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1.
Facial Plast Surg ; 40(4): 424-432, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38378042

RESUMEN

Deficits in corneal innervation lead to neurotrophic keratopathy (NK). NK is frequently associated with facial palsy, and corneal damage can be accelerated by facial palsy deficits. Corneal nerves are important regulators of limbal stem cells, which play a critical role in epithelial maintenance and healing. Nonsurgical treatments of NK have undergone recent innovation, and growth factors implicated in corneal epithelial renewal are a promising therapeutic avenue. However, surgical intervention with corneal neurotization (CN) remains the only definitive treatment of NK. CN involves the transfer of unaffected sensory donor nerve branches to the affected cornea, and a variety of donor nerves and approaches have been described. CN can be performed in a direct or indirect manner; employ the supraorbital, supratrochlear, infraorbital, or great auricular nerves; and utilize autograft, allograft, or nerve transfer alone. Unfortunately, comparative studies of these factors are limited due to the procedure's novelty and varied recovery timelines after CN. Regardless of the chosen approach, CN has been shown to be a safe and effective procedure to restore corneal sensation and improve visual acuity in patients with NK.


Asunto(s)
Córnea , Enfermedades de la Córnea , Parálisis Facial , Transferencia de Nervios , Humanos , Córnea/inervación , Córnea/cirugía , Enfermedades de la Córnea/cirugía , Parálisis Facial/cirugía , Transferencia de Nervios/métodos
2.
Int J Mol Sci ; 24(16)2023 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-37628951

RESUMEN

Peripheral nerve injuries have far-reaching implications for individuals and society, leading to functional impairments, prolonged rehabilitation, and substantial socioeconomic burdens. Tacrolimus, a potent immunosuppressive drug known for its neuroregenerative properties, has emerged in experimental studies as a promising candidate to accelerate nerve fiber regeneration. This review investigates the therapeutic potential of tacrolimus by exploring the postulated mechanisms of action in relation to biological barriers to nerve injury recovery. By mapping both the preclinical and clinical evidence, the benefits and drawbacks of systemic tacrolimus administration and novel delivery systems for localized tacrolimus delivery after nerve injury are elucidated. Through synthesizing the current evidence, identifying practical barriers for clinical translation, and discussing potential strategies to overcome the translational gap, this review provides insights into the translational perspectives of tacrolimus as an adjunct therapy for nerve regeneration.


Asunto(s)
Medicina , Tacrolimus , Humanos , Tacrolimus/farmacología , Tacrolimus/uso terapéutico , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Administración Cutánea , Regeneración Nerviosa
3.
Int J Mol Sci ; 24(16)2023 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-37628793

RESUMEN

The cornea is the window through which we see the world. Corneal clarity is required for vision, and blindness occurs when the cornea becomes opaque. The cornea is covered by unique transparent epithelial cells that serve as an outermost cellular barrier bordering between the cornea and the external environment. Corneal sensory nerves protect the cornea from injury by triggering tearing and blink reflexes, and are also thought to regulate corneal epithelial renewal via unknown mechanism(s). When protective corneal sensory innervation is absent due to infection, trauma, intracranial tumors, surgery, or congenital causes, permanent blindness results from repetitive epithelial microtraumas and failure to heal. The condition is termed neurotrophic keratopathy (NK), with an incidence of 5:10,000 people worldwide. In this report, we review the currently available therapeutic solutions for NK and discuss the progress in our understanding of how the sensory nerves induce corneal epithelial renewal.


Asunto(s)
Distrofias Hereditarias de la Córnea , Fenómenos Fisiológicos del Sistema Nervioso , Humanos , Córnea , Ceguera , Vías Aferentes
4.
J Neurosci ; 34(15): 5089-98, 2014 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-24719088

RESUMEN

Clustering of Na(+) channels at the nodes of Ranvier is coordinated by myelinating glia. In the peripheral nervous system, axoglial contact at the nodes is mediated by the binding of gliomedin and glial NrCAM to axonal neurofascin 186 (NF186). This interaction is crucial for the initial clustering of Na(+) channels at heminodes. As a result, it is not clear whether continued axon-glial contact at nodes of Ranvier is required to maintain these channels at the nodal axolemma. Here, we report that, in contrast to mice that lack either gliomedin or NrCAM, absence of both molecules (and hence the glial clustering signal) resulted in a gradual loss of Na(+) channels and other axonal components from the nodes, the formation of binary nodes, and dysregulation of nodal gap length. Therefore, these mice exhibit neurological abnormalities and slower nerve conduction. Disintegration of the nodes occurred in an orderly manner, starting with the disappearance of neurofascin 186, followed by the loss of Na(+) channels and ankyrin G, and then ßIV spectrin, a sequence that reflects the assembly of nodes during development. Finally, the absence of gliomedin and NrCAM led to the invasion of the outermost layer of the Schwann cell membrane beyond the nodal area and the formation of paranodal-like junctions at the nodal gap. Our results reveal that axon-glial contact mediated by gliomedin, NrCAM, and NF186 not only plays a role in Na(+) channel clustering during development, but also contributes to the long-term maintenance of Na(+) channels at nodes of Ranvier.


Asunto(s)
Moléculas de Adhesión Celular Neuronal/metabolismo , Moléculas de Adhesión Celular/metabolismo , Neuroglía/metabolismo , Nódulos de Ranvier/metabolismo , Canales de Sodio Activados por Voltaje/metabolismo , Potenciales de Acción , Animales , Ancirinas/metabolismo , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular Neuronal/genética , Membrana Celular/metabolismo , Femenino , Eliminación de Gen , Masculino , Ratones , Factores de Crecimiento Nervioso/genética , Factores de Crecimiento Nervioso/metabolismo , Transporte de Proteínas , Nódulos de Ranvier/fisiología , Espectrina/metabolismo
5.
Hum Mol Genet ; 21(9): 1954-67, 2012 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-22262731

RESUMEN

Apoptosis, or programmed cell death, is a cellular pathway involved in normal cell turnover, developmental tissue remodeling, embryonic development, cellular homeostasis maintenance and chemical-induced cell death. Caspases are a family of intracellular proteases that play a key role in apoptosis. Aberrant activation of caspases has been implicated in human diseases. In particular, numerous findings implicate Caspase-6 (Casp6) in neurodegenerative diseases, including Alzheimer disease (AD) and Huntington disease (HD), highlighting the need for a deeper understanding of Casp6 biology and its role in brain development. The use of targeted caspase-deficient mice has been instrumental for studying the involvement of caspases in apoptosis. The goal of this study was to perform an in-depth neuroanatomical and behavioral characterization of constitutive Casp6-deficient (Casp6-/-) mice in order to understand the physiological function of Casp6 in brain development, structure and function. We demonstrate that Casp6-/- neurons are protected against excitotoxicity, nerve growth factor deprivation and myelin-induced axonal degeneration. Furthermore, Casp6-deficient mice show an age-dependent increase in cortical and striatal volume. In addition, these mice show a hypoactive phenotype and display learning deficits. The age-dependent behavioral and region-specific neuroanatomical changes observed in the Casp6-/- mice suggest that Casp6 deficiency has a more pronounced effect in brain regions that are involved in neurodegenerative diseases, such as the striatum in HD and the cortex in AD.


Asunto(s)
Caspasa 6/fisiología , Degeneración Nerviosa/enzimología , Envejecimiento/patología , Envejecimiento/fisiología , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/patología , Animales , Apoptosis/fisiología , Secuencia de Bases , Conducta Animal/fisiología , Encéfalo/enzimología , Encéfalo/patología , Caspasa 6/deficiencia , Caspasa 6/genética , Humanos , Enfermedad de Huntington/enzimología , Enfermedad de Huntington/patología , Ratones , Ratones Noqueados , Actividad Motora/fisiología , Degeneración Nerviosa/genética , Degeneración Nerviosa/patología , Neuronas/enzimología , Neuronas/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de N-Metil-D-Aspartato/fisiología
6.
Bioengineering (Basel) ; 11(8)2024 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-39199733

RESUMEN

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.

7.
Invest Ophthalmol Vis Sci ; 64(4): 7, 2023 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-37036418

RESUMEN

Purpose: Corneal sensory nerves protect the cornea from injury. They are also thought to stimulate limbal stem cells (LSCs) to produce transparent epithelial cells constantly, enabling vision. In other organs, Schwann cells (SCs) associated with tissue-innervating axon terminals mediate tissue regeneration. This study defines the critical role of the corneal axon-ensheathing SCs in homeostatic and regenerative corneal epithelial cell renewal. Methods: SC localization in the cornea was determined by in situ hybridization and immunohistochemistry with SC markers. In vivo SC visualization and/or ablation were performed in mice with inducible corneal SC-specific expression of tdTomato and/or Diphtheria toxin, respectively. The relative locations of SCs and LSCs were observed with immunohistochemical analysis of harvested genetically SC-prelabeled mouse corneas with LSC-specific antibodies. The correlation between cornea-innervating axons and the appearance of SCs was ascertained using corneal denervation in rats. To determine the limbal niche cellular composition and gene expression changes associated with innervation-dependent epithelial renewal, single-cell RNA sequencing (scRNA-seq) of dissociated healthy, de-epithelized, and denervated cornea limbi was performed. Results: We observed limbal enrichment of corneal axon-associated myelinating and non-myelinating SCs. Induced local genetic ablation of SCs, although leaving corneal sensory innervation intact, markedly inhibited corneal epithelial renewal. scRNA-seq analysis (1) highlighted the transcriptional heterogenicity of cells populating the limbal niche, and (2) identified transcriptional changes associated with corneal innervation and during wound healing that model potential regulatory paracrine interactions between SCs and LSCs. Conclusions: Limbal SCs are required for innervation-dependent corneal epithelial renewal.


Asunto(s)
Epitelio Corneal , Limbo de la Córnea , Células de Schwann , Animales , Ratones , Ratas , Córnea/inervación , Células Epiteliales , Epitelio Corneal/metabolismo , Células Madre/metabolismo
8.
J Cell Biol ; 177(3): 551-62, 2007 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-17485493

RESUMEN

The interaction between gliomedin and the axonodal cell adhesion molecules (CAMs) neurofascin and NrCAM induces the clustering of Na(+) channels at the nodes of Ranvier. We define new interactions of gliomedin that are essential for its clustering activity. We show that gliomedin exists as both transmembrane and secreted forms that are generated by proteolytic cleavage of the protein, and that only the latter is detected at the nodes of Ranvier. The secreted extracellular domain of gliomedin binds to Schwann cells and is incorporated into the extracellular matrix (ECM) in a heparin-dependent manner, suggesting the involvement of heparan sulfate proteoglycans (HSPGs). Furthermore, we show that the N-terminal region of gliomedin serves as an oligomerization domain that mediates self-association of the molecule, which is required for its binding to neurofascin and NrCAM. Our results indicate that the deposition of gliomedin multimers at the nodal gap by binding to HSPGs facilitates the clustering of the axonodal CAMs and Na(+) channels.


Asunto(s)
Moléculas de Adhesión Celular Neuronal/metabolismo , Matriz Extracelular/metabolismo , Proteoglicanos de Heparán Sulfato/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Procesamiento Proteico-Postraduccional/fisiología , Nódulos de Ranvier/metabolismo , Animales , Células Cultivadas , Heparina/metabolismo , Estructura Cuaternaria de Proteína/fisiología , Estructura Terciaria de Proteína/fisiología , Ratas , Canales de Sodio/metabolismo
9.
Proc Natl Acad Sci U S A ; 106(39): 16704-9, 2009 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-19805360

RESUMEN

The nonreceptor tyrosine phosphatase Shp2 (PTPN11) has been implicated in tyrosine kinase, cytokine, and integrin receptor signaling. We show here that conditional mutation of Shp2 in neural crest cells and in myelinating Schwann cells resulted in deficits in glial development that are remarkably similar to those observed in mice mutant for Neuregulin-1 (Nrg1) or the Nrg1 receptors, ErbB2 and ErbB3. In cultured Shp2 mutant Schwann cells, Nrg1-evoked cellular responses like proliferation and migration were virtually abolished, and Nrg1-dependent intracellular signaling was altered. Pharmacological inhibition of Src family kinases mimicked all cellular and biochemical effects of the Shp2 mutation, implicating Src as a primary Shp2 target during Nrg1 signaling. Together, our genetic and biochemical analyses demonstrate that Shp2 is an essential component in the transduction of Nrg1/ErbB signals.


Asunto(s)
Receptores ErbB/metabolismo , Neurregulina-1/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Células de Schwann/metabolismo , Transducción de Señal , Animales , Técnica del Anticuerpo Fluorescente , Ratones , Cresta Neural/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Células de Schwann/enzimología
10.
Ther Adv Rare Dis ; 3: 26330040221118099, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-37180418

RESUMEN

This article is written by the parent of a child living with PMM2-congenital disorder of glycosylation (abbreviated to PMM2-CDG). It provides a parental perspective of the journey taken from diagnosis to present day and details the effect of off-label treatment with epalrestat.


What is PMM2-CDG? PMM2-CDG is a rare multisystem disorder that involves a normal, but complex, chemical process known as glycosylation. Glycosylation is the process by which sugar chains (glycans) are created, altered and chemically attached to certain proteins or fats (lipids). When these sugar molecules are attached to proteins, they form glycoproteins. Glycoproteins have various important functions within the body, like the development of the brain, and coordination, and are essential for the normal growth and function of coagulation, hormonal regulation and organs like the liver and heart. PMM2-CDG can affect virtually any part of the body, although most cases usually have an important neurological component. PMM2-CDG is associated with a broad and highly variable range of symptoms and can vary in severity from mild cases to severe with disabling or life-threatening symptoms. Most cases are apparent in infancy. PMM2-CDG is caused by mutations of the PMM2 (phosphomannomutase-2) gene and is inherited as an autosomal recessive condition (two copies of an abnormal gene product must be present in order for the disease or trait to develop. Available treatments Effective treatment for PMM2-CDG remains an unmet need. A potential path to therapy for PMM2-CDG is repurposing already approved drugs like epalrestat, which was found as a drug target in a worm model by drug screening. Why is this article important? It is important to share these perspectives so researchers, clinicians and other parents and patients can learn from each other's journeys and, importantly, to highlight that you are not alone.

11.
Sci Rep ; 12(1): 8444, 2022 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-35589940

RESUMEN

Diabetes is by far, the most common cause of neuropathy, inducing neurodegeneration of terminal sensory nerve fibers associated with loss of sensation, paresthesia, and persistent pain. Foretinib prevents die-back degeneration in cultured sensory and sympathetic neurons by rescuing mitochondrial activity and has been proven safe in prospective clinical trials. Here we aimed at investigating a potential neuroprotective effect of Foretinib in experimental diabetic neuropathy. A mouse model of streptozotocin induced diabetes was used that expresses yellow fluorescent protein (YFP) in peripheral nerve fibers under the thy-1 promoter. Streptozotocin-injected mice developed a stable diabetic state (blood glucose > 270 mg/dl), with a significant reduction of intraepidermal nerve fiber density by 25% at 5 weeks compared to the non-diabetic controls. When diabetic mice were treated with Foretinib, a significantly greater volume of the cutaneous nerve fibers (67.3%) in the plantar skin was preserved compared to vehicle treated (37.8%) and non-treated (44.9%) diabetic mice while proximal nerve fiber morphology was not affected. Our results indicate a neuroprotective effect of Foretinib on cutaneous nerve fibers in experimental diabetic neuropathy. As Foretinib treated mice showed greater weight loss compared to vehicle treated controls, future studies may define more sustainable treatment regimen and thereby may allow patients to take advantage of this neuroprotective drug in chronic neurodegenerative diseases like diabetic neuropathy.


Asunto(s)
Diabetes Mellitus Experimental , Neuropatías Diabéticas , Fármacos Neuroprotectores , Anilidas , Animales , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Neuropatías Diabéticas/etiología , Humanos , Ratones , Fibras Nerviosas/metabolismo , Fármacos Neuroprotectores/farmacología , Estudios Prospectivos , Quinolinas , Estreptozocina/farmacología
12.
Transl Vis Sci Technol ; 11(8): 20, 2022 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-35984668

RESUMEN

Purpose: Corneal nerve fibers provide sensation and maintain the epithelial renewal process. Insufficient corneal innervation can cause neurotrophic keratopathy. Here, topically delivered tacrolimus is evaluated for its therapeutic potential to promote corneal reinnervation in rats. Methods: A compartmentalized neuronal cell culture was used to determine the effect of locally delivered tacrolimus on sensory axon regeneration in vitro. The regenerating axons but not the cell bodies were exposed to tacrolimus (50 ng/mL), nerve growth factor (50 ng/mL), or a vehicle control. Axon area and length were measured after 48 hours. Then, a biodegradable nanofiber drug delivery system was fabricated via electrospinning of a tacrolimus-loaded polycarbonate-urethane polymer. Biocompatibility, degradation, drug biodistribution, and therapeutic effectiveness were tested in a rat model of neurotrophic keratopathy induced by stereotactic trigeminal nerve ablation. Results: Sensory neurons whose axons were exposed to tacrolimus regenerated significantly more and longer axons compared to vehicle-treated cultures. Trigeminal nerve ablation in rats reliably induced corneal denervation. Four weeks after denervation, rats that had received tacrolimus topically showed similar limbal innervation but a significantly higher nerve fiber density in the center of the cornea compared to the non-treated control. Topically applied tacrolimus was detectable in the ipsilateral vitreal body, the plasma, and the ipsilateral trigeminal ganglion but not in their contralateral counterparts and vital organs after 4 weeks of topical release. Conclusions: Locally delivered tacrolimus promotes axonal regeneration in vitro and corneal reinnervation in vivo with minimal systemic drug exposure. Translational Relevance: Topically applied tacrolimus may provide a readily translatable approach to promote corneal reinnervation.


Asunto(s)
Distrofias Hereditarias de la Córnea , Queratitis , Enfermedades del Nervio Trigémino , Animales , Axones/fisiología , Córnea/inervación , Córnea/fisiología , Preparaciones de Acción Retardada/farmacología , Sistemas de Liberación de Medicamentos , Regeneración Nerviosa/fisiología , Ratas , Tacrolimus/farmacología , Distribución Tisular , Enfermedades del Nervio Trigémino/cirugía
13.
Neuron ; 106(5): 806-815.e6, 2020 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-32209430

RESUMEN

During development of the peripheral nervous system (PNS), Schwann-cell-secreted gliomedin induces the clustering of Na+ channels at the edges of each myelin segment to form nodes of Ranvier. Here we show that bone morphogenetic protein-1 (BMP1)/Tolloid (TLD)-like proteinases confine Na+ channel clustering to these sites by negatively regulating the activity of gliomedin. Eliminating the Bmp1/TLD cleavage site in gliomedin or treating myelinating cultures with a Bmp1/TLD inhibitor results in the formation of numerous ectopic Na+ channel clusters along axons that are devoid of myelin segments. Furthermore, genetic deletion of Bmp1 and Tll1 genes in mice using a Schwann-cell-specific Cre causes ectopic clustering of nodal proteins, premature formation of heminodes around early ensheathing Schwann cells, and altered nerve conduction during development. Our results demonstrate that by inactivating gliomedin, Bmp1/TLD functions as an additional regulatory mechanism to ensure the correct spatial and temporal assembly of PNS nodes of Ranvier.


Asunto(s)
Proteína Morfogenética Ósea 1/genética , Moléculas de Adhesión Celular Neuronal/metabolismo , Vaina de Mielina/metabolismo , Nódulos de Ranvier/metabolismo , Metaloproteinasas Similares a Tolloid/genética , Canales de Sodio Activados por Voltaje/metabolismo , Animales , Proteína Morfogenética Ósea 1/metabolismo , Ratones , Ratones Noqueados , Conducción Nerviosa , Sistema Nervioso Periférico , Transporte de Proteínas , Células de Schwann/metabolismo , Metaloproteinasas Similares a Tolloid/metabolismo
14.
Neuron ; 47(2): 215-29, 2005 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-16039564

RESUMEN

Accumulation of Na(+) channels at the nodes of Ranvier is a prerequisite for saltatory conduction. In peripheral nerves, clustering of these channels along the axolemma is regulated by myelinating Schwann cells through a yet unknown mechanism. We report the identification of gliomedin, a glial ligand for neurofascin and NrCAM, two axonal immunoglobulin cell adhesion molecules that are associated with Na+ channels at the nodes of Ranvier. Gliomedin is expressed by myelinating Schwann cells and accumulates at the edges of each myelin segment during development, where it aligns with the forming nodes. Eliminating the expression of gliomedin by RNAi, or the addition of a soluble extracellular domain of neurofascin to myelinating cultures, which caused the redistribution of gliomedin along the internodes, abolished node formation. Furthermore, a soluble gliomedin induced nodal-like clusters of Na+ channels in the absence of Schwann cells. We propose that gliomedin provides a glial cue for the formation of peripheral nodes of Ranvier.


Asunto(s)
Axones/metabolismo , Moléculas de Adhesión Celular/metabolismo , Sustancias Macromoleculares/metabolismo , Nódulos de Ranvier/metabolismo , Células de Schwann/metabolismo , Factores de Edad , Secuencia de Aminoácidos , Animales , Ancirinas/metabolismo , Northern Blotting/métodos , Western Blotting/métodos , Moléculas de Adhesión Celular/inmunología , Moléculas de Adhesión Celular Neuronal/metabolismo , Compartimento Celular , Células Cultivadas , Chlorocebus aethiops , Claudinas , Clonación Molecular/métodos , Proteínas del Citoesqueleto , Técnica del Anticuerpo Fluorescente/métodos , Ganglios Espinales/metabolismo , Regulación del Desarrollo de la Expresión Génica , Humanos , Sustancias Macromoleculares/inmunología , Proteínas de la Membrana/metabolismo , Proteínas de Microfilamentos/metabolismo , Microscopía Inmunoelectrónica/métodos , Proteína Básica de Mielina/metabolismo , Glicoproteína Asociada a Mielina/metabolismo , Proteínas de Neurofilamentos/metabolismo , Fosfoproteínas/metabolismo , Unión Proteica/fisiología , Estructura Terciaria de Proteína , Nódulos de Ranvier/ultraestructura , Ratas , Receptores de Péptidos/metabolismo , Proteínas S100/metabolismo , Células de Schwann/ultraestructura , Nervio Ciático/crecimiento & desarrollo , Nervio Ciático/metabolismo , Canales de Sodio/metabolismo , Espectrina/metabolismo , Transfección/métodos
15.
J Cell Biol ; 216(11): 3655-3675, 2017 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-28877995

RESUMEN

Axon degeneration is an early event and pathological in neurodegenerative conditions and nerve injuries. To discover agents that suppress neuronal death and axonal degeneration, we performed drug screens on primary rodent neurons and identified the pan-kinase inhibitor foretinib, which potently rescued sympathetic, sensory, and motor wt and SOD1 mutant neurons from trophic factor withdrawal-induced degeneration. By using primary sympathetic neurons grown in mass cultures and Campenot chambers, we show that foretinib protected neurons by suppressing both known degenerative pathways and a new pathway involving unliganded TrkA and transcriptional regulation of the proapoptotic BH3 family members BimEL, Harakiri,and Puma, culminating in preservation of mitochondria in the degenerative setting. Foretinib delayed chemotherapy-induced and Wallerian axonal degeneration in culture by preventing axotomy-induced local energy deficit and preserving mitochondria, and peripheral Wallerian degeneration in vivo. These findings identify a new axon degeneration pathway and a potentially clinically useful therapeutic drug.


Asunto(s)
Anilidas/farmacología , Lesiones por Aplastamiento/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Quinolinas/farmacología , Receptor trkA/antagonistas & inhibidores , Nervio Ciático/efectos de los fármacos , Neuropatía Ciática/tratamiento farmacológico , Degeneración Walleriana , Fibras Adrenérgicas/efectos de los fármacos , Fibras Adrenérgicas/enzimología , Fibras Adrenérgicas/patología , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Axones/efectos de los fármacos , Axones/enzimología , Axones/patología , Células Cultivadas , Lesiones por Aplastamiento/enzimología , Lesiones por Aplastamiento/genética , Lesiones por Aplastamiento/patología , Citoprotección , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Genotipo , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitocondrias/enzimología , Mitocondrias/patología , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/enzimología , Neuronas Motoras/patología , Mutación , Neuronas/enzimología , Neuronas/patología , Fenotipo , Fosforilación , Ratas Sprague-Dawley , Receptor trkA/genética , Receptor trkA/metabolismo , Nervio Ciático/enzimología , Nervio Ciático/lesiones , Nervio Ciático/patología , Neuropatía Ciática/enzimología , Neuropatía Ciática/genética , Neuropatía Ciática/patología , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/enzimología , Células Receptoras Sensoriales/patología , Transducción de Señal , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Factores de Tiempo , Transcripción Genética
16.
Stem Cell Reports ; 3(1): 85-100, 2014 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-25068124

RESUMEN

Recent reports of directed reprogramming have raised questions about the stability of cell lineages. Here, we have addressed this issue, focusing upon skin-derived precursors (SKPs), a dermally derived precursor cell. We show by lineage tracing that murine SKPs from dorsal skin originate from mesenchymal and not neural crest-derived cells. These mesenchymally derived SKPs can, without genetic manipulation, generate functional Schwann cells, a neural crest cell type, and are highly similar at the transcriptional level to Schwann cells isolated from the peripheral nerve. This is not a mouse-specific phenomenon, since human SKPs that are highly similar at the transcriptome level can be made from neural crest-derived facial and mesodermally derived foreskin dermis and the foreskin SKPs can make myelinating Schwann cells. Thus, nonneural crest-derived mesenchymal precursors can differentiate into bona fide peripheral glia in the absence of genetic manipulation, suggesting that developmentally defined lineage boundaries are more flexible than widely thought.


Asunto(s)
Células Madre Multipotentes/citología , Células de Schwann/citología , Piel/citología , Animales , Diferenciación Celular/fisiología , Células Cultivadas , Humanos , Ratones SCID , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína 1 Relacionada con Twist/genética , Proteína 1 Relacionada con Twist/metabolismo
17.
Neuron ; 65(4): 490-502, 2010 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-20188654

RESUMEN

Saltatory conduction requires high-density accumulation of Na(+) channels at the nodes of Ranvier. Nodal Na(+) channel clustering in the peripheral nervous system is regulated by myelinating Schwann cells through unknown mechanisms. During development, Na(+) channels are first clustered at heminodes that border each myelin segment, and later in the mature nodes that are formed by the fusion of two heminodes. Here, we show that initial clustering of Na(+) channels at heminodes requires glial NrCAM and gliomedin, as well as their axonal receptor neurofascin 186 (NF186). We further demonstrate that heminodal clustering coincides with a second, paranodal junction (PNJ)-dependent mechanism that allows Na(+) channels to accumulate at mature nodes by restricting their distribution between two growing myelin internodes. We propose that Schwann cells assemble the nodes of Ranvier by capturing Na(+) channels at heminodes and by constraining their distribution to the nodal gap. Together, these two cooperating mechanisms ensure fast and efficient conduction in myelinated nerves.


Asunto(s)
Axones/metabolismo , Moléculas de Adhesión Celular Neuronal/metabolismo , Moléculas de Adhesión Celular/metabolismo , Nódulos de Ranvier/metabolismo , Células de Schwann/metabolismo , Canales de Sodio/metabolismo , Potenciales de Acción/fisiología , Análisis de Varianza , Animales , Western Blotting , Moléculas de Adhesión Celular Neuronal/genética , Células Cultivadas , Electrofisiología , Técnica del Anticuerpo Fluorescente , Ratones , Ratones Noqueados , Microscopía Electrónica , Vaina de Mielina/metabolismo , Fibras Nerviosas Mielínicas/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Conducción Nerviosa , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
18.
Neural Regen Res ; 20(1): 291-304, 2025 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-38767493

RESUMEN

JOURNAL/nrgr/04.03/01300535-202501000-00036/figure1/v/2024-05-14T021156Z/r/image-tiff Axonal regeneration following surgical nerve repair is slow and often incomplete, resulting in poor functional recovery which sometimes contributes to lifelong disability. Currently, there are no FDA-approved therapies available to promote nerve regeneration. Tacrolimus accelerates axonal regeneration, but systemic side effects presently outweigh its potential benefits for peripheral nerve surgery. The authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site, with suitable properties for scalable production and clinical application, aiming to promote nerve regeneration and functional recovery with minimal systemic drug exposure. Tacrolimus is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days. Size and drug loading are adjustable for applications in small and large caliber nerves, and the wrap degrades within 120 days into biocompatible byproducts. Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80% compared with systemic delivery. Given its surgical suitability and preclinical efficacy and safety, this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.

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