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1.
J Neurosci ; 44(39)2024 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-39151953

RESUMO

Oligodendrocyte myelination and remyelination after injury are intricately regulated by various intrinsic and extrinsic factors, including transcriptional regulators. Among these, the zinc-finger protein ZFP488 is an oligodendrocyte-enriched transcriptional regulator that promotes oligodendrocyte differentiation in the developing neural tube and in oligodendroglial cell lines. However, the specific in vivo genetic requirements for ZFP488 during oligodendrocyte development and remyelination have not been defined. To address this gap, we generated a lineage-traceable ZFP488 knock-out mouse line, wherein an H2b-GFP reporter replaces the ZFP488-coding region. Using these mice of either sex, we examined the dynamics of ZFP488 expression from the endogenous promoter in the developing central nervous system (CNS). We observed a unique expression pattern in the oligodendrocyte lineage, with ZFP488 expression particularly enriched in differentiated oligodendrocytes. ZFP488 loss resulted in delayed myelination in the developing CNS and impaired remyelination after demyelinating injury in the brain. Integrated transcriptomic and genomic profiling further revealed that ZFP488 loss decreased the expression of myelination-associated genes but not oligodendrocyte progenitor-associated genes, suggesting that ZFP488 serves as a positive regulator of myelination by regulating maturation programs. Thus, our genetic loss-of-function study revealed that ZFP488 regulates a stage-dependent differentiation program that controls the timing of CNS myelination and remyelination.


Assuntos
Bainha de Mielina , Oligodendroglia , Remielinização , Animais , Feminino , Masculino , Camundongos , Diferenciação Celular/fisiologia , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Remielinização/fisiologia
2.
J Neurosci ; 44(28)2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38749703

RESUMO

Dysregulation of oligodendrocyte progenitor cell (OPC) recruitment and oligodendrocyte differentiation contribute to failure of remyelination in human demyelinating diseases such as multiple sclerosis (MS). Deletion of muscarinic receptor enhances OPC differentiation and remyelination. However, the role of ligand-dependent signaling versus constitutive receptor activation is unknown. We hypothesized that dysregulated acetylcholine (ACh) release upon demyelination contributes to ligand-mediated activation hindering myelin repair. Following chronic cuprizone (CPZ)-induced demyelination (male and female mice), we observed a 2.5-fold increase in ACh concentration. This increase in ACh concentration could be attributed to increased ACh synthesis or decreased acetylcholinesterase-/butyrylcholinesterase (BChE)-mediated degradation. Using choline acetyltransferase (ChAT) reporter mice, we identified increased ChAT-GFP expression following both lysolecithin and CPZ demyelination. ChAT-GFP expression was upregulated in a subset of injured and uninjured axons following intraspinal lysolecithin-induced demyelination. In CPZ-demyelinated corpus callosum, ChAT-GFP was observed in Gfap+ astrocytes and axons indicating the potential for neuronal and astrocytic ACh release. BChE expression was significantly decreased in the corpus callosum following CPZ demyelination. This decrease was due to the loss of myelinating oligodendrocytes which were the primary source of BChE. To determine the role of ligand-mediated muscarinic signaling following lysolecithin injection, we administered neostigmine, a cholinesterase inhibitor, to artificially raise ACh. We identified a dose-dependent decrease in mature oligodendrocyte density with no effect on OPC recruitment. Together, these results support a functional role of ligand-mediated activation of muscarinic receptors following demyelination and suggest that dysregulation of ACh homeostasis directly contributes to failure of remyelination in MS.


Assuntos
Doenças Desmielinizantes , Oligodendroglia , Transdução de Sinais , Animais , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Camundongos , Oligodendroglia/metabolismo , Oligodendroglia/efeitos dos fármacos , Feminino , Masculino , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Camundongos Endogâmicos C57BL , Acetilcolina/metabolismo , Cuprizona/toxicidade , Lisofosfatidilcolinas/toxicidade , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Colina O-Acetiltransferase/metabolismo , Remielinização/fisiologia , Remielinização/efeitos dos fármacos , Bainha de Mielina/metabolismo , Bainha de Mielina/efeitos dos fármacos , Camundongos Transgênicos
3.
Brain ; 147(5): 1871-1886, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38128553

RESUMO

Multiple sclerosis is a chronic inflammatory disease in which disability results from the disruption of myelin and axons. During the initial stages of the disease, injured myelin is replaced by mature myelinating oligodendrocytes that differentiate from oligodendrocyte precursor cells. However, myelin repair fails in secondary and chronic progressive stages of the disease and with ageing, as the environment becomes progressively more hostile. This may be attributable to inhibitory molecules in the multiple sclerosis environment including activation of the p38MAPK family of kinases. We explored oligodendrocyte precursor cell differentiation and myelin repair using animals with conditional ablation of p38MAPKγ from oligodendrocyte precursors. We found that p38γMAPK ablation accelerated oligodendrocyte precursor cell differentiation and myelination. This resulted in an increase in both the total number of oligodendrocytes and the migration of progenitors ex vivo and faster remyelination in the cuprizone model of demyelination/remyelination. Consistent with its role as an inhibitor of myelination, p38γMAPK was significantly downregulated as oligodendrocyte precursor cells matured into oligodendrocytes. Notably, p38γMAPK was enriched in multiple sclerosis lesions from patients. Oligodendrocyte progenitors expressed high levels of p38γMAPK in areas of failed remyelination but did not express detectable levels of p38γMAPK in areas where remyelination was apparent. Our data suggest that p38γ could be targeted to improve myelin repair in multiple sclerosis.


Assuntos
Esclerose Múltipla , Bainha de Mielina , Oligodendroglia , Remielinização , Animais , Remielinização/fisiologia , Esclerose Múltipla/patologia , Esclerose Múltipla/metabolismo , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Camundongos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Humanos , Proteína Quinase 12 Ativada por Mitógeno/metabolismo , Proteína Quinase 12 Ativada por Mitógeno/genética , Diferenciação Celular/fisiologia , Cuprizona/toxicidade , Camundongos Endogâmicos C57BL , Masculino , Feminino , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Células Precursoras de Oligodendrócitos/patologia , Camundongos Transgênicos
4.
Mol Cell Neurosci ; 129: 103937, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38796120

RESUMO

Experimental models of multiple sclerosis (MS) have significantly contributed to our understanding of pathophysiology and the development of therapeutic interventions. Various in vivo animal models have successfully replicated key features of MS and associated pathophysiological processes, shedding light on the sequence of events leading to disease initiation, progression, and resolution. Nevertheless, these models often entail substantial costs and prolonged treatment periods. In contrast, in vitro models offer distinct advantages, including cost-effectiveness and precise control over experimental conditions, thereby facilitating more reproducible results. We have developed a novel in vitro model tailored to the study of oligodendroglial maturation and myelin deposition under demyelinating and remyelinating conditions, which encompasses all the cell types present in the central nervous system (CNS). Of note, our model enables the evaluation of microglial cell commitment through a protocol involving their depletion and subsequent repopulation. Given that the development and survival of microglia are critically reliant on colony-stimulating factor-1 receptor (CSF-1R) signaling, we have employed CSF-1R inhibition to effectively deplete microglia. This versatile model holds promise for the assessment of potential therapies aimed at promoting oligodendroglial differentiation to safeguard and repair myelin, hence mitigate neurodegenerative processes.


Assuntos
Microglia , Bainha de Mielina , Oligodendroglia , Remielinização , Microglia/metabolismo , Animais , Oligodendroglia/metabolismo , Bainha de Mielina/metabolismo , Camundongos , Remielinização/fisiologia , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Diferenciação Celular/fisiologia , Células Cultivadas
5.
Proc Natl Acad Sci U S A ; 119(46): e2120393119, 2022 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-36343243

RESUMO

Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Why endogenous repair mechanisms frequently fail in these disorders is poorly understood. However, there is now evidence indicating that this is related to an overly inflammatory microenvironment combined with the intrinsic inability of oligodendrocyte precursor cells (OPCs) to differentiate into mature myelinating cells. Previously, we found that phloretin, a flavonoid abundantly present in apples and strawberries, reduces neuroinflammation by driving macrophages toward an antiinflammatory phenotype. Here, we show that phloretin also markedly stimulates remyelination in ex vivo and in vivo animal models. Improved remyelination was attributed to a direct impact of phloretin on OPC maturation and occurred independently from alterations in microglia function and inflammation. We found, mechanistically, that phloretin acts as a direct ligand for the fatty acid sensing nuclear receptor peroxisome proliferator-activated receptor gamma, thereby promoting the maturation of OPCs. Together, our findings indicate that phloretin has proregenerative properties in central nervous system disorders, with potentially broad implications for the development of therapeutic strategies and dietary interventions aimed at promoting remyelination.


Assuntos
Células Precursoras de Oligodendrócitos , Remielinização , Animais , Camundongos , Remielinização/fisiologia , Floretina/farmacologia , Camundongos Endogâmicos C57BL , Oligodendroglia , Diferenciação Celular/fisiologia , Bainha de Mielina
6.
Glia ; 72(9): 1674-1692, 2024 09.
Artigo em Inglês | MEDLINE | ID: mdl-38899731

RESUMO

Spinal cord injury (SCI) can result in severe motor and sensory deficits, for which currently no effective cure exists. The pathological process underlying this injury is extremely complex and involves many cell types in the central nervous system. In this study, we have uncovered a novel function for macrophage G protein-coupled receptor kinase-interactor 1 (GIT1) in promoting remyelination and functional repair after SCI. Using GIT1flox/flox Lyz2-Cre (GIT1 CKO) mice, we identified that GIT1 deficiency in macrophages led to an increased generation of tumor necrosis factor-alpha (TNFα), reduced proportion of mature oligodendrocytes (mOLs), impaired remyelination, and compromised functional recovery in vivo. These effects in GIT1 CKO mice were reversed with the administration of soluble TNF inhibitor. Moreover, bone marrow transplantation from GIT1 CWT mice reversed adverse outcomes in GIT1 CKO mice, further indicating the role of macrophage GIT1 in modulating spinal cord injury repair. Our in vitro experiments showed that macrophage GIT1 plays a critical role in secreting TNFα and influences the differentiation of oligodendrocyte precursor cells (OPCs) after stimulation with myelin debris. Collectively, our data uncovered a new role of macrophage GIT1 in regulating the transformation of OPCs into mOLs, essential for functional remyelination after SCI, suggesting that macrophage GIT1 could be a promising treatment target of SCI.


Assuntos
Diferenciação Celular , Macrófagos , Células Precursoras de Oligodendrócitos , Remielinização , Traumatismos da Medula Espinal , Animais , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Macrófagos/metabolismo , Remielinização/fisiologia , Diferenciação Celular/fisiologia , Células Precursoras de Oligodendrócitos/metabolismo , Camundongos , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Recuperação de Função Fisiológica/fisiologia , Modelos Animais de Doenças , Fator de Necrose Tumoral alfa/metabolismo , Camundongos Transgênicos , Feminino , Proteínas Ativadoras de GTPase/metabolismo , Proteínas Ativadoras de GTPase/genética , Oligodendroglia/metabolismo
7.
Glia ; 72(9): 1555-1571, 2024 09.
Artigo em Inglês | MEDLINE | ID: mdl-38829008

RESUMO

As one of the top causes of blindness worldwide, glaucoma leads to diverse optic neuropathies such as degeneration of retinal ganglion cells (RGCs). It is widely accepted that the level of intraocular pressure (IOP) is a major risk factor in human glaucoma, and reduction of IOP level is the principally most well-known method to prevent cell death of RGCs. However, clinical studies show that lowering IOP fails to prevent RGC degeneration in the progression of glaucoma. Thus, a comprehensive understanding of glaucoma pathological process is required for developing new therapeutic strategies. In this study, we provide functional and histological evidence showing that optic nerve defects occurred before retina damage in an ocular hypertension glaucoma mouse model, in which oligodendroglial lineage cells were responsible for the subsequent neuropathology. By treatment with clemastine, an Food and Drug Administration (FDA)-approved first-generation antihistamine medicine, we demonstrate that the optic nerve and retina damages were attenuated via promoting oligodendrocyte precursor cell (OPC) differentiation and enhancing remyelination. Taken together, our results reveal the timeline of the optic neuropathies in glaucoma and highlight the potential role of oligodendroglial lineage cells playing in its treatment. Clemastine may be used in future clinical applications for demyelination-associated glaucoma.


Assuntos
Clemastina , Glaucoma , Camundongos Endogâmicos C57BL , Remielinização , Retina , Animais , Clemastina/farmacologia , Clemastina/uso terapêutico , Glaucoma/patologia , Glaucoma/tratamento farmacológico , Retina/patologia , Retina/efeitos dos fármacos , Remielinização/efeitos dos fármacos , Remielinização/fisiologia , Camundongos , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/patologia , Modelos Animais de Doenças , Doenças do Nervo Óptico/tratamento farmacológico , Doenças do Nervo Óptico/patologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia
8.
Glia ; 72(8): 1392-1401, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38572807

RESUMO

Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) characterized by demyelination, axonal damage and, for the majority of people, a decline in neurological function in the long-term. Remyelination could assist in the protection of axons and their functional recovery, but such therapies are not, as yet, available. The TAM (Tyro3, Axl, and MERTK) receptor ligand GAS6 potentiates myelination in vitro and promotes recovery in pre-clinical models of MS. However, it has remained unclear which TAM receptor is responsible for transducing this effect and whether post-translational modification of GAS6 is required. In this study, we show that the promotion of myelination requires post-translational modification of the GLA domain of GAS6 via vitamin K-dependent γ-carboxylation. We also confirmed that the intracerebroventricular provision of GAS6 for 2 weeks to demyelinated wild-type (WT) mice challenged with cuprizone increased the density of myelinated axons in the corpus callosum by over 2-fold compared with vehicle control. Conversely, the provision of GAS6 to Tyro3 KO mice did not significantly improve the density of myelinated axons. The improvement in remyelination following the provision of GAS6 to WT mice was also accompanied by an increased density of CC1+ve mature oligodendrocytes compared with vehicle control, whereas this improvement was not observed in the absence of Tyro3. This effect occurs independent of any influence on microglial activation. This work therefore establishes that the remyelinative activity of GAS6 is dependent on Tyro3 and includes potentiation of oligodendrocyte numbers.


Assuntos
Cuprizona , Doenças Desmielinizantes , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Proteína Tirosina Quinases , Remielinização , Animais , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Remielinização/fisiologia , Remielinização/efeitos dos fármacos , Receptores Proteína Tirosina Quinases/metabolismo , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Cuprizona/toxicidade , Camundongos , Modelos Animais de Doenças , Bainha de Mielina/metabolismo , Bainha de Mielina/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Masculino , Feminino
9.
Glia ; 72(8): 1469-1483, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38771121

RESUMO

Myelination is the terminal step in a complex and precisely timed program that orchestrates the proliferation, migration and differentiation of oligodendroglial cells. It is thought that Sonic Hedgehog (Shh) acting on Smoothened (Smo) participates in regulating this process, but that these effects are highly context dependent. Here, we investigate oligodendroglial development and remyelination from three specific transgenic lines: NG2-CreERT2 (control), Smofl/fl/NG2-CreERT2 (loss of function), and SmoM2/NG2-CreERT2 (gain of function), as well as pharmacological manipulation that enhance or inhibit the Smo pathway (Smoothened Agonist (SAG) or cyclopamine treatment, respectively). To explore the effects of Shh/Smo on differentiation and myelination in vivo, we developed a highly quantifiable model by transplanting oligodendrocyte precursor cells (OPCs) in the retina. We find that myelination is greatly enhanced upon cyclopamine treatment and hypothesize that Shh/Smo could promote OPC proliferation to subsequently inhibit differentiation. Consistent with this hypothesis, we find that the genetic activation of Smo significantly increased numbers of OPCs and decreased oligodendrocyte differentiation when we examined the corpus callosum during development and after cuprizone demyelination and remyelination. However, upon loss of function with the conditional ablation of Smo, myelination in the same scenarios are unchanged. Taken together, our present findings suggest that the Shh pathway is sufficient to maintain OPCs in an undifferentiated state, but is not necessary for myelination and remyelination.


Assuntos
Diferenciação Celular , Proteínas Hedgehog , Camundongos Transgênicos , Bainha de Mielina , Células Precursoras de Oligodendrócitos , Receptor Smoothened , Animais , Proteínas Hedgehog/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Receptor Smoothened/metabolismo , Receptor Smoothened/genética , Bainha de Mielina/metabolismo , Diferenciação Celular/fisiologia , Diferenciação Celular/efeitos dos fármacos , Alcaloides de Veratrum/farmacologia , Camundongos , Remielinização/fisiologia , Remielinização/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/fisiologia , Camundongos Endogâmicos C57BL , Transdução de Sinais/fisiologia , Transdução de Sinais/efeitos dos fármacos
10.
J Neuroinflammation ; 21(1): 243, 2024 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-39342313

RESUMO

Demyelination occurs widely in the central nervous system (CNS) neurodegenerative diseases, especially the multiple sclerosis (MS), which with a complex and inflammatory lesion microenvironment inhibiting remyelination. Sirtuin6 (SIRT6), a histone/protein deacetylase is of interest for its promising effect in transcriptional regulation, cell cycling, inflammation, metabolism and longevity. Here we show that SIRT6 participates in the remyelination process in mice subjected to LPC-induced demyelination. Using pharmacological SIRT6 inhibitor or activator, we found that SIRT6 modulated LPC-induced damage in motor or cognitive function. Inhibition of SIRT6 impaired myelin regeneration, exacerbated neurological deficits, and decreased oligodendrocyte precursor cells (OPCs) proliferation and differentiation, whereas activation of SIRT6 reversed behavioral performance in mice, demonstrating a beneficial effect of SIRT6. Importantly, based on RNA sequencing analysis of the corpus callosum tissues, it was further revealed that SIRT6 took charge in regulation of glial activation during remyelination, and significant alterations in CHI3L1 were obtained, a glycoprotein specifically secreted by astrocytes. Impaired proliferation and differentiation of OPCs could be induced in vitro using supernatants from reactive astrocyte, especially when SIRT6 was inhibited. Mechanistically, SIRT6 regulates the secretion of CHI3L1 from reactive astrocytes by histone-H3-lysine-9 acetylation (H3K9Ac). Adeno-associated virus-overexpression of SIRT6 (AAV-SIRT6-OE) in astrocytes improved remyelination and functional recovery after LPC-induced demyelination, whereas together with AAV-CHI3L1-OE inhibits this therapeutic effect. Collectively, our data elucidate the role of SIRT6 in remyelination and further reveal astrocytic SIRT6/CHI3L1 as the key regulator for improving the remyelination environment, which may be a potential target for MS therapy.


Assuntos
Astrócitos , Doenças Desmielinizantes , Sirtuínas , Animais , Masculino , Camundongos , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Células Cultivadas , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Lisofosfatidilcolinas/toxicidade , Camundongos Endogâmicos C57BL , Remielinização/efeitos dos fármacos , Remielinização/fisiologia , Sirtuínas/metabolismo , Sirtuínas/genética
11.
Acta Neuropathol ; 147(1): 75, 2024 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-38656399

RESUMO

In multiple sclerosis (MS), persisting disability can occur independent of relapse activity or development of new central nervous system (CNS) inflammatory lesions, termed chronic progression. This process occurs early and it is mostly driven by cells within the CNS. One promising strategy to control progression of MS is the inhibition of the enzyme Bruton's tyrosine kinase (BTK), which is centrally involved in the activation of both B cells and myeloid cells, such as macrophages and microglia. The benefit of BTK inhibition by evobrutinib was shown as we observed reduced pro-inflammatory activation of microglia when treating chronic experimental autoimmune encephalomyelitis (EAE) or following the adoptive transfer of activated T cells. Additionally, in a model of toxic demyelination, evobrutinib-mediated BTK inhibition promoted the clearance of myelin debris by microglia, leading to an accelerated remyelination. These findings highlight that BTK inhibition has the potential to counteract underlying chronic progression of MS.


Assuntos
Tirosina Quinase da Agamaglobulinemia , Encefalomielite Autoimune Experimental , Microglia , Bainha de Mielina , Piperidinas , Pirimidinas , Animais , Feminino , Camundongos , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Compostos de Bifenilo/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Camundongos Endogâmicos C57BL , Microglia/patologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Bainha de Mielina/patologia , Bainha de Mielina/metabolismo , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Remielinização/fisiologia , Remielinização/efeitos dos fármacos
12.
Nat Chem Biol ; 18(9): 925-933, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35995862

RESUMO

Remyelination, or the restoration of myelin sheaths around axons in the central nervous system, is a multi-stage repair process that remains a major need for millions of patients with multiple sclerosis and other diseases of myelin. Even into adulthood, rodents and humans can generate new myelin-producing oligodendrocytes, leading to the therapeutic hypothesis that enhancing remyelination could lessen disease burden in multiple sclerosis. Multiple labs have used phenotypic screening to identify dozens of drugs that enhance oligodendrocyte formation, and several hit molecules have now advanced to clinical evaluation. Target identification studies have revealed that a large majority of these hits share the ability to inhibit a narrow range of cholesterol pathway enzymes and thereby induce cellular accumulation of specific sterol precursors to cholesterol. This Perspective surveys the recent fruitful intersection of chemical biology and remyelination and suggests multiple approaches toward new targets and lead molecules to promote remyelination.


Assuntos
Esclerose Múltipla , Remielinização , Adulto , Colesterol/metabolismo , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Remielinização/fisiologia
13.
Brain ; 146(6): 2453-2463, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-36995973

RESUMO

In multiple sclerosis, while remarkable progress has been accomplished to control the inflammatory component of the disease, repair of demyelinated lesions is still an unmet need. Despite encouraging results generated in experimental models, several candidates favouring or promoting remyelination have not reached the expected outcomes in clinical trials. One possible reason for these failures is that, in most cases, during preclinical testing, efficacy was evaluated on histology only, while functional recovery had not been assessed. We have generated a Xenopus laevis transgenic model Tg(mbp:GFP-NTR) of conditional demyelination in which spontaneous remyelination can be accelerated using candidate molecules. Xenopus laevis is a classic model for in vivo studies of myelination because tadpoles are translucent. We reasoned that demyelination should translate into loss of sensorimotor functions followed by behavioural recovery upon remyelination. To this end, we measured the swimming speed and distance travelled before and after demyelination and during the ongoing spontaneous remyelination and have developed a functional assay based on the visual avoidance of a virtual collision. Here we show that alteration of these functional and clinical performances correlated well with the level of demyelination and that histological remyelination, assayed by counting in vivo the number of myelinating oligodendrocytes in the optic nerve, translated in clinical-functional recovery. This method was further validated in tadpoles treated with pro-remyelinating agents (clemastine, siponimod) showing that increased remyelination in the optic nerve was associated with functional improvement. Our data illustrate the potential interest of correlating histopathological parameters and functional-clinical parameters to screen molecules promoting remyelination in a simple in vivo model of conditional demyelination.


Assuntos
Esclerose Múltipla , Remielinização , Animais , Esclerose Múltipla/patologia , Oligodendroglia/patologia , Remielinização/fisiologia , Nervo Óptico/patologia , Modelos Animais de Doenças , Xenopus laevis , Bainha de Mielina/patologia
14.
J Neuroophthalmol ; 44(2): 143-156, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38654413

RESUMO

INTRODUCTION: Amelioration of disability in multiple sclerosis requires the development of complementary therapies that target neurodegeneration and promote repair. Remyelination is a promising neuroprotective strategy that may protect axons from damage and subsequent neurodegeneration. METHODS: A review of key literature plus additional targeted search of PubMed and Google Scholar was conducted. RESULTS: There has been a rapid expansion of clinical trials studying putative remyelinating candidates, but further growth of the field is limited by the lack of consensus on key aspects of trial design. We have not yet defined the ideal study population, duration of therapy, or the appropriate outcome measures to detect remyelination in humans. The varied natural history of multiple sclerosis, coupled with the short time frame of phase II clinical trials, requires that we develop and validate biomarkers of remyelination that can serve as surrogate endpoints in clinical trials. CONCLUSIONS: We propose that the visual system may be the most well-suited and validated model for the study potential remyelinating agents. In this review, we discuss the pathophysiology of demyelination and summarize the current clinical trial landscape of remyelinating agents. We present some of the challenges in the study of remyelinating agents and discuss current potential biomarkers of remyelination and repair, emphasizing both established and emerging visual outcome measures.


Assuntos
Esclerose Múltipla , Remielinização , Humanos , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla/tratamento farmacológico , Remielinização/fisiologia , Remielinização/efeitos dos fármacos , Bainha de Mielina
15.
Proc Natl Acad Sci U S A ; 118(28)2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34244440

RESUMO

Oligodendrocyte precursor cells (OPCs) retain the capacity to remyelinate axons in the corpus callosum (CC) upon demyelination. However, the dynamics of OPC activation, mode of cell division, migration, and differentiation on a single-cell level remain poorly understood due to the lack of longitudinal observations of individual cells within the injured brain. After inducing focal demyelination with lysophosphatidylcholin in the CC of adult mice, we used two-photon microscopy to follow for up to 2 mo OPCs and their differentiating progeny, genetically labeled through conditional recombination driven by the regulatory elements of the gene Achaete-scute homolog 1. OPCs underwent several rounds of symmetric and asymmetric cell divisions, producing a subset of daughter cells that differentiates into myelinating oligodendrocytes. While OPCs continue to proliferate, differentiation into myelinating oligodendrocytes declines with time, and death of OPC-derived daughter cells increases. Thus, chronic in vivo imaging delineates the cellular principles leading to remyelination in the adult brain, providing a framework for the development of strategies to enhance endogenous brain repair in acute and chronic demyelinating disease.


Assuntos
Envelhecimento/fisiologia , Corpo Caloso/diagnóstico por imagem , Imageamento Tridimensional , Remielinização/fisiologia , Animais , Morte Celular , Divisão Celular , Movimento Celular , Células Clonais , Camundongos , Células Precursoras de Oligodendrócitos/citologia
16.
Bull Exp Biol Med ; 176(5): 666-671, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38727956

RESUMO

This paper shows for the first time that co-transplantation of human olfactory ensheathing cells with neurotrophin-3 into spinal cord cysts is more effective for activation of remyelination than transplantation of cells with brain-derived neurotrophic factor and a combination of these two factors. The studied neurotrophic factors do not affect proliferation and migration of ensheathing cells in vitro. It can be concluded that the maximum improvement of motor function in rats receiving ensheathing cells with neurotrophin-3 is largely determined by activation of remyelination.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Neurotrofina 3 , Bulbo Olfatório , Remielinização , Animais , Ratos , Neurotrofina 3/metabolismo , Humanos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Remielinização/fisiologia , Bulbo Olfatório/citologia , Proliferação de Células , Medula Espinal/metabolismo , Bainha de Mielina/metabolismo , Bainha de Mielina/fisiologia , Células Cultivadas , Movimento Celular , Cistos/patologia , Feminino , Cistos do Sistema Nervoso Central/cirurgia , Cistos do Sistema Nervoso Central/patologia
17.
Semin Cell Dev Biol ; 116: 3-9, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33082115

RESUMO

The biology of CNS remyelination has attracted considerable interest in recent years because of its translational potential to yield regenerative therapies for the treatment of chronic and progressive demyelinating diseases such as multiple sclerosis (MS). Critical to devising myelin regenerative therapies is a detailed understanding of how remyelination occurs. The accepted dogma, based on animal studies, has been that the myelin sheaths of remyelination are made by oligodendrocytes newly generated from adult oligodendrocyte progenitor cells in a classical regenerative process of progenitor migration, proliferation and differentiation. However, recent human and a growing number of animal studies have revealed a second mode of remyelination in which mature oligodendrocytes surviving within an area of demyelination are able to regenerate new myelin sheaths. This discovery, while opening up new opportunities for therapeutic remyelination, has also raised the question of whether there are fundamental differences in myelin regeneration between humans and some of the species in which experimental remyelination studies are conducted. Here we review how this second mode of remyelination can be integrated into a wider and revised framework for understanding remyelination in which apparent species differences can be reconciled but that also raises important questions for future research.


Assuntos
Sistema Nervoso Central/fisiologia , Bainha de Mielina/fisiologia , Remielinização/fisiologia , Animais , Humanos
18.
Glia ; 71(9): 2180-2195, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37203250

RESUMO

central nervous system (CNS) inflammation triggers activation of the integrated stress response (ISR). We previously reported that prolonging the ISR protects remyelinating oligodendrocytes and promotes remyelination in the presence of inflammation. However, the exact mechanisms through which this occurs remain unknown. Here, we investigated whether the ISR modulator Sephin1 in combination with the oligodendrocyte differentiation enhancing reagent bazedoxifene (BZA) is able to accelerate remyelination under inflammation, and the underlying mechanisms mediating this pathway. We find that the combined treatment of Sephin1 and BZA is sufficient to accelerate early-stage remyelination in mice with ectopic IFN-γ expression in the CNS. IFN-γ, which is a critical inflammatory cytokine in multiple sclerosis (MS), inhibits oligodendrocyte precursor cell (OPC) differentiation in culture and triggers a mild ISR. Mechanistically, we further show that BZA promotes OPC differentiation in the presence of IFN-γ, while Sephin1 enhances the IFN-γ-induced ISR by reducing protein synthesis and increasing RNA stress granule formation in differentiating oligodendrocytes. Finally, pharmacological suppression of the ISR blocks stress granule formation in vitro and partially lessens the beneficial effect of Sephin1 on disease progression in a mouse model of MS, experimental autoimmune encephalitis (EAE). Overall, our findings uncover distinct mechanisms of action of BZA and Sephin1 on oligodendrocyte lineage cells under inflammatory stress, suggesting that a combination therapy may effectively promote restoring neuronal function in MS patients.


Assuntos
Esclerose Múltipla , Remielinização , Camundongos , Animais , Remielinização/fisiologia , Oligodendroglia/fisiologia , Diferenciação Celular , Inflamação , Camundongos Endogâmicos C57BL
19.
Glia ; 71(2): 284-304, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36089914

RESUMO

Neuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory autoimmune disease of the central nervous system that is manifested as secondary myelin loss. Oligodendrocyte progenitor cells (OPCs) are the principal source of myelinating oligodendrocytes (OLs) and are abundant in demyelinated regions of NMOSD patients, thus possibly representing a cellular target for pharmacological intervention. To explore the therapeutic compounds that enhance myelination due to endogenous OPCs, we screened the candidate drugs in mouse neural progenitor cell (NPC)-derived OPCs. We identified drug edaravone, which is approved by the Food and Drug Administration (FDA), as a promoter of OPC differentiation into mature OLs. Edaravone enhanced remyelination in organotypic slice cultures and in mice, even when edaravone was administered following NMO-IgG-induced demyelination, and ameliorated motor impairment in a systemic mouse model of NMOSD. The results of mechanistic studies in NMO-IgG-treated mice and the biopsy samples of the brain tissues of NMOSD patients indicated that the mTORC1 signaling pathway was significantly inhibited, and edaravone promoted OPC maturation and remyelination by activating mTORC1 signaling. Furthermore, pharmacological activation of mTORC1 signaling significantly enhanced myelin regeneration in NMOSD. Thus, edaravone is a potential therapeutic agent that promotes lesion repair in NMOSD patients by enhancing OPC maturation.


Assuntos
Neuromielite Óptica , Remielinização , Animais , Camundongos , Remielinização/fisiologia , Neuromielite Óptica/tratamento farmacológico , Edaravone/metabolismo , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Diferenciação Celular/fisiologia , Transdução de Sinais , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Imunoglobulina G
20.
Neurobiol Dis ; 177: 105988, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36603746

RESUMO

CXC chemokine receptor 2 (CXCR2) plays an important role in demyelinating diseases, but the detailed mechanisms were not yet clarified. In the present study, we mainly investigated the critical function and the potential molecular mechanisms of CXCR2 on oligodendrocyte precursor cell (OPC) differentiation and remyelination. The present study demonstrated that inhibiting CXCR2 significantly enhanced OPC differentiation and remyelination in primary cultured OPCs and ethidium bromide (EB)-intoxicated rats by facilitating the formation of myelin proteins, including PDGFRα, MBP, MAG, MOG, and Caspr. Further investigation identified phosphodiesterase 10A (PDE10A) as a main downstream protein of CXCR2, interacting with the receptor to regulate OPC differentiation, in that inhibition of CXCR2 reduced PDE10A expression while suppression of PDE10A did not affect CXCR2. Furthermore, inhibition of PDE10A promoted OPC differentiation, whereas overexpression of PDE10A down-regulated OPC differentiation. Our data also revealed that inhibition of CXCR2/PDE10A activated the cAMP/ERK1/2 signaling pathway, and up-regulated the expression of key transcription factors, including SOX10, OLIG2, MYRF, and ZFP24, that ultimately promoted remyelination and myelin protein biosynthesis. In conclusion, our findings suggested that inhibition of CXCR2 promoted OPC differentiation and enhanced remyelination by regulating PDE10A/cAMP/ERK1/2 signaling pathway. The present data also highlighted that CXCR2 may serve as a potential target for the treatment of demyelination diseases.


Assuntos
Doenças Desmielinizantes , Remielinização , Ratos , Animais , Camundongos , Remielinização/fisiologia , Receptores de Interleucina-8B/metabolismo , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/metabolismo , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Transdução de Sinais , Diferenciação Celular/fisiologia , Camundongos Endogâmicos C57BL , Diester Fosfórico Hidrolases/metabolismo
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