factors that promote nerve regeneration can replace the endogenous factors whose expression declines with time. But the profuse axonal outgrowth they provoke and the difficulties in their delivery hinder their efficacy. Brief (1 h) low-frequency (20 Hz) electrical stimulation (ES) proximal to the injury site promotes the expression of endogenous growth factors and, in turn, dramatically accelerates axon outgrowth and target reinnervation. The latter ES effect has been demonstrated in both rats and humans. A conditioning ES of intact nerve days prior to nerve injury increases axonal outgrowth and regeneration rate. Thereby, this form of ES is amenable for nerve transfer surgeries and end-to-side neurorrhaphies. However, additional surgery for applying the required electrodes may be a hurdle. ES is applicable in all surgeries with excellent outcomes.
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Affiliation(s)
- Tessa Gordon
- Division of Reconstructive Surgery, Department of Surgery, University of Toronto, Toronto, ON M4G 1X8, Canada
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22
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Umansky D, Elzinga K, Midha R. Surgery for mononeuropathies. HANDBOOK OF CLINICAL NEUROLOGY 2024; 201:227-249. [PMID: 38697743 DOI: 10.1016/b978-0-323-90108-6.00012-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2024]
Abstract
Advancement in microsurgical techniques and innovative approaches including greater use of nerve and tendon transfers have resulted in better peripheral nerve injury (PNI) surgical outcomes. Clinical evaluation of the patient and their injury factors along with a shift toward earlier time frame for intervention remain key. A better understanding of the pathophysiology and biology involved in PNI and specifically mononeuropathies along with advances in ultrasound and magnetic resonance imaging allow us, nowadays, to provide our patients with a logical and sophisticated approach. While functional outcomes are constantly being refined through different surgical techniques, basic scientific concepts are being advanced and translated to clinical practice on a continuous basis. Finally, a combination of nerve transfers and technological advances in nerve/brain and machine interfaces are expanding the scope of nerve surgery to help patients with amputations, spinal cord, and brain lesions.
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Affiliation(s)
- Daniel Umansky
- Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, UT, United States
| | - Kate Elzinga
- Division of Plastic Surgery, Department of Surgery, University of Calgary, Calgary, AB, Canada
| | - Rajiv Midha
- Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
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23
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Choinière W, Petit È, Monfette V, Pelletier S, Godbout-Lavoie C, Lauzon MA. Dynamic three-dimensional coculture model: The future of tissue engineering applied to the peripheral nervous system. J Tissue Eng 2024; 15:20417314241265916. [PMID: 39139455 PMCID: PMC11320398 DOI: 10.1177/20417314241265916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 06/18/2024] [Indexed: 08/15/2024] Open
Abstract
Traumatic injuries to the peripheral nervous system (PNI) can lead to severe consequences such as paralysis. Unfortunately, current treatments rarely allow for satisfactory functional recovery. The high healthcare costs associated with PNS injuries, worker disability, and low patient satisfaction press for alternative solutions that surpass current standards. For the treatment of injuries with a deficit of less than 30 mm to bridge, the use of synthetic nerve conduits (NGC) is favored. However, to develop such promising therapeutic strategies, in vitro models that more faithfully mimic nerve physiology are needed. The absence of a clinically scaled model with essential elements such as a three-dimension environment and dynamic coculture has hindered progress in this field. The presented research focuses on the development of an in vitro coculture model of the peripheral nervous system (PNS) involving the use of functional biomaterial which microstructure replicates nerve topography. Initially, the behavior of neuron-derived cell lines (N) and Schwann cells (SC) in contact with a short section of biomaterial (5 mm) was studied. Subsequent investigations, using fluorescent markers and survival assays, demonstrated the synergistic effects of coculture. These optimized parameters were then applied to longer biomaterials (30 mm), equivalent to clinically used NGC. The results obtained demonstrated the possibility of maintaining an extended coculture of SC and N over a 7-day period on a clinically scaled biomaterial, observing some functionality. In the long term, the knowledge gained from this work will contribute to a better understanding of the PNS regeneration process and promote the development of future therapeutic approaches while reducing reliance on animal experimentation. This model can be used for drug screening and adapted for personalized medicine trials. Ultimately, this work fills a critical gap in current research, providing a transformative approach to study and advance treatments for PNS injuries.
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Affiliation(s)
- William Choinière
- Department of Chemical Engineering and Biotechnological Engineering, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Ève Petit
- Department of Chemical Engineering and Biotechnological Engineering, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Vincent Monfette
- Department of Chemical Engineering and Biotechnological Engineering, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Samuel Pelletier
- Department of Electrical and Informatics Engineering, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Catherine Godbout-Lavoie
- Department of Chemical Engineering and Biotechnological Engineering, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Marc-Antoine Lauzon
- Department of Chemical Engineering and Biotechnological Engineering, Université de Sherbrooke, Sherbrooke, QC, Canada
- Research Center on Aging, CIUSS de l’ESTRIE-CHUS, Sherbrooke, QC, Canada
- The Quebec Network for Research on Protein Function, Engineering, and Applications, Montréal, QC, Canada
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24
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Fuentes-Flores A, Geronimo-Olvera C, Girardi K, Necuñir-Ibarra D, Patel SK, Bons J, Wright MC, Geschwind D, Hoke A, Gomez-Sanchez JA, Schilling B, Rebolledo DL, Campisi J, Court FA. Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury. EMBO Mol Med 2023; 15:e17907. [PMID: 37860842 DOI: 10.15252/emmm.202317907] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 09/14/2023] [Accepted: 09/18/2023] [Indexed: 10/21/2023] Open
Abstract
Following peripheral nerve injury, successful axonal growth and functional recovery require Schwann cell (SC) reprogramming into a reparative phenotype, a process dependent upon c-Jun transcription factor activation. Unfortunately, axonal regeneration is greatly impaired in aged organisms and following chronic denervation, which can lead to poor clinical outcomes. While diminished c-Jun expression in SCs has been associated with regenerative failure, it is unclear whether the inability to maintain a repair state is associated with the transition into an axonal growth inhibition phenotype. We here find that reparative SCs transition into a senescent phenotype, characterized by diminished c-Jun expression and secretion of inhibitory factors for axonal regeneration in aging and chronic denervation. In both conditions, the elimination of senescent SCs by systemic senolytic drug treatment or genetic targeting improved nerve regeneration and functional recovery, increased c-Jun expression and decreased nerve inflammation. This work provides the first characterization of senescent SCs and their influence on axonal regeneration in aging and chronic denervation, opening new avenues for enhancing regeneration and functional recovery after peripheral nerve injuries.
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Affiliation(s)
- Andrés Fuentes-Flores
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile
- Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile
| | - Cristian Geronimo-Olvera
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile
- Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile
| | - Karina Girardi
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile
- Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile
| | - David Necuñir-Ibarra
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile
- Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile
| | | | - Joanna Bons
- Buck Institute for Research on Aging, Novato, CA, USA
| | - Megan C Wright
- Departments of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Daniel Geschwind
- Departments of Neurology, Psychiatry, and Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Ahmet Hoke
- Departments of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Jose A Gomez-Sanchez
- Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain
- Instituto de Neurociencias de Alicante, UMH-CSIC, San Juan de Alicante, Spain
| | | | - Daniela L Rebolledo
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile
- Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile
| | | | - Felipe A Court
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile
- Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile
- Buck Institute for Research on Aging, Novato, CA, USA
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25
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De Virgiliis F, Mueller F, Palmisano I, Chadwick JS, Luengo-Gutierrez L, Giarrizzo A, Yan Y, Danzi MC, Picon-Muñoz C, Zhou L, Kong G, Serger E, Hutson TH, Maldonado-Lasuncion I, Song Y, Scheiermann C, Brancaccio M, Di Giovanni S. The circadian clock time tunes axonal regeneration. Cell Metab 2023; 35:2153-2164.e4. [PMID: 37951214 DOI: 10.1016/j.cmet.2023.10.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 08/18/2023] [Accepted: 10/16/2023] [Indexed: 11/13/2023]
Abstract
Nerve injuries cause permanent neurological disability due to limited axonal regeneration. Injury-dependent and -independent mechanisms have provided important insight into neuronal regeneration, however, common denominators underpinning regeneration remain elusive. A comparative analysis of transcriptomic datasets associated with neuronal regenerative ability revealed circadian rhythms as the most significantly enriched pathway. Subsequently, we demonstrated that sensory neurons possess an endogenous clock and that their regenerative ability displays diurnal oscillations in a murine model of sciatic nerve injury. Consistently, transcriptomic analysis showed a time-of-day-dependent enrichment for processes associated with axonal regeneration and the circadian clock. Conditional deletion experiments demonstrated that Bmal1 is required for neuronal intrinsic circadian regeneration and target re-innervation. Lastly, lithium enhanced nerve regeneration in wild-type but not in clock-deficient mice. Together, these findings demonstrate that the molecular clock fine-tunes the regenerative ability of sensory neurons and propose compounds affecting clock pathways as a novel approach to nerve repair.
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Affiliation(s)
- Francesco De Virgiliis
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London W120NN, UK; Department of Pathology and Immunology, University of Geneva, Geneva 1211, Switzerland.
| | - Franziska Mueller
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London W120NN, UK
| | - Ilaria Palmisano
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London W120NN, UK; Department of Neuroscience, Ohio State College of Medicine, Columbus, OH 43210, USA
| | - Jessica Sarah Chadwick
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London W120NN, UK
| | - Lucia Luengo-Gutierrez
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London W120NN, UK
| | - Angela Giarrizzo
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London W120NN, UK
| | - Yuyang Yan
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London W120NN, UK
| | - Matt Christopher Danzi
- Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami, Miami, FL 33136, USA
| | - Carmen Picon-Muñoz
- Department of Pathology and Immunology, University of Geneva, Geneva 1211, Switzerland
| | - Luming Zhou
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London W120NN, UK
| | - Guiping Kong
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London W120NN, UK
| | - Elisabeth Serger
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London W120NN, UK
| | - Thomas Haynes Hutson
- Defitech Center for Interventional Neurotherapies (NeuroRestore), EPFL/CHUV/UNIL, Lausanne 1015, Switzerland
| | - Ines Maldonado-Lasuncion
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London W120NN, UK
| | - Yayue Song
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London W120NN, UK
| | - Christoph Scheiermann
- Department of Pathology and Immunology, University of Geneva, Geneva 1211, Switzerland
| | - Marco Brancaccio
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London W120NN, UK; UK Dementia Research Institute at Imperial College London, London W120NN, UK.
| | - Simone Di Giovanni
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London W120NN, UK.
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26
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Chen SY, Yang RL, Wu XC, Zhao DZ, Fu SP, Lin FQ, Li LY, Yu LM, Zhang Q, Zhang T. Mesenchymal Stem Cell Transplantation: Neuroprotection and Nerve Regeneration After Spinal Cord Injury. J Inflamm Res 2023; 16:4763-4776. [PMID: 37881652 PMCID: PMC10595983 DOI: 10.2147/jir.s428425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 10/03/2023] [Indexed: 10/27/2023] Open
Abstract
Spinal Cord Injury (SCI), with its morbidity characteristics of high disability rate and high mortality rate, is a disease that is highly destructive to both the physiology and psychology of the patient, and for which there is still a lack of effective treatment. Following spinal cord injury, a cascade of secondary injury reactions known as ischemia, peripheral inflammatory cell infiltration, oxidative stress, etc. create a microenvironment that is unfavorable to neural recovery and ultimately results in apoptosis and necrosis of neurons and glial cells. Mesenchymal stem cell (MSC) transplantation has emerged as a more promising therapeutic options in recent years. MSC can promote spinal cord injury repair through a variety of mechanisms, including immunomodulation, neuroprotection, and nerve regeneration, giving patients with spinal cord injury hope. In this paper, it is discussed the neuroprotection and nerve regeneration components of MSCs' therapeutic method for treating spinal cord injuries.
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Affiliation(s)
- Si-Yu Chen
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Rui-Lin Yang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Xiang-Chong Wu
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - De-Zhi Zhao
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Sheng-Ping Fu
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Feng-Qin Lin
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Lin-Yan Li
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Li-Mei Yu
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Qian Zhang
- Department of Human Anatomy, Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Tao Zhang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
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27
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Nasiri M, Esmaeili J, Tebyani A, Basati H. A review about the role of additives in nerve tissue engineering: growth factors, vitamins, and drugs. Growth Factors 2023; 41:101-113. [PMID: 37343121 DOI: 10.1080/08977194.2023.2226938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 05/08/2023] [Indexed: 06/23/2023]
Abstract
Notably the integration of additives such as growth factors, vitamins, and drugs with scaffolds promoted nerve tissue engineering. This study tried to provide a concise review of all these additives that facilitates nerve regeneration. An attempt was first made to provide information on the main principle of nerve tissue engineering, and then to shed light on the effectiveness of these additives on nerve tissue engineering. Our research has shown that growth factors accelerate cell proliferation and survival, while vitamins play an effective role in cell signalling, differentiation, and tissue growth. They can also act as hormones, antioxidants, and mediators. Drugs also have an excellent and necessary effect on this process by reducing inflammation and immune responses. This review shows that growth factors were more effective than vitamins and drugs in nerve tissue engineering. Nevertheless, vitamins were the most commonly used additive in the production of nerve tissue.
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Affiliation(s)
- Mehrsa Nasiri
- Tissue Engineering Department, TISSUEHUB Co, Tehran, Iran
- Department of Biomedical Engineering, Islamic Azad University Science and Research Branch, Tehran, Iran
| | - Javad Esmaeili
- Tissue Engineering Department, TISSUEHUB Co, Tehran, Iran
- Department of Chemical Engineering, Faculty of Engineering, Arak University, Arak, Iran
| | - Amir Tebyani
- Tissue Engineering Department, TISSUEHUB Co, Tehran, Iran
- Department of Chemical Engineering, Faculty of Engineering, Tehran University, Tehran, Iran
| | - Hojat Basati
- Tissue Engineering Department, TISSUEHUB Co, Tehran, Iran
- Department of Chemical Engineering, Faculty of Engineering, Tehran University, Tehran, Iran
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28
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Chen S, Chen Q, Zhang X, Shen Y, Shi X, Dai X, Yi S. Schwann cell-derived amphiregulin enhances nerve regeneration via supporting the proliferation and migration of Schwann cells and the elongation of axons. J Neurochem 2023; 166:678-691. [PMID: 37439370 DOI: 10.1111/jnc.15916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/29/2023] [Accepted: 06/30/2023] [Indexed: 07/14/2023]
Abstract
Peripheral nerves have limited regeneration ability following nerve injury. Applying growth factors with neurotrophic roles is beneficial for accelerating peripheral nerve regeneration. Here we show that after rat sciatic nerve injury, growth factor amphiregulin (AREG) is upregulated in Schwann cells of sciatic nerves. Elevated AREG stimulates the proliferation and migration of Schwann cells by activating ERK1/2 cascade. Schwann cell-secreted AREG further facilitates the outgrowth of neurites and the elongation of injured axons. Administration of AREG to injured sciatic nerves stimulates the proliferation of Schwann cells to replace lost cell population, encourages the migration of Schwann cells to form cell cords, and facilitates the regrowth of axons. Overall, our results identify AREG as an important neurotrophic factor and thus provide a promising therapeutic avenue towards peripheral nerve injury.
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Affiliation(s)
- Sailing Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Qianqian Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Xiaojiao Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Yinying Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
- Medical School of Nantong University, Nantong University, Nantong, China
| | - Xinyu Shi
- Medical School of Nantong University, Nantong University, Nantong, China
| | - Xiu Dai
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Sheng Yi
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
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29
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Liu Y, Zhang X, Xiao C, Liu B. Engineered hydrogels for peripheral nerve repair. Mater Today Bio 2023; 20:100668. [PMID: 37273791 PMCID: PMC10232914 DOI: 10.1016/j.mtbio.2023.100668] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 05/06/2023] [Accepted: 05/16/2023] [Indexed: 06/06/2023] Open
Abstract
Peripheral nerve injury (PNI) is a complex disease that often appears in young adults. It is characterized by a high incidence, limited treatment options, and poor clinical outcomes. This disease not only causes dysfunction and psychological disorders in patients but also brings a heavy burden to the society. Currently, autologous nerve grafting is the gold standard in clinical treatment, but complications, such as the limited source of donor tissue and scar tissue formation, often further limit the therapeutic effect. Recently, a growing number of studies have used tissue-engineered materials to create a natural microenvironment similar to the nervous system and thus promote the regeneration of neural tissue and the recovery of impaired neural function with promising results. Hydrogels are often used as materials for the culture and differentiation of neurogenic cells due to their unique physical and chemical properties. Hydrogels can provide three-dimensional hydration networks that can be integrated into a variety of sizes and shapes to suit the morphology of neural tissues. In this review, we discuss the recent advances of engineered hydrogels for peripheral nerve repair and analyze the role of several different therapeutic strategies of hydrogels in PNI through the application characteristics of hydrogels in nerve tissue engineering (NTE). Furthermore, the prospects and challenges of the application of hydrogels in the treatment of PNI are also discussed.
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Affiliation(s)
- Yao Liu
- Hand and Foot Surgery Department, First Hospital of Jilin University, Xinmin Street, Changchun, 130061, PR China
| | - Xiaonong Zhang
- Key Laboratory of Polymer Ecomaterials, Jilin Biomedical Polymers Engineering Laboratory, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, PR China
| | - Chunsheng Xiao
- Key Laboratory of Polymer Ecomaterials, Jilin Biomedical Polymers Engineering Laboratory, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, PR China
| | - Bin Liu
- Hand and Foot Surgery Department, First Hospital of Jilin University, Xinmin Street, Changchun, 130061, PR China
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Sousa CS, Lima R, Cibrão JR, Gomes ED, Fernandes LS, Pinho TS, Silva D, Campos J, Salgado AJ, Silva NA. Pre-Clinical Assessment of Roflumilast Therapy in a Thoracic Model of Spinal Cord Injury. Pharmaceutics 2023; 15:1556. [PMID: 37242797 PMCID: PMC10222626 DOI: 10.3390/pharmaceutics15051556] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 05/14/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023] Open
Abstract
The failure of axons to regenerate after a spinal cord injury (SCI) remains one of the greatest challenges in neuroscience. The initial mechanical trauma is followed by a secondary injury cascade, creating a hostile microenvironment, which not only is not permissive to regeneration but also leads to further damage. One of the most promising approaches for promoting axonal regeneration is to maintain the levels of cyclic adenosine monophosphate (cAMP), specifically by a phosphodiesterase-4 (PDE4) inhibitor expressed in neural tissues. Therefore, in our study, we evaluated the therapeutic effect of an FDA-approved PDE4 inhibitor, Roflumilast (Rof), in a thoracic contusion rat model. Results indicate that the treatment was effective in promoting functional recovery. Rof-treated animals showed improvements in both gross and fine motor function. Eight weeks post-injury, the animals significantly recovered by achieving occasional weight-supported plantar steps. Histological assessment revealed a significant decrease in cavity size, less reactive microglia, as well as higher axonal regeneration in treated animals. Molecular analysis revealed that IL-10 and IL-13 levels, as well as VEGF, were increased in the serum of Rof-treated animals. Overall, Roflumilast promotes functional recovery and supports neuroregeneration in a severe thoracic contusion injury model and may be important in SCI treatment.
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Affiliation(s)
- Carla S Sousa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's Associate Lab, PT Government Associated Lab, 4805-017 Guimarães, Portugal
- Department of Neurosurgery, Hospital Garcia de Orta, 2805-267 Almada, Portugal
| | - Rui Lima
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's Associate Lab, PT Government Associated Lab, 4805-017 Guimarães, Portugal
| | - Jorge R Cibrão
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's Associate Lab, PT Government Associated Lab, 4805-017 Guimarães, Portugal
| | - Eduardo D Gomes
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's Associate Lab, PT Government Associated Lab, 4805-017 Guimarães, Portugal
| | - Luís S Fernandes
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's Associate Lab, PT Government Associated Lab, 4805-017 Guimarães, Portugal
| | - Tiffany S Pinho
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's Associate Lab, PT Government Associated Lab, 4805-017 Guimarães, Portugal
| | - Deolinda Silva
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's Associate Lab, PT Government Associated Lab, 4805-017 Guimarães, Portugal
| | - Jonas Campos
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's Associate Lab, PT Government Associated Lab, 4805-017 Guimarães, Portugal
| | - António J Salgado
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's Associate Lab, PT Government Associated Lab, 4805-017 Guimarães, Portugal
| | - Nuno A Silva
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's Associate Lab, PT Government Associated Lab, 4805-017 Guimarães, Portugal
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31
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Redigolo L, Sanfilippo V, La Mendola D, Forte G, Satriano C. Bioinspired Nanoplatforms Based on Graphene Oxide and Neurotrophin-Mimicking Peptides. MEMBRANES 2023; 13:membranes13050489. [PMID: 37233550 DOI: 10.3390/membranes13050489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/22/2023] [Accepted: 04/26/2023] [Indexed: 05/27/2023]
Abstract
Neurotrophins (NTs), which are crucial for the functioning of the nervous system, are also known to regulate vascularization. Graphene-based materials may drive neural growth and differentiation, and, thus, have great potential in regenerative medicine. In this work, we scrutinized the nano-biointerface between the cell membrane and hybrids made of neurotrophin-mimicking peptides and graphene oxide (GO) assemblies (pep-GO), to exploit their potential in theranostics (i.e., therapy and imaging/diagnostics) for targeting neurodegenerative diseases (ND) as well as angiogenesis. The pep-GO systems were assembled via spontaneous physisorption onto GO nanosheets of the peptide sequences BDNF(1-12), NT3(1-13), and NGF(1-14), mimicking the brain-derived neurotrophic factor (BDNF), the neurotrophin 3 (NT3), and the nerve growth factor (NGF), respectively. The interaction of pep-GO nanoplatforms at the biointerface with artificial cell membranes was scrutinized both in 3D and 2D by utilizing model phospholipids self-assembled as small unilamellar vesicles (SUVs) or planar-supported lipid bilayers (SLBs), respectively. The experimental studies were paralleled via molecular dynamics (MD) computational analyses. Proof-of-work in vitro cellular experiments with undifferentiated neuroblastoma (SH-SY5Y), neuron-like, differentiated neuroblastoma (dSH-SY5Y), and human umbilical vein endothelial cells (HUVECs) were carried out to shed light on the capability of the pep-GO nanoplatforms to stimulate the neurite outgrowth as well as tubulogenesis and cell migration.
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Affiliation(s)
- Luigi Redigolo
- Nano Hybrid Biointerfaces Lab (NHBIL), Department of Chemical Sciences, University of Catania, Viale Andrea Doria, 6, 95125 Catania, Italy
| | - Vanessa Sanfilippo
- Nano Hybrid Biointerfaces Lab (NHBIL), Department of Chemical Sciences, University of Catania, Viale Andrea Doria, 6, 95125 Catania, Italy
| | - Diego La Mendola
- Department of Pharmacy, University of Pisa, Via Bonanno Pisano, 6, 56126 Pisa, Italy
| | - Giuseppe Forte
- Department of Drug and Health Science, University of Catania, Viale Andrea Doria, 6, 95125 Catania, Italy
| | - Cristina Satriano
- Nano Hybrid Biointerfaces Lab (NHBIL), Department of Chemical Sciences, University of Catania, Viale Andrea Doria, 6, 95125 Catania, Italy
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Abstract
ABSTRACT Peripheral nerve injury is a common injury disease. Understanding of the mechanisms of periphery nerve repair and regeneration after injury is an essential prerequisite for treating related diseases. Although the biological mechanisms of peripheral nerve injury and regeneration have been studied comprehensively, the clinical treatment methods are still limited. The bottlenecks of the treatments are the shortage of donor nerves and the limited surgical precision. Apart from the knowledge regarding the fundamental characteristics and physical processes of peripheral nerve injury, numerous studies have found that Schwann cells, growth factors, and extracellular matrix are main factors affecting the repair and regeneration process of injured nerves. At present, the therapeutical methods of the disease include microsurgery, autologous nerve transplantation, allograft nerve transplantation and tissue engineering technology. Tissue engineering technology, which combines seed cells, neurotrophic factors, and scaffold materials together, is promising for treating the patients with long-gapped and large nerve damage. With the development of neuron science and technology, the treatment of peripheral nerve injury diseases will continue being improved.
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Bianchini M, Micera S, Redolfi Riva E. Recent Advances in Polymeric Drug Delivery Systems for Peripheral Nerve Regeneration. Pharmaceutics 2023; 15:pharmaceutics15020640. [PMID: 36839962 PMCID: PMC9965241 DOI: 10.3390/pharmaceutics15020640] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 02/17/2023] Open
Abstract
When a traumatic event causes complete denervation, muscle functional recovery is highly compromised. A possible solution to this issue is the implantation of a biodegradable polymeric tubular scaffold, providing a biomimetic environment to support the nerve regeneration process. However, in the case of consistent peripheral nerve damage, the regeneration capabilities are poor. Hence, a crucial challenge in this field is the development of biodegradable micro- nanostructured polymeric carriers for controlled and sustained release of molecules to enhance nerve regeneration. The aim of these systems is to favor the cellular processes that support nerve regeneration to increase the functional recovery outcome. Drug delivery systems (DDSs) are interesting solutions in the nerve regeneration framework, due to the possibility of specifically targeting the active principle within the site of interest, maximizing its therapeutical efficacy. The scope of this review is to highlight the recent advances regarding the study of biodegradable polymeric DDS for nerve regeneration and to discuss their potential to enhance regenerative performance in those clinical scenarios characterized by severe nerve damage.
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Affiliation(s)
- Marta Bianchini
- The BioRobotics Institute, Department of Excellence in Robotics and AI, Scuola Superiore Sant’Anna, 56127 Pisa, Italy
| | - Silvestro Micera
- The BioRobotics Institute, Department of Excellence in Robotics and AI, Scuola Superiore Sant’Anna, 56127 Pisa, Italy
- Translational Neuroengineering, Centre for Neuroprosthetics and Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne (EPFL), 1000 Lausanne, Switzerland
| | - Eugenio Redolfi Riva
- The BioRobotics Institute, Department of Excellence in Robotics and AI, Scuola Superiore Sant’Anna, 56127 Pisa, Italy
- Correspondence:
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Wang X, Xu G, Liu H, Chen Z, Huang S, Yuan J, Xie C, Du L. Inhibiting apoptosis of Schwann cell under the high-glucose condition: A promising approach to treat diabetic peripheral neuropathy using Chinese herbal medicine. Biomed Pharmacother 2023; 157:114059. [PMID: 36462309 DOI: 10.1016/j.biopha.2022.114059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 11/15/2022] [Accepted: 11/27/2022] [Indexed: 12/05/2022] Open
Abstract
Diabetic peripheral neuropathy (DPN) is a common complication of diabetes. Glycemic control and lifestyle alterations cannot prevent the development of DPN; therefore, investigating effective treatments for DPN is crucial. Schwann cells (SCs) maintain the physiological function of peripheral nerves and promote the repair and regeneration of injured nerves. Inhibiting the apoptosis of SCs through various pathological pathways in a high-glucose environment plays an important role in developing DPN. Therefore, inhibiting the apoptosis of SCs can be a novel treatment strategy for DPN. Previous studies have indicated the potential of Chinese herbal medicine (CHM) in treating DPN. In this study, we have reviewed the effects of CHM (both monomers and extracts) on the apoptosis of SCs by interfering with the production of advanced glycation end products, oxidative stress, and endoplasmic reticulum stress pathological pathways. This review will demonstrate the potentialities of CHM in inhibiting apoptosis in SCs, providing new insights and perspectives for treating DPN.
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Affiliation(s)
- Xueru Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu610072, Sichuan, China; TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu, 610072, Sichuan, China.
| | - Gang Xu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu610072, Sichuan, China; TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu, 610072, Sichuan, China.
| | - Hanyu Liu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu610072, Sichuan, China.
| | - Zhengtao Chen
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu610072, Sichuan, China.
| | - Susu Huang
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, China.
| | - Jiushu Yuan
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu610072, Sichuan, China.
| | - Chunguang Xie
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu610072, Sichuan, China; TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu, 610072, Sichuan, China.
| | - Lian Du
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, China.
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Comparative Proteomics Analysis of Growth-Primed Adult Dorsal Root Ganglia Reveals Key Molecular Mediators for Peripheral Nerve Regeneration. eNeuro 2023; 10:ENEURO.0168-22.2022. [PMID: 36526365 PMCID: PMC9829101 DOI: 10.1523/eneuro.0168-22.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 12/02/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
Injuries to peripheral nerves are frequent, yet no drug therapies are available for effective nerve repair. The slow growth rate of axons and inadequate access to growth factors challenge natural repair of nerves. A better understanding of the molecules that can promote the rate of axon growth may reveal therapeutic opportunities. Molecular profiling of injured neurons at early intervals of injury, when regeneration is at the maximum, has been the gold standard for exploring growth promoters. A complementary in vitro regenerative priming model was recently shown to induce enhanced outgrowth in adult sensory neurons. In this work, we exploited the in vitro priming model to reveal novel candidates for adult nerve regeneration. We performed a whole-tissue proteomics analysis of the in vitro primed dorsal root ganglia (DRGs) from adult SD rats and compared their molecular profile with that of the in vivo primed, and control DRGs. The proteomics data generated are available via ProteomeXchange with identifier PXD031927. From the follow-up analysis, Bioinformatics interventions, and literature curation, we identified several molecules that were differentially expressed in the primed DRGs with a potential to modulate adult nerve regrowth. We then validated the growth promoting roles of mesencephalic astrocyte-derived neurotrophic factor (MANF), one of the hits we identified, in adult rat sensory neurons. Overall, in this study, we explored two growth priming paradigm and shortlisted several candidates, and validated MANF, as potential targets for adult nerve regeneration. We also demonstrate that the in vitro priming model is a valid tool for adult nerve regeneration studies.
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36
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Schwann cell functions in peripheral nerve development and repair. Neurobiol Dis 2023; 176:105952. [PMID: 36493976 DOI: 10.1016/j.nbd.2022.105952] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 11/23/2022] [Accepted: 12/05/2022] [Indexed: 12/12/2022] Open
Abstract
The glial cell of the peripheral nervous system (PNS), the Schwann cell (SC), counts among the most multifaceted cells of the body. During development, SCs secure neuronal survival and participate in axonal path finding. Simultaneously, they orchestrate the architectural set up of the developing nerves, including the blood vessels and the endo-, peri- and epineurial layers. Perinatally, in rodents, SCs radially sort and subsequently myelinate individual axons larger than 1 μm in diameter, while small calibre axons become organised in non-myelinating Remak bundles. SCs have a vital role in maintaining axonal health throughout life and several specialized SC types perform essential functions at specific locations, such as terminal SC at the neuromuscular junction (NMJ) or SC within cutaneous sensory end organs. In addition, neural crest derived satellite glia maintain a tight communication with the soma of sensory, sympathetic, and parasympathetic neurons and neural crest derivatives are furthermore an indispensable part of the enteric nervous system. The remarkable plasticity of SCs becomes evident in the context of a nerve injury, where SC transdifferentiate into intriguing repair cells, which orchestrate a regenerative response that promotes nerve repair. Indeed, the multiple adaptations of SCs are captivating, but remain often ill-resolved on the molecular level. Here, we summarize and discuss the knowns and unknowns of the vast array of functions that this single cell type can cover in peripheral nervous system development, maintenance, and repair.
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Axonal Regeneration: Underlying Molecular Mechanisms and Potential Therapeutic Targets. Biomedicines 2022; 10:biomedicines10123186. [PMID: 36551942 PMCID: PMC9775075 DOI: 10.3390/biomedicines10123186] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 11/21/2022] [Accepted: 12/01/2022] [Indexed: 12/13/2022] Open
Abstract
Axons in the peripheral nervous system have the ability to repair themselves after damage, whereas axons in the central nervous system are unable to do so. A common and important characteristic of damage to the spinal cord, brain, and peripheral nerves is the disruption of axonal regrowth. Interestingly, intrinsic growth factors play a significant role in the axonal regeneration of injured nerves. Various factors such as proteomic profile, microtubule stability, ribosomal location, and signalling pathways mark a line between the central and peripheral axons' capacity for self-renewal. Unfortunately, glial scar development, myelin-associated inhibitor molecules, lack of neurotrophic factors, and inflammatory reactions are among the factors that restrict axonal regeneration. Molecular pathways such as cAMP, MAPK, JAK/STAT, ATF3/CREB, BMP/SMAD, AKT/mTORC1/p70S6K, PI3K/AKT, GSK-3β/CLASP, BDNF/Trk, Ras/ERK, integrin/FAK, RhoA/ROCK/LIMK, and POSTN/integrin are activated after nerve injury and are considered significant players in axonal regeneration. In addition to the aforementioned pathways, growth factors, microRNAs, and astrocytes are also commendable participants in regeneration. In this review, we discuss the detailed mechanism of each pathway along with key players that can be potentially valuable targets to help achieve quick axonal healing. We also identify the prospective targets that could help close knowledge gaps in the molecular pathways underlying regeneration and shed light on the creation of more powerful strategies to encourage axonal regeneration after nervous system injury.
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Chernov AV, Shubayev VI. Sexual dimorphism of early transcriptional reprogramming in degenerating peripheral nerves. Front Mol Neurosci 2022; 15:1029278. [DOI: 10.3389/fnmol.2022.1029278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 10/06/2022] [Indexed: 11/13/2022] Open
Abstract
Sexual dimorphism is a powerful yet understudied factor that influences the timing and efficiency of gene regulation in axonal injury and repair processes in the peripheral nervous system. Here, we identified common and distinct biological processes in female and male degenerating (distal) nerve stumps based on a snapshot of transcriptional reprogramming 24 h after axotomy reflecting the onset of early phase Wallerian degeneration (WD). Females exhibited transcriptional downregulation of a larger number of genes than males. RhoGDI, ERBB, and ERK5 signaling pathways increased activity in both sexes. Males upregulated genes and canonical pathways that exhibited robust baseline expression in females in both axotomized and sham nerves, including signaling pathways controlled by neuregulin and nerve growth factors. Cholesterol biosynthesis, reelin signaling, and synaptogenesis signaling pathways were downregulated in females. Signaling by Rho Family GTPases, cAMP-mediated signaling, and sulfated glycosaminoglycan biosynthesis were downregulated in both sexes. Estrogens potentially influenced sex-dependent injury response due to distinct regulation of estrogen receptor expression. A crosstalk of cytokines and growth hormones could promote sexually dimorphic transcriptional responses. We highlighted prospective regulatory activities due to protein phosphorylation, extracellular proteolysis, sex chromosome-specific expression, major urinary proteins (MUPs), and genes involved in thyroid hormone metabolism. Combined with our earlier findings in the corresponding dorsal root ganglia (DRG) and regenerating (proximal) nerve stumps, sex-specific and universal early phase molecular triggers of WD enrich our knowledge of transcriptional regulation in peripheral nerve injury and repair.
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Jiang Y, Tang X, Li T, Ling J, Yang Y. The success of biomaterial-based tissue engineering strategies for peripheral nerve regeneration. Front Bioeng Biotechnol 2022; 10:1039777. [PMID: 36329703 PMCID: PMC9622790 DOI: 10.3389/fbioe.2022.1039777] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 10/04/2022] [Indexed: 11/26/2022] Open
Abstract
Peripheral nerve injury is a clinically common injury that causes sensory dysfunction and locomotor system degeneration, which seriously affects the quality of the patients' daily life. Long gapped defects in large nerve are difficult to repair via surgery and limited donor source of autologous nerve greatly challenges the successful nerve repair by transplantation. Significantly, remarkable progress has been made in repairing the peripheral nerve injury using artificial nerve grafts and a variety of products for peripheral nerve repair have emerged been approved globally in recent years. The raw materials of these commercial products includes natural/synthetic polymers, extracellular matrix. Despite a lot of effort, the desirable functional recovery still remains great challenges in long gapped nerve defects. Thus this review discusses the recent development of tissue engineering products for peripheral nerve repair and the design of bionic grafts improving the local microenvironment for accelerating nerve regeneration against locomotor disorder, which may provide potential strategies for the repair of long gaps or thick nerve defects by multifunctional biomaterials.
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Affiliation(s)
- Yuhui Jiang
- Medical School of Nantong University, Nantong University, Nantong, China
- Key Laboratory of Neuroregeneration, Ministry of Education and Jiangsu Province, Co-innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, China
| | - Xiaoxuan Tang
- Medical School of Nantong University, Nantong University, Nantong, China
- Key Laboratory of Neuroregeneration, Ministry of Education and Jiangsu Province, Co-innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, China
| | - Tao Li
- Key Laboratory of Neuroregeneration, Ministry of Education and Jiangsu Province, Co-innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, China
| | - Jue Ling
- Key Laboratory of Neuroregeneration, Ministry of Education and Jiangsu Province, Co-innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, China
| | - Yumin Yang
- Medical School of Nantong University, Nantong University, Nantong, China
- Key Laboratory of Neuroregeneration, Ministry of Education and Jiangsu Province, Co-innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, China
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40
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Kim M, Hyun SH. Neurotrophic factors in the porcine ovary: Their effects on follicular growth, oocyte maturation, and developmental competence. Front Vet Sci 2022; 9:931402. [PMID: 36032306 PMCID: PMC9399750 DOI: 10.3389/fvets.2022.931402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 07/20/2022] [Indexed: 12/01/2022] Open
Abstract
Pigs are cost-effective industrial animals because they produce a large number of offspring and have shorter rebreeding intervals compared with other animals, such as non-human primates. The reproductive physiology of pigs has been studied over the past several decades. However, there is not enough research on the effects of the neurotrophic factors on the ovarian physiology and development in pigs. As the ovary is a highly innervated organ, various neurotrophic factors during ovarian development can promote the growth of nerve fibers and improve the development of ovarian cells. Thus, investigating the role of neurotrophic factors on ovarian development, and the relationship between neurotrophic factors and porcine female reproduction is worth studying. In this review, we focused on the physiological roles of various neurotrophic factors in porcine ovaries and summarized the current status of the studies related to the relationship between neurotrophic factors and porcine ovarian development.
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Affiliation(s)
- Mirae Kim
- Laboratory of Veterinary Embryology and Biotechnology, Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, South Korea
- Institute of Stem Cell and Regenerative Medicine, Chungbuk National University, Cheongju, South Korea
| | - Sang-Hwan Hyun
- Laboratory of Veterinary Embryology and Biotechnology, Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, South Korea
- Institute of Stem Cell and Regenerative Medicine, Chungbuk National University, Cheongju, South Korea
- Graduate School of Veterinary Biosecurity and Protection, Chungbuk National University, Cheongju, South Korea
- *Correspondence: Sang-Hwan Hyun
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41
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Rao Z, Lin Z, Song P, Quan D, Bai Y. Biomaterial-Based Schwann Cell Transplantation and Schwann Cell-Derived Biomaterials for Nerve Regeneration. Front Cell Neurosci 2022; 16:926222. [PMID: 35836742 PMCID: PMC9273721 DOI: 10.3389/fncel.2022.926222] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 05/31/2022] [Indexed: 12/13/2022] Open
Abstract
Schwann cells (SCs) dominate the regenerative behaviors after peripheral nerve injury by supporting axonal regrowth and remyelination. Previous reports also demonstrated that the existence of SCs is beneficial for nerve regeneration after traumatic injuries in central nervous system. Therefore, the transplantation of SCs/SC-like cells serves as a feasible cell therapy to reconstruct the microenvironment and promote nerve functional recovery for both peripheral and central nerve injury repair. However, direct cell transplantation often leads to low efficacy, due to injection induced cell damage and rapid loss in the circulatory system. In recent years, biomaterials have received great attention as functional carriers for effective cell transplantation. To better mimic the extracellular matrix (ECM), many biodegradable materials have been engineered with compositional and/or topological cues to maintain the biological properties of the SCs/SCs-like cells. In addition, ECM components or factors secreted by SCs also actively contribute to nerve regeneration. Such cell-free transplantation approaches may provide great promise in clinical translation. In this review, we first present the current bio-scaffolds engineered for SC transplantation and their achievement in animal models and clinical applications. To this end, we focus on the physical and biological properties of different biomaterials and highlight how these properties affect the biological behaviors of the SCs/SC-like cells. Second, the SC-derived biomaterials are also reviewed and discussed. Finally, the relationship between SCs and functional biomaterials is summarized, and the trends of their future development are predicted toward clinical applications.
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Affiliation(s)
- Zilong Rao
- Guangdong Engineering Technology Research Centre for Functional Biomaterials, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, China
| | - Zudong Lin
- PCFM Lab, GD HPPC Lab, School of Chemistry, Sun Yat-sen University, Guangzhou, China
| | - Panpan Song
- Guangdong Engineering Technology Research Centre for Functional Biomaterials, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, China
| | - Daping Quan
- Guangdong Engineering Technology Research Centre for Functional Biomaterials, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, China
| | - Ying Bai
- Guangdong Engineering Technology Research Centre for Functional Biomaterials, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, China
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42
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The Bridging Effect of Controlled-Release Glial Cell-Derived Neurotrophic Factor Microcapsules within Nerve Conduits on Rat Facial Nerve Regeneration. DISEASE MARKERS 2022; 2022:8942985. [PMID: 35774850 PMCID: PMC9239766 DOI: 10.1155/2022/8942985] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/09/2022] [Accepted: 05/30/2022] [Indexed: 12/04/2022]
Abstract
Objectives The study is aimed at exploring the effect of the controlled release of the glial-derived neurotrophic factor (GDNF) on nerve regeneration. Methods The PLGA/chitosan composite nerve conduit was used to bridge the dissected trunk of the rat facial nerve. GDNF microcapsules were loaded into the nerve conduit. Nine weeks after surgery, the facial nerve zygomatic and buccal branches were labeled with fluorescent indicators. The incorrectly grown facial neurons were reversed and counted. The facial nerve functional recovery was assessed by measuring the maximum evoked potential. Results The nerve conduit was filled with different regenerating factors, such as the GDNF, GDNF microcapsules, or saline (control). The number of incorrectly regenerated neurons was lower with the nerve conduits filled with GDNF microcapsules than with those supplied with just the GDNF. However, neither the GDNF nor GDNF microcapsules affected the number of regenerated neurons. The functional recovery of the facial nerve was the best, with the nerve conduit filled with GDNF microcapsules closest to the healthy uncut facial nerve. Conclusion The stable slow-release GNDF microcapsule inside the biodegradable nerve conduit can reduce the extent of incorrect growth of the facial nerve neuron when bridging the dissected rat facial nerve trunk. The technique has a good effect on functional nerve recovery.
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43
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Wang L, Fu LL, Deng ZR, Zhang J, Zu MD, Wu JC, Wang Y. Overexpression of BDNF in the ventrolateral periaqueductal gray regulates the behavior of epilepsy-migraine comorbid rats. Brain Behav 2022; 12:e2594. [PMID: 35557046 PMCID: PMC9226826 DOI: 10.1002/brb3.2594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 02/15/2022] [Accepted: 04/04/2022] [Indexed: 11/21/2022] Open
Abstract
OBJECTIVE To investigate the effects of brain-derived neurotrophic factor (BDNF) overexpression in the ventrolateral periaqueductal gray (vlPAG) on behavioral changes in epilepsy-migraine comorbid rats. METHOD We used an adeno-associated virus (AAV)-mediated vector to supplement BDNF in the vlPAG area prior to the establishment of a pilocarpine-nitroglycerin (Pilo-NTG) combination-induced comorbid model of epilepsy and migraine. Seizure- and migraine-related behaviors were analyzed. Cell loss and apoptosis in vlPAG were detected through hematoxylin-eosin (HE) and TUNEL staining. Immunofluorescence staining analyses were employed to detect expressions of BDNF and its receptor, tyrosine kinase B (TrkB), in vlPAG. Immunohistochemical staining was conducted to detect expressions of c-Fos and calcitonin gene-related peptide (CGRP) in the trigeminal nucleus caudalis (TNC) and trigeminal ganglion (TG). RESULTS Comparing to control group, AAV-BDNF injected comorbid group showed lower pain sensitivity, scratching head, and spontaneous seizures accompanied by the downregulation of c-Fos labeling neurons and CGRP immunoreactivity in the TNC and TG. However, these changes were still significantly higher in the comorbid group than those in both epilepsy and migraine groups under the same intervention. CONCLUSION These data demonstrated that supplying BDNF to vlPAG may protect structural and functional abnormalities in vlPAG and provide an antiepileptic and analgesic therapy.
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Affiliation(s)
- Long Wang
- Department of Neurology, The Second People's Hospital of Hefei, Hefei, China.,Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Lu-Lan Fu
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zi-Ru Deng
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Juan Zhang
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Mei-Dan Zu
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jun-Cang Wu
- Department of Neurology, The Second People's Hospital of Hefei, Hefei, China
| | - Yu Wang
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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44
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Liu Z, Liu Y, Yushan M, Yusufu A. Enhanced Nerve Regeneration by Bionic Conductive Nerve Scaffold Under Electrical Stimulation. Front Neurosci 2022; 16:810676. [PMID: 35573307 PMCID: PMC9091912 DOI: 10.3389/fnins.2022.810676] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 02/14/2022] [Indexed: 11/15/2022] Open
Abstract
Repair of peripheral nerve defect (PND) with a poor prognosis is hard to deal with. Neural conduit applied to nerve defect at present could not achieve the effect of autologous nerve transplantation. We prepared bionic conductive neural scaffolds to provide a new strategy for the treatment of PNDs. The highly aligned poly (L-lactic acid) (PLLA) fiber mats and the multi-microchannel conductive scaffolds were combined into bionic conductive nerve scaffolds, which were implanted into rats with sciatic nerve defects. The experimental animals were divided into the scaffold group (S), scaffold with electrical stimulation (ES) group (S&E), and autologous nerve transplantation group (AT). The regenerative effect of bionic conductive nerve scaffolds was analyzed. Compared with aligned PLLA fiber mats (APFMs), highly aligned fiber mats had a higher fiber orientation and did not change the tensile strength, Young’s modulus, degradation rate, elongation at break of the fiber membrane, and biocompatibility. The bionic conductive nerve scaffolds were well matched with the rat sciatic nerve. The evaluations of the sciatic nerve in Group S&E were close to those in Group AT and better than those in Group S. Immunohistochemical results showed that the expression levels of neurofilament heavy polypeptide (NF-H) and protein S100-B (S100-β) in Group S&E were higher than those in Group S, and the expression levels of low-density lipoprotein receptor-related protein 4 (LRP4), mitogen-activated protein kinase (MAPK) p38, extracellular signal-regulated kinase (ERK), and mitogen-activated protein kinase kinase (MEK) in Group AT were higher than those in Group S. Bionic conductive nerve scaffolds combined with ES could enhance peripheral nerve regeneration and achieve satisfactory nerve regeneration close to autologous nerve grafts. ERK, p38 MAPK, MEK, and LRP4 may be involved in peripheral nerve regeneration under ES.
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Affiliation(s)
- Zhenhui Liu
- Department of Orthopedics, Henan Provincial People’s Hospital, Zhengzhou, China
- People’s Hospital of Zhengzhou University, Zhengzhou, China
- People’s Hospital of Henan University, Zhengzhou, China
- Department of Trauma and Micro Reconstructive Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Yanshi Liu
- Department of Trauma and Micro Reconstructive Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Maimaiaili Yushan
- Department of Trauma and Micro Reconstructive Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Aihemaitijiang Yusufu
- Department of Trauma and Micro Reconstructive Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
- *Correspondence: Aihemaitijiang Yusufu,
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45
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Abstract
Diabetic neuropathy is a commonly occurring complication of diabetes that affects hundreds of millions of patients worldwide. Patients suffering from diabetic neuropathy experience abnormal sensations and have damage in their peripheral nerve axons as well as myelin, a tightly packed Schwann cell sheath that wraps around axons to provide insulation and increases electrical conductivity along the nerve fibers. The molecular events underlying myelin damage in diabetic neuropathy are largely unknown, and there is no efficacious treatment for the disease. The current study, using a diabetic mouse model and human patient nerve samples, uncovered a molecular mechanism underlying myelin sheath damage in diabetic neuropathy and provides a potential treatment strategy for the disease. Demyelination is a pathological feature of diabetic neuropathy, a common and painful complication of diabetes, yet the mechanisms underlying diabetes-induced demyelination remain unclear. Here, we show that targeting mixed lineage kinase domain–like protein (MLKL), a protein critical in necroptosis, using Schwann cell–specific genetic knockout, S441A single–amino acid knockin mutation, or pharmacological inhibition all blocked myelin sheath decompaction and prevented the decrease of nerve conduction velocity in streptozotocin-induced diabetic mice. The decompaction of the myelin sheaths of sural nerves was observed in biopsy samples from diabetic patients, and the MLKL-mediated myelin breakdown was activated in human diabetic neuropathy patients. Our study establishes a direct myelin degradation–related role for MLKL in diabetic neuropathy and defines MLKL as a druggable target for developing agents to prevent or treat diabetic neuropathy.
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46
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Mann A, Steinecker-Frohnwieser B, Naghilou A, Millesi F, Supper P, Semmler L, Wolf S, Marinova L, Weigl L, Weiss T, Radtke C. Nuclear Magnetic Resonance Treatment Accelerates the Regeneration of Dorsal Root Ganglion Neurons in vitro. Front Cell Neurosci 2022; 16:859545. [PMID: 35418835 PMCID: PMC8995532 DOI: 10.3389/fncel.2022.859545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 03/03/2022] [Indexed: 11/15/2022] Open
Abstract
Functional recovery from peripheral nerve injuries depends on a multitude of factors. Schwann cells (SCs) are key players in the regenerative process as they develop repair-specific functions to promote axon regrowth. However, chronically denervated SCs lose their repair phenotype, which is considered as a main reason for regeneration failure. Previous studies reported a modulatory effect of low nuclear magnetic resonance therapy (NMRT) on cell proliferation and gene expression. To provide first insight into a possible effect of NMRT on cells involved in peripheral nerve regeneration, this study investigated whether NMRT is able to influence the cellular behavior of primary SC and dorsal root ganglion (DRG) neuron cultures in vitro. The effect of NMRT on rat SCs was evaluated by comparing the morphology, purity, proliferation rate, and expression levels of (repair) SC associated genes between NMRT treated and untreated SC cultures. In addition, the influence of (1) NMRT and (2) medium obtained from NMRT treated SC cultures on rat DRG neuron regeneration was examined by analyzing neurite outgrowth and the neuronal differentiation status. Our results showed that NMRT stimulated the proliferation of SCs without changing their morphology, purity, or expression of (repair) SC associated markers. Furthermore, NMRT promoted DRG neuron regeneration shown by an increased cell survival, enhanced neurite network formation, and progressed neuronal differentiation status. Furthermore, the medium of NMRT treated SC cultures was sufficient to support DRG neuron survival and neurite outgrowth. These findings demonstrate a beneficial impact of NMRT on DRG neuron survival and neurite formation, which is primarily mediated via SC stimulation. Our data suggest that NMRT could be suitable as a non-invasive auxiliary treatment option for peripheral nerve injuries and encourage future studies that investigate the effect of NMRT in a physiological context.
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Affiliation(s)
- Anda Mann
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
| | | | - Aida Naghilou
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
| | - Flavia Millesi
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Paul Supper
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
| | - Lorenz Semmler
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
| | - Sonja Wolf
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
| | - Lena Marinova
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
| | - Lukas Weigl
- Department of Special Anesthesia and Pain Therapy, Medical University of Vienna, Vienna, Austria
| | - Tamara Weiss
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
- *Correspondence: Tamara Weiss,
| | - Christine Radtke
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
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Bittner GD, Bushman JS, Ghergherehchi CL, Roballo KCS, Shores JT, Smith TA. Typical and atypical properties of peripheral nerve allografts enable novel strategies to repair segmental-loss injuries. J Neuroinflammation 2022; 19:60. [PMID: 35227261 PMCID: PMC8886977 DOI: 10.1186/s12974-022-02395-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 01/19/2022] [Indexed: 12/20/2022] Open
Abstract
We review data showing that peripheral nerve injuries (PNIs) that involve the loss of a nerve segment are the most common type of traumatic injury to nervous systems. Segmental-loss PNIs have a poor prognosis compared to other injuries, especially when one or more mixed motor/sensory nerves are involved and are typically the major source of disability associated with extremities that have sustained other injuries. Relatively little progress has been made, since the treatment of segmental loss PNIs with cable autografts that are currently the gold standard for repair has slow and incomplete (often non-existent) functional recovery. Viable peripheral nerve allografts (PNAs) to repair segmental-loss PNIs have not been experimentally or clinically useful due to their immunological rejection, Wallerian degeneration (WD) of anucleate donor graft and distal host axons, and slow regeneration of host axons, leading to delayed re-innervation and producing atrophy or degeneration of distal target tissues. However, two significant advances have recently been made using viable PNAs to repair segmental-loss PNIs: (1) hydrogel release of Treg cells that reduce the immunological response and (2) PEG-fusion of donor PNAs that reduce the immune response, reduce and/or suppress much WD, immediately restore axonal conduction across the donor graft and re-innervate many target tissues, and restore much voluntary behavioral functions within weeks, sometimes to levels approaching that of uninjured nerves. We review the rather sparse cellular/biochemical data for rejection of conventional PNAs and their acceptance following Treg hydrogel and PEG-fusion of PNAs, as well as cellular and systemic data for their acceptance and remarkable behavioral recovery in the absence of tissue matching or immune suppression. We also review typical and atypical characteristics of PNAs compared with other types of tissue or organ allografts, problems and potential solutions for PNA use and storage, clinical implications and commercial availability of PNAs, and future possibilities for PNAs to repair segmental-loss PNIs.
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Affiliation(s)
- George D Bittner
- Department of Neuroscience, University of Texas at Austin, Austin, TX, 78712, USA.
| | - Jared S Bushman
- School of Pharmacy, University of Wyoming, Laramie, WY, 82072, USA
| | - Cameron L Ghergherehchi
- Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX, 78712, USA
| | | | - Jaimie T Shores
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Tyler A Smith
- Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX, 78712, USA
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48
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Does hyperbaric oxygen therapy facilitate peripheral nerve recovery in upper extremity injuries? A prospective study of 74 patients. Eur J Trauma Emerg Surg 2022; 48:3997-4003. [DOI: 10.1007/s00068-022-01920-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 02/12/2022] [Indexed: 11/03/2022]
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49
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Drewry M, Dailey MT, Rothermund K, Backman C, Dahl KN, Syed-Picard FN. Promoting and Orienting Axon Extension Using Scaffold-Free Dental Pulp Stem Cell Sheets. ACS Biomater Sci Eng 2022; 8:814-825. [PMID: 34982537 PMCID: PMC9821555 DOI: 10.1021/acsbiomaterials.1c01517] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Current treatments of facial nerve injury result in poor functional outcomes due to slow and inefficient axon regeneration and aberrant reinnervation. To address these clinical challenges, bioactive scaffold-free cell sheets were engineered using neurotrophic dental pulp stem/progenitor cells (DPCs) and their aligned extracellular matrix (ECM). DPCs endogenously supply high levels of neurotrophic factors (NTFs), growth factors capable of stimulating axonal regeneration, and an aligned ECM provides guidance cues to direct axon extension. Human DPCs were grown on a substrate comprising parallel microgrooves, inducing the cells to align and deposit a linearly aligned, collagenous ECM. The resulting cell sheets were robust and could be easily removed from the underlying substrate. DPC sheets produced NTFs at levels previously shown capable of promoting axon regeneration, and, moreover, inducing DPC alignment increased the expression of select NTFs relative to unaligned controls. Furthermore, the aligned DPC sheets were able to stimulate functional neuritogenic effects in neuron-like cells in vitro. Neuronally differentiated neuroblastoma SH-SY5Y cells produced neurites that were significantly more oriented and less branched when cultured on aligned cell sheets relative to unaligned sheets. These data demonstrate that the linearly aligned DPC sheets can biomechanically support axon regeneration and improve axonal guidance which, when applied to a facial nerve injury, will result in more accurate reinnervation. The aligned DPC sheets generated here could be used in combination with commercially available nerve conduits to enhance their bioactivity or be formed into stand-alone scaffold-free nerve conduits capable of facilitating improved facial nerve recovery.
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Affiliation(s)
- Michelle
D. Drewry
- Department
of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States
| | - Matthew T. Dailey
- Department
of Oral and Maxillofacial Surgery, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States
| | - Kristi Rothermund
- Department
of Oral Biology and Center for Craniofacial Regeneration, School of
Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States
| | - Charles Backman
- Department
of Chemical Engineering, College of Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States
| | - Kris N. Dahl
- Department
of Chemical Engineering, College of Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States,Department
of Biomedical Engineering, College of Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States,McGowan
Institute for Regenerative Medicine, Pittsburgh, Pennsylvania 15219, United States,Forensics, Thornton Tomasetti, New York, New York 10271, United States
| | - Fatima N. Syed-Picard
- Department
of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States,Department
of Oral Biology and Center for Craniofacial Regeneration, School of
Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States,McGowan
Institute for Regenerative Medicine, Pittsburgh, Pennsylvania 15219, United States,. Phone: 412-648-8824
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50
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Jessen KR, Mirsky R. The Role of c-Jun and Autocrine Signaling Loops in the Control of Repair Schwann Cells and Regeneration. Front Cell Neurosci 2022; 15:820216. [PMID: 35221918 PMCID: PMC8863656 DOI: 10.3389/fncel.2021.820216] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 12/30/2021] [Indexed: 12/12/2022] Open
Abstract
After nerve injury, both Schwann cells and neurons switch to pro-regenerative states. For Schwann cells, this involves reprogramming of myelin and Remak cells to repair Schwann cells that provide the signals and mechanisms needed for the survival of injured neurons, myelin clearance, axonal regeneration and target reinnervation. Because functional repair cells are essential for regeneration, it is unfortunate that their phenotype is not robust. Repair cell activation falters as animals get older and the repair phenotype fades during chronic denervation. These malfunctions are important reasons for the poor outcomes after nerve damage in humans. This review will discuss injury-induced Schwann cell reprogramming and the concept of the repair Schwann cell, and consider the molecular control of these cells with emphasis on c-Jun. This transcription factor is required for the generation of functional repair cells, and failure of c-Jun expression is implicated in repair cell failures in older animals and during chronic denervation. Elevating c-Jun expression in repair cells promotes regeneration, showing in principle that targeting repair cells is an effective way of improving nerve repair. In this context, we will outline the emerging evidence that repair cells are sustained by autocrine signaling loops, attractive targets for interventions aimed at promoting regeneration.
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Affiliation(s)
- Kristjan R. Jessen
- Department of Cell and Developmental Biology, University College London, London, United Kingdom
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