RESUMEN
Multiple sclerosis (MS) is a debilitating demyelinating disease characterized by remyelination failure attributed to inadequate oligodendrocyte precursor cells (OPCs) differentiation and aberrant astrogliosis. A comprehensive cell atlas reanalysis of clinical specimens brings to light heightened clusterin (CLU) expression in a specific astrocyte subtype links to active lesions in MS patients. Our investigation reveals elevated astrocytic CLU levels in both active lesions of patient tissues and female murine MS models. CLU administration stimulates primary astrocyte proliferation while concurrently impeding astrocyte-mediated clearance of myelin debris. Intriguingly, CLU overload directly impedes OPC differentiation and induces OPCs and OLs apoptosis. Mechanistically, CLU suppresses PI3K-AKT signaling in primary OPCs via very low-density lipoprotein receptor. Pharmacological activation of AKT rescues the damage inflicted by excess CLU on OPCs and ameliorates demyelination in the corpus callosum. Furthermore, conditional knockout of CLU emerges as a promising intervention, showcasing improved remyelination processes and reduced severity in murine MS models.
Asunto(s)
Astrocitos , Clusterina , Enfermedades Desmielinizantes , Modelos Animales de Enfermedad , Remielinización , Animales , Femenino , Humanos , Ratones , Apoptosis/efectos de los fármacos , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Clusterina/metabolismo , Clusterina/genética , Cuerpo Calloso/metabolismo , Cuerpo Calloso/patología , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Vaina de Mielina/metabolismo , Células Precursoras de Oligodendrocitos/metabolismo , Células Precursoras de Oligodendrocitos/efectos de los fármacos , Oligodendroglía/metabolismo , Oligodendroglía/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Remielinización/efectos de los fármacos , Transducción de SeñalRESUMEN
Aging leads to alterations that precipitate or aggravate several diseases that occur across our lifespan. In the CNS, aging affects the capacity to maintain and repair the myelin sheaths that protect axons and facilitate neuronal signaling. Tiwari et al. report aging-associated transcriptional responses in microglia after demyelination, which could be reversed by epigenetic remodeling after BCG vaccination.
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Envejecimiento , Vacuna BCG , Vaina de Mielina , Remielinización , Vacuna BCG/inmunología , Humanos , Envejecimiento/inmunología , Animales , Vaina de Mielina/inmunología , Vaina de Mielina/metabolismo , Microglía/inmunología , Enfermedades Desmielinizantes/inmunología , Epigénesis Genética , Ratones , VacunaciónRESUMEN
BACKGROUND AND OBJECTIVES: Myelin and iron play essential roles in remyelination processes of multiple sclerosis (MS) lesions. χ-separation, a novel biophysical model applied to multiecho T2*-data and T2-data, estimates the contribution of myelin and iron to the obtained susceptibility signal. We used this method to investigate myelin and iron levels in lesion and nonlesion brain areas in patients with MS and healthy individuals. METHODS: This prospective MS cohort study included patients with MS fulfilling the McDonald Criteria 2017 and healthy individuals, aged 18 years or older, with no other neurologic comorbidities. Participants underwent MRI at baseline and after 2 years, including multiecho GRE-(T2*) and FAST-(T2) sequences. Using χ-separation, we generated myelin-sensitive and iron-sensitive susceptibility maps. White matter lesions (WMLs), cortical lesions (CLs), surrounding normal-appearing white matter (NAWM), and normal-appearing gray matter were segmented on fluid-attenuated inversion recovery and magnetization-prepared 2 rapid gradient echo images, respectively. Cross-sectional group comparisons used Wilcoxon rank-sum tests, longitudinal analyses applied Wilcoxon signed-rank tests. Associations with clinical outcomes (disease phenotype, age, sex, disease duration, disability measured by Expanded Disability Status Scale [EDSS], neurofilament light chain levels, and T2-lesion number and volume) were assessed using linear regression models. RESULTS: Of 168 patients with MS (median [interquartile range (IQR)] age 47.0 [21.7] years; 101 women; 6,898 WMLs, 775 CLs) and 103 healthy individuals (age 33.0 [10.5] years, 57 women), 108 and 62 were followed for a median of 2 years, respectively (IQR 0.1; 5,030 WMLs, 485 CLs). At baseline, WMLs had lower myelin (median 0.025 [IQR 0.015] parts per million [ppm]) and iron (0.017 [0.015] ppm) than the corresponding NAWM (myelin 0.030 [0.012]; iron 0.019 [0.011] ppm; both p < 0.001). After 2 years, both myelin (0.027 [0.014] ppm) and iron had increased (0.018 [0.015] ppm; both p < 0.001). Younger age (p < 0.001, b = -5.111 × 10-5), lower disability (p = 0.04, b = -2.352 × 10-5), and relapsing-remitting phenotype (RRMS, 0.003 [0.01] vs primary progressive 0.002 [IQR 0.01], p < 0.001; vs secondary progressive 0.0004 [IQR 0.01], p < 0.001) at baseline were associated with remyelination. Increment of myelin correlated with clinical improvement measured by EDSS (p = 0.015, b = -6.686 × 10-4). DISCUSSION: χ-separation, a novel mathematical model applied to multiecho T2*-images and T2-images shows that young RRMS patients with low disability exhibit higher remyelination capacity, which correlated with clinical disability over a 2-year follow-up.
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Imagen por Resonancia Magnética , Esclerosis Múltiple , Remielinización , Sustancia Blanca , Humanos , Femenino , Masculino , Adulto , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Remielinización/fisiología , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Estudios Prospectivos , Vaina de Mielina/patología , Hierro/metabolismo , Estudios Transversales , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Estudios de CohortesRESUMEN
ABSTRACT: Multiple sclerosis (MS) is a complicated, inflammatory disease that causes demyelination of the central nervous system (CNS), resulting in a variety of neurological abnormalities. Over the past several decades, different animal models have been used to replicate the clinical symptoms and neuropathology of MS. The experimental model of experimental autoimmune/allergic encephalomyelitis (EAE) and viral and toxin-induced model was widely used to investigate the clinical implications of MS. Discoidin domain receptor 1 (DDR1) signaling in oligodendrocytes (OL) brings a new dimension to our understanding of MS pathophysiology. DDR1 is effectively involved in the OL during neurodevelopment and remyelination. It has been linked to many cellular processes, including migration, invasion, proliferation, differentiation, and adhesion. However, the exact functional involvement of DDR1 in developing OL and myelinogenesis in the CNS remains undefined. In this review, we critically evaluate the current literature on DDR1 signaling in OL and its proliferation, migration, differentiation, and myelination mechanism in OL in association with the progression of MS. It increases our knowledge of DDR1 in OL as a novel target molecule for oligodendrocyte-associated diseases in the CNS, including MS.
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Sistema Nervioso Central , Receptor con Dominio Discoidina 1 , Vaina de Mielina , Oligodendroglía , Remielinización , Transducción de Señal , Animales , Humanos , Diferenciación Celular , Sistema Nervioso Central/metabolismo , Receptor con Dominio Discoidina 1/metabolismo , Receptor con Dominio Discoidina 1/genética , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Remielinización/fisiologíaRESUMEN
Axons wrapped around the myelin sheath enable fast transmission of neuronal signals in the Central Nervous System (CNS). Unfortunately, myelin can be damaged by injury, viral infection, and inflammatory and neurodegenerative diseases. Remyelination is a spontaneous process that can restore nerve conductivity and thus movement and cognition after a demyelination event. Cumulative evidence indicates that remyelination can be pharmacologically stimulated, either by targeting natural inhibitors of Oligodendrocyte Precursor Cells (OPCs) differentiation or by reactivating quiescent Neural Stem Cells (qNSCs) proliferation and differentiation in myelinating Oligodendrocytes (OLs). Although promising results were obtained in animal models for demyelination diseases, none of the compounds identified have passed all the clinical stages. The significant number of patients who could benefit from remyelination therapies reinforces the urgent need to reassess drug selection approaches and develop strategies that effectively promote remyelination. Integrating Artificial Intelligence (AI)-driven technologies with patient-derived cell-based assays and organoid models is expected to lead to novel strategies and drug screening pipelines to achieve this goal. In this review, we explore the current literature on these technologies and their potential to enhance the identification of more effective drugs for clinical use in CNS remyelination therapies.
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Evaluación Preclínica de Medicamentos , Remielinización , Humanos , Remielinización/efectos de los fármacos , Animales , Enfermedades Desmielinizantes/tratamiento farmacológico , Enfermedades Desmielinizantes/patología , Vaina de Mielina/metabolismo , Oligodendroglía/efectos de los fármacos , Oligodendroglía/metabolismo , Oligodendroglía/citología , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Diferenciación Celular/efectos de los fármacosRESUMEN
In people with multiple sclerosis (MS), newborn and surviving oligodendrocytes (OLs) can contribute to remyelination, however, current therapies are unable to enhance or sustain endogenous repair. Low intensity repetitive transcranial magnetic stimulation (LI-rTMS), delivered as an intermittent theta burst stimulation (iTBS), increases the survival and maturation of newborn OLs in the healthy adult mouse cortex, but it is unclear whether LI-rTMS can promote remyelination. To examine this possibility, we fluorescently labelled oligodendrocyte progenitor cells (OPCs; Pdgfrα-CreER transgenic mice) or mature OLs (Plp-CreER transgenic mice) in the adult mouse brain and traced the fate of each cell population over time. Daily sessions of iTBS (600 pulses; 120 mT), delivered during cuprizone (CPZ) feeding, did not alter new or pre-existing OL survival but increased the number of myelin internodes elaborated by new OLs in the primary motor cortex (M1). This resulted in each new M1 OL producing ~ 471 µm more myelin. When LI-rTMS was delivered after CPZ withdrawal (during remyelination), it significantly increased the length of the internodes elaborated by new M1 and callosal OLs, increased the number of surviving OLs that supported internodes in the corpus callosum (CC), and increased the proportion of axons that were myelinated. The ability of LI-rTMS to modify cortical neuronal activity and the behaviour of new and surviving OLs, suggests that it may be a suitable adjunct intervention to enhance remyelination in people with MS.
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Cuprizona , Enfermedades Desmielinizantes , Vaina de Mielina , Oligodendroglía , Remielinización , Estimulación Magnética Transcraneal , Animales , Estimulación Magnética Transcraneal/métodos , Oligodendroglía/metabolismo , Enfermedades Desmielinizantes/terapia , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/patología , Ratones , Vaina de Mielina/metabolismo , Modelos Animales de Enfermedad , Ratones Transgénicos , Corteza Motora/patología , Corteza Motora/metabolismo , Supervivencia Celular , Ratones Endogámicos C57BL , Esclerosis Múltiple/terapia , Esclerosis Múltiple/patologíaRESUMEN
Multiple sclerosis (MS) is a devastating autoimmune disease that leads to profound disability. This disability arises from the stochastic, regional loss of myelin-the insulating sheath surrounding neurons-in the central nervous system (CNS). The demyelinated regions are dominated by the brain's resident macrophages: microglia. Microglia perform a variety of functions in MS and are thought to initiate and perpetuate demyelination through their interactions with peripheral immune cells that traffic into the brain. However, microglia are also likely essential for recruiting and promoting the differentiation of cells that can restore lost myelin in a process known as remyelination. Given these seemingly opposing functions, an overarching beneficial or detrimental role is yet to be ascribed to these immune cells. In this chapter, we will discuss microglia dynamics throughout the MS disease course and probe the apparent dichotomy of microglia as the drivers of both demyelination and remyelination.
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Microglía , Esclerosis Múltiple , Vaina de Mielina , Microglía/metabolismo , Microglía/patología , Humanos , Esclerosis Múltiple/patología , Esclerosis Múltiple/inmunología , Vaina de Mielina/patología , Vaina de Mielina/metabolismo , Remielinización/fisiología , Animales , Encéfalo/patología , Encéfalo/inmunología , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/metabolismoRESUMEN
Revealing unknown cues that regulate oligodendrocyte progenitor cell (OPC) function in remyelination is important to optimise the development of regenerative therapies for multiple sclerosis (MS). Platelets are present in chronic non-remyelinated lesions of MS and an increase in circulating platelets has been described in experimental autoimmune encephalomyelitis (EAE) mice, an animal model for MS. However, the contribution of platelets to remyelination remains unexplored. Here we show platelet aggregation in proximity to OPCs in areas of experimental demyelination. Partial depletion of circulating platelets impaired OPC differentiation and remyelination, without altering blood-brain barrier stability and neuroinflammation. Transient exposure to platelets enhanced OPC differentiation in vitro, whereas sustained exposure suppressed this effect. In a mouse model of thrombocytosis (Calr+/-), there was a sustained increase in platelet aggregation together with a reduction of newly-generated oligodendrocytes following toxin-induced demyelination. These findings reveal a complex bimodal contribution of platelet to remyelination and provide insights into remyelination failure in MS.
Asunto(s)
Plaquetas , Diferenciación Celular , Células Precursoras de Oligodendrocitos , Remielinización , Animales , Células Precursoras de Oligodendrocitos/fisiología , Remielinización/fisiología , Ratones , Plaquetas/fisiología , Encefalomielitis Autoinmune Experimental/patología , Ratones Endogámicos C57BL , Esclerosis Múltiple/patología , Modelos Animales de Enfermedad , Oligodendroglía/fisiología , FemeninoRESUMEN
INTRODUCTION: Excessive neuroinflammation, apoptosis, glial scar, and demyelination triggered by spinal cord injury (SCI) are major obstacles to SCI repair. Fucoidan, a natural marine plant extract, possesses broad-spectrum anti-inflammatory and immunomodulatory effects and is regarded as a potential therapeutic for various diseases, including neurological disorders. However, its role in SCI has not been investigated. METHODS: In this study, we established an SCI model in mice and intervened in injury repair by daily intraperitoneal injections of different doses of fucoidan (10 and 20 mg/kg). Concurrently, primary oligodendrocyte precursor cells (OPCs) were treated in vitro to validate the differentiation-promoting effect of fucoidan on OPCs. Basso Mouse Scale (BMS), Louisville Swim Scale (LSS), and Rotarod test were carried out to measure the functional recovery. Immunofluorescence staining, and transmission electron microscopy (TEM) were performed to assess the neuroinflammation, apoptosis, glial scar, and remyelination. Western blot analysis was conducted to clarify the underlying mechanism of remyelination. RESULTS: Our results indicate that in the SCI model, fucoidan exhibits significant anti-inflammatory effects and promotes the transformation of pro-inflammatory M1-type microglia/macrophages into anti-inflammatory M2-type ones. Fucoidan enhances the survival of neurons and axons in the injury area and improves remyelination. Additionally, fucoidan promotes OPCs differentiation into mature oligodendrocytes by activating the PI3K/AKT/mTOR pathway. CONCLUSION: Fucoidan improves SCI repair by modulating the microenvironment and promoting remyelination.
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Ratones Endogámicos C57BL , Polisacáridos , Recuperación de la Función , Remielinización , Traumatismos de la Médula Espinal , Animales , Polisacáridos/farmacología , Ratones , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/patología , Remielinización/efectos de los fármacos , Remielinización/fisiología , Recuperación de la Función/efectos de los fármacos , Células Precursoras de Oligodendrocitos/efectos de los fármacos , Femenino , Microambiente Celular/efectos de los fármacosRESUMEN
Peripheral nerve injuries (PNIs) represent a significant clinical challenge, particularly in elderly populations where axonal remyelination and regeneration are impaired. Developing therapies to enhance these processes is crucial for improving PNI repair outcomes. Glutamate carboxypeptidase II (GCPII) is a neuropeptidase that plays a pivotal role in modulating glutamate signaling through its enzymatic cleavage of the abundant neuropeptide N-acetyl aspartyl glutamate (NAAG) to liberate glutamate. Within the PNS, GCPII is expressed in Schwann cells and activated macrophages, and its expression is amplified with aging. In this study, we explored the therapeutic potential of inhibiting GCPII activity following PNI. We report significant GCPII protein and activity upregulation following PNI, which was normalized by the potent and selective GCPII inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA). In vitro, 2-PMPA robustly enhanced myelination in dorsal root ganglion (DRG) explants. In vivo, using a sciatic nerve crush injury model in aged mice, 2-PMPA accelerated remyelination, as evidenced by increased myelin sheath thickness and higher numbers of remyelinated axons. These findings suggest that GCPII inhibition may be a promising therapeutic strategy to enhance remyelination and potentially improve functional recovery after PNI, which is especially relevant in elderly PNI patients where this process is compromised.
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Glutamato Carboxipeptidasa II , Traumatismos de los Nervios Periféricos , Remielinización , Animales , Ratones , Traumatismos de los Nervios Periféricos/tratamiento farmacológico , Traumatismos de los Nervios Periféricos/metabolismo , Remielinización/efectos de los fármacos , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Glutamato Carboxipeptidasa II/metabolismo , Vaina de Mielina/metabolismo , Vaina de Mielina/efectos de los fármacos , Envejecimiento/efectos de los fármacos , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Ratones Endogámicos C57BL , Regeneración Nerviosa/efectos de los fármacos , Nervio Ciático/lesiones , Nervio Ciático/efectos de los fármacos , Masculino , Axones/efectos de los fármacos , Axones/metabolismoRESUMEN
Multiple sclerosis (MS) is a chronic and debilitating neurological disease that results in inflammatory demyelination. While endogenous remyelination helps to recover function, this restorative process tends to become less efficient over time. Currently, intense efforts aimed at the mechanisms that promote remyelination are being considered promising therapeutic approaches. The M1 muscarinic acetylcholine receptor (M1R) was previously identified as a negative regulator of oligodendrocyte differentiation and myelination. Here, we validate M1R as a target for remyelination by characterizing expression in human and rodent oligodendroglial cells (including those in human MS tissue) using a highly selective M1R probe. As a breakthrough to conventional methodology, we conjugated a fluorophore to a highly M1R selective peptide (MT7) which targets the M1R in the subnanomolar range. This allows for exceptional detection of M1R protein expression in the human CNS. More importantly, we introduce PIPE-307, a brain-penetrant, small-molecule antagonist with favorable drug-like properties that selectively targets M1R. We evaluate PIPE-307 in a series of in vitro and in vivo studies to characterize potency and selectivity for M1R over M2-5R and confirm the sufficiency of blocking this receptor to promote differentiation and remyelination. Further, PIPE-307 displays significant efficacy in the mouse experimental autoimmune encephalomyelitis model of MS as evaluated by quantifying disability, histology, electron microscopy, and visual evoked potentials. Together, these findings support targeting M1R for remyelination and support further development of PIPE-307 for clinical studies.
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Esclerosis Múltiple , Oligodendroglía , Receptor Muscarínico M1 , Remielinización , Animales , Humanos , Ratones , Ratas , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/metabolismo , Ratones Endogámicos C57BL , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/metabolismo , Antagonistas Muscarínicos/farmacología , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Oligodendroglía/efectos de los fármacos , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M1/antagonistas & inhibidores , Remielinización/efectos de los fármacosRESUMEN
Multiple sclerosis is a chronic inflammatory demyelinating disorder of the CNS characterized by continuous myelin damage accompanied by deterioration in functions. Clobetasol propionate (CP) is the most potent topical corticosteroid with serious side effects related to systemic absorption. Previous studies introduced CP for remyelination without considering systemic toxicity. This work aimed at fabrication and optimization of double coated nano-oleosomes loaded with CP to achieve brain targeting through intranasal administration. The optimized formulation was coated with lactoferrin and chitosan for the first time. The obtained double-coated oleosomes had particle size (220.07 ± 0.77 nm), zeta potential (+30.23 ± 0.41 mV) along with antioxidant capacity 9.8 µM ascorbic acid equivalents. Double coating was well visualized by TEM and significantly decreased drug release. Three different doses of CP were assessed in-vivo using cuprizone-induced demyelination in C57Bl/6 mice. Neurobehavioral tests revealed improvement in motor and cognitive functions of mice in a dose-dependent manner. Histopathological examination of the brain showed about 2.3 folds increase in corpus callosum thickness in 0.3 mg/kg CP dose. Moreover, the measured biomarkers highlighted the significant antioxidant and anti-inflammatory capacity of the formulation. In conclusion, the elaborated biopolymer-integrating nanocarrier succeeded in remyelination with 6.6 folds reduction in CP dose compared to previous studies.
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Quitosano , Clobetasol , Cuprizona , Enfermedades Desmielinizantes , Modelos Animales de Enfermedad , Lactoferrina , Esclerosis Múltiple , Remielinización , Animales , Lactoferrina/química , Lactoferrina/farmacología , Quitosano/química , Ratones , Clobetasol/farmacología , Clobetasol/química , Remielinización/efectos de los fármacos , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/tratamiento farmacológico , Enfermedades Desmielinizantes/patología , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inducido químicamente , Liposomas/química , Ratones Endogámicos C57BL , Masculino , Tamaño de la Partícula , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/metabolismo , Antioxidantes/farmacología , Antioxidantes/química , Liberación de FármacosRESUMEN
The research aims to study the therapeutic impact of HEK293-XPack-Olig2 cell-derived exosomes on remyelination of the corpus callosum in a cuprizone-induced demyelinating disease model. A lentiviral vector expressing Olig2 was constructed using XPack technology. The highly abundant Olig2 exosomes (ExoOs) were isolated by centrifugation for subsequent experiments. Western blot, nanoparticle tracking analysis (NTA), and electron microscopy showed no significant difference in particle size and morphology between Exos and ExoOs, and a high level of Olig2 expression could be detected in ExoOs, indicating that exosome modification by XPack technology was successful. The Black Gold/Fluromyelin staining analysis showed that the ExoOs group significantly reduced the demyelination area in the corpus callosum compared to the PBS and Exos groups. Additionally, the PDGFRα/APC staining of the demyelinating region revealed an increase in APC+ oligodendrocytes and a decrease in PDGFRα+ oligodendrocyte progenitor cells (OPCs) in the ExoOs group. Furthermore, there was evident myelin regeneration in the demyelinated areas after ExoOs treatment, with better g-ratio and a higher number of intact myelin compared to the other treatment groups. The level of Sox10 expression in the brain tissue of the ExoOs group were higher compared to those of the PBS and Exos groups. The demyelination process can be significantly slowed down by the XPack-modified exosomes, the differentiation of OPCs promoted, and myelin regeneration accelerated under pathological conditions. This process is presumed to be achieved by changing the expression level of intracellular differentiation-related genes after exosomes transport Olig2 enriched into oligodendrocyte progenitors.
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Cuprizona , Enfermedades Desmielinizantes , Exosomas , Factor de Transcripción 2 de los Oligodendrocitos , Exosomas/metabolismo , Cuprizona/toxicidad , Animales , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Factor de Transcripción 2 de los Oligodendrocitos/metabolismo , Humanos , Células HEK293 , Vaina de Mielina/metabolismo , Vaina de Mielina/patología , Remielinización/fisiología , Ratones , Células Precursoras de Oligodendrocitos/metabolismo , Ratones Endogámicos C57BL , Cuerpo Calloso/metabolismo , Cuerpo Calloso/patología , Masculino , Oligodendroglía/metabolismo , Modelos Animales de EnfermedadRESUMEN
Fu's subcutaneous needling (FSN) is a traditional Chinese acupuncture procedure used to treat pain-related neurological disorders. Moreover, the regulation of inflammatory cytokines may provide a favorable environment for peripheral nerve regeneration. In light of this, FSN may be an important novel therapeutic strategy to alleviate pain associated with peripheral neuropathy; however, the underlying molecular mechanisms remain unclear. This study revealed that patients who had osteoarthritis with peripheral neuropathic pain significantly recovered after 1 to 2 weeks of FSN treatment according to the visual analog scale, Western Ontario and McMaster Universities Osteoarthritis Index, Lequesne index, walking speed, and passive range of motion. Similarly, we demonstrated that FSN treatment in an animal model of chronic constriction injury (CCI) significantly improved sciatic nerve pain using paw withdrawal thresholds, sciatic functional index scores, and compound muscle action potential amplitude tests. In addition, transmission electron microscopy images of sciatic nerve tissue showed that FSN effectively reduced axonal swelling, abnormal myelin sheaths, and the number of organelle vacuoles in CCI-induced animals. Mechanistically, RNA sequencing and gene set enrichment analysis revealed significantly reduced inflammatory pathways, neurotransmitters, and endoplasmic reticulum stress pathways and increased nerve regeneration factors in the FSN+CCI group, compared with that in the CCI group. Finally, immunohistochemistry, immunoblotting and enzyme-linked immunosorbent assay showed similar results in the dorsal root ganglia and sciatic nerve. Our findings suggest that FSN can effectively ameliorate peripheral neuropathic pain by regulate inflammation and endoplasmic reticulum stress, thereby determine its beneficial application in patients with peripheral nerve injuries.
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Axones , Estrés del Retículo Endoplásmico , Inflamación , Regeneración Nerviosa , Remielinización , Animales , Masculino , Inflamación/terapia , Inflamación/patología , Axones/fisiología , Humanos , Terapia por Acupuntura/métodos , Neuralgia/terapia , Nervio Ciático/lesiones , Persona de Mediana Edad , Femenino , Ratas , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , AncianoRESUMEN
The reduced ability of the central nervous system to regenerate with increasing age limits functional recovery following demyelinating injury. Previous work has shown that myelin debris can overwhelm the metabolic capacity of microglia, thereby impeding tissue regeneration in aging, but the underlying mechanisms are unknown. In a model of demyelination, we found that a substantial number of genes that were not effectively activated in aged myeloid cells displayed epigenetic modifications associated with restricted chromatin accessibility. Ablation of two class I histone deacetylases in microglia was sufficient to restore the capacity of aged mice to remyelinate lesioned tissue. We used Bacillus Calmette-Guerin (BCG), a live-attenuated vaccine, to train the innate immune system and detected epigenetic reprogramming of brain-resident myeloid cells and functional restoration of myelin debris clearance and lesion recovery. Our results provide insight into aging-associated decline in myeloid function and how this decay can be prevented by innate immune reprogramming.
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Envejecimiento , Sistema Nervioso Central , Inmunidad Innata , Ratones Endogámicos C57BL , Microglía , Células Mieloides , Remielinización , Animales , Ratones , Envejecimiento/inmunología , Microglía/inmunología , Microglía/metabolismo , Células Mieloides/inmunología , Células Mieloides/metabolismo , Sistema Nervioso Central/inmunología , Vaina de Mielina/metabolismo , Vaina de Mielina/inmunología , Epigénesis Genética , Enfermedades Desmielinizantes/inmunología , Modelos Animales de EnfermedadRESUMEN
Maternal inflammation can lead to premature birth and fetal brain damage. CircRNA_19038 and lncRNA-AK016022 have been shown to be significantly reduced in brain tissues of preterm mice, while whether they are involved in the regulation of preterm white matter injury remains to be explored. Pregnant mice were intraperitoneally injected with lipopolysaccharide (LPS) to establish a preterm brain injury model. Healthy mice born at term served as controls. Lentivirus-mediated circ_19038 overexpression vector (LV-circ_19038), LV-lnc-AK016022, LV-Sirt1 and LV-sh-Sirt1 were administered to preterm mice through the ventricles. The expression levels of circ_19038, lnc-AK016022 and Sirt1 in the brain tissues of preterm mice were significantly lower than those of full-term healthy mice, and circ_19038 and lnc-AK016022 were co-localized in the brain tissues. Upregulation of circ_19038 or/and lnc-AK016022 promoted remyelination and alleviated white matter structural damage, neuroinflammation, and long-term cognitive and motor deficits in preterm mice, and the combined effect of circ_19038 and lnc-AK016022 showed better results. Primary mouse neuronal cells were isolated to investigate the regulatory effects of circ_19038 and lnc-AK016022 on Sirt1. Circ_19038 and lnc-AK016022 jointly promoted the expression of Sirt1 by adsorbing miR-1b and miR-328, respectively. Moreover, silencing Sirt1 antagonized the beneficial effects of circ_19038 or/and lnc-AK016022 on brain white matter injury in preterm mice. In conclusion, circ_19038 and lnc-AK016022 synergistically regulated Sirt1 expression to promote remyelination and alleviate white matter injury in preterm mice.
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ARN Circular , ARN Largo no Codificante , Sirtuina 1 , Sustancia Blanca , Animales , Sirtuina 1/metabolismo , Sirtuina 1/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Ratones , Sustancia Blanca/metabolismo , Sustancia Blanca/patología , Sustancia Blanca/lesiones , Femenino , Embarazo , ARN Circular/genética , ARN Circular/metabolismo , Remielinización , Ratones Endogámicos C57BL , Lipopolisacáridos/toxicidad , Nacimiento Prematuro , Encéfalo/metabolismo , Encéfalo/patologíaRESUMEN
INTRODUCTION: The quest for novel MS therapies focuses on promoting remyelination and neuroprotection, necessitating innovative drug design paradigms and robust preclinical validation methods to ensure efficient clinical translation. The complexity of new drugs action mechanisms is strengthening the need for solid biological validation attempting to address all possible pitfalls and biases precluding access to efficient and safe drugs. AREAS COVERED: In this review, the authors describe the different in vitro and in vivo models that should be used to create an integrated approach for preclinical validation of novel drugs, including the evaluation of the action mechanism. This encompasses 2D, 3D in vitro models and animal models presented in such a way to define the appropriate use in a global process of drug screening and hit validation. EXPERT OPINION: None of the current available tests allow the concomitant evaluation of anti-inflammatory, immune regulators or remyelinating agents with sufficient reliability. Consequently, the collaborative efforts of academia, industry, and regulatory agencies are essential for establishing standardized protocols, validating novel methodologies, and translating preclinical findings into clinically meaningful outcomes.
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Modelos Animales de Enfermedad , Descubrimiento de Drogas , Esclerosis Múltiple , Animales , Esclerosis Múltiple/tratamiento farmacológico , Humanos , Descubrimiento de Drogas/métodos , Remielinización/efectos de los fármacos , Evaluación Preclínica de Medicamentos/métodos , Reproducibilidad de los Resultados , Diseño de FármacosRESUMEN
BACKGROUND: Multiple sclerosis (MS) therapeutic goals have traditionally been dichotomized into two distinct avenues: immune-modulatory-centric interventions and pro-regenerative strategies. Oligodendrocyte progenitor cells (OPCs) were regarded for many years solely in concern to their potential to generate oligodendrocytes and myelin in the central nervous system (CNS). However, accumulating data elucidate the multifaceted roles of OPCs, including their immunomodulatory functions, positioning them as cardinal constituents of the CNS's immune landscape. MAIN BODY: In this review, we will discuss how the two therapeutic approaches converge. We present a model by which (1) an inflammation is required for the appropriate pro-myelinating immune function of OPCs in the chronically inflamed CNS, and (2) the immune function of OPCs is crucial for their ability to differentiate and promote remyelination. This model highlights the reciprocal interactions between OPCs' pro-myelinating and immune-modulating functions. Additionally, we review the specific effects of anti- and pro-inflammatory interventions on OPCs, suggesting that immunosuppression adversely affects OPCs' differentiation and immune functions. CONCLUSION: We suggest a multi-systemic therapeutic approach, which necessitates not a unidimensional focus but a harmonious balance between OPCs' pro-myelinating and immune-modulatory functions.
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Inflamación , Esclerosis Múltiple , Células Precursoras de Oligodendrocitos , Remielinización , Humanos , Remielinización/fisiología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/terapia , Esclerosis Múltiple/patología , Animales , Inflamación/inmunología , Diferenciación Celular/fisiología , Vaina de Mielina , OligodendroglíaRESUMEN
Strategies for treating progressive multiple sclerosis (MS) remain limited. Here, we found that miR-145-5p is overabundant uniquely in chronic lesion tissues from secondary progressive MS patients. We induced both acute and chronic demyelination in miR-145 knockout mice to determine its contributions to remyelination failure. Following acute demyelination, no advantage to miR-145 loss could be detected. However, after chronic demyelination, animals with miR-145 loss demonstrated increased remyelination and functional recovery, coincident with altered presence of astrocytes and microglia within the corpus callosum relative to wild-type animals. This improved response in miR-145 knockout animals coincided with a pathological upregulation of miR-145-5p in wild-type animals with chronic cuprizone exposure, paralleling human chronic lesions. Furthermore, miR-145 overexpression specifically in oligodendrocytes (OLs) severely stunted differentiation and negatively impacted survival. RNAseq analysis showed altered transcriptome in these cells with downregulated major pathways involved in myelination. Our data suggest that pathological accumulation of miR-145-5p is a distinctive feature of chronic demyelination and is strongly implicated in the failure of remyelination, possibly due to the inhibition of OL differentiation together with alterations in other glial cells. This is mirrored in chronic MS lesions, and thus miR-145-5p serves as a potential relevant therapeutic target in progressive forms of MS.