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1.
Stem Cell Res Ther ; 15(1): 35, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38321505

RESUMO

BACKGROUND: Spinal cord injury (SCI) is a devastating disease that causes extensive damage to oligodendrocytes and neurons leading to demyelination and axonal degeneration. In this study, we co-transplanted cell grafts containing oligodendrocyte progenitor cells (OPCs) derived from human-induced pluripotent stem cells (iPSCs) combined with human umbilical vein endothelial cells (HUVECs), which were reported to promote OPCs survival and migration, into rat contusion models to promote functional recovery after SCI. METHODS: OPCs were derived from iPSCs and identified by immunofluorescence at different time points. Functional assays in vitro were performed to evaluate the effect of HUVECs on the proliferation, migration, and survival of OPCs by co-culture and migration assay, as well as on the neuronal axonal growth. A combination of OPCs and HUVECs was transplanted into the rat contusive model. Upon 8 weeks, immunofluorescence staining was performed to test the safety of transplanted cells and to observe the neuronal repairment, myelination, and neural circuit reconstruction at the injured area; also, the functional recovery was assessed by Basso, Beattie, and Bresnahan open-field scale, Ladder climb, SEP, and MEP. Furthermore, the effect of HUVECs on grafts was also determined in vivo. RESULTS: Data showed that HUVECs promote the proliferation, migration, and survival of OPCs both in vitro and in vivo. Furthermore, 8 weeks upon engraftment, the rats with OPCs and HUVECs co-transplantation noticeably facilitated remyelination, enhanced functional connection between the grafts and the host and promoted functional recovery. In addition, compared with the OPCs-alone transplantation, the co-transplantation generated more sensory neurons at the lesion border and significantly improved the sensory functional recovery. CONCLUSIONS: Our study demonstrates that transplantation of OPCs combined with HUVECs significantly enhances both motor and sensory functional recovery after SCI. No significance was observed between OPCs combined with HUVECs group and OPCs-alone group in motor function recovery, while the sensory function recovery was significantly promoted in OPCs combined with HUVECs groups compared with the other two groups. These findings provide novel insights into the field of SCI research.


Assuntos
Células-Tronco Pluripotentes Induzidas , Células Precursoras de Oligodendrócitos , Traumatismos da Medula Espinal , Ratos , Humanos , Animais , Células Precursoras de Oligodendrócitos/patologia , Células Precursoras de Oligodendrócitos/transplante , Células Endoteliais da Veia Umbilical Humana , Recuperação de Função Fisiológica , Células-Tronco Pluripotentes Induzidas/transplante , Traumatismos da Medula Espinal/patologia , Oligodendroglia , Medula Espinal/patologia , Diferenciação Celular/fisiologia
2.
J Vis Exp ; (204)2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38407295

RESUMO

Tissue-specific neural stem cells (NSCs) remain active in the mammalian postnatal brain. They reside in specialized niches, where they generate new neurons and glia. One such niche is the subependymal zone (SEZ; also called the ventricular-subventricular zone), which is located across the lateral walls of the lateral ventricles, adjacent to the ependymal cell layer. Oligodendrocyte progenitor cells (OPCs) are abundantly distributed throughout the central nervous system, constituting a pool of proliferative progenitor cells that can generate oligodendrocytes. Both NSCs and OPCs exhibit self-renewal potential and quiescence/activation cycles. Due to their location, the isolation and experimental investigation of these cells is performed postmortem. Here, we describe in detail "brain milking", a method for the isolation of NSCs and OPCs, amongst other cells, from live animals. This is a two-step protocol designed for use in rodents and tested in rats. First, cells are "released" from the tissue via stereotaxic intracerebroventricular (i.c.v.) injection of a "release cocktail". The main components are neuraminidase, which targets ependymal cells and induces ventricular wall denudation, an integrin-ß1-blocking antibody, and fibroblast growth factor-2. At a second "collection" step, liquid biopsies of cerebrospinal fluid are performed from the cisterna magna, in anesthetized rats without the need of an incision. Results presented here show that isolated cells retain their endogenous profile and that NSCs of the SEZ preserve their quiescence. The denudation of the ependymal layer is restricted to the anatomical level of injection and the protocol (release and collection) is tolerated well  by the animals. This novel approach paves the way for performing longitudinal studies of endogenous neurogenesis and gliogenesis in experimental animals.


Assuntos
Células-Tronco Neurais , Células Precursoras de Oligodendrócitos , Ratos , Animais , Encéfalo , Sistema Nervoso Central , Neuroglia , Mamíferos
3.
Sci Rep ; 14(1): 4091, 2024 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-38374232

RESUMO

In the central nervous system, oligodendrocyte precursor cells (OPCs) proliferate and differentiate into myelinating oligodendrocytes throughout life, allowing for ongoing myelination and myelin repair. With age, differentiation efficacy decreases and myelin repair fails; therefore, recent therapeutic efforts have focused on enhancing differentiation. Many cues are thought to regulate OPC differentiation, including neuronal activity, which OPCs can sense and respond to via their voltage-gated ion channels and glutamate receptors. However, OPCs' density of voltage-gated ion channels and glutamate receptors differs with age and brain region, and correlates with their proliferation and differentiation potential, suggesting that OPCs exist in different functional cell states, and that age-associated states might underlie remyelination failure. Here, we use whole-cell patch-clamp to investigate whether clemastine and metformin, two pro-remyelination compounds, alter OPC membrane properties and promote a specific OPC state. We find that clemastine and metformin extend the window of NMDAR surface expression, promoting an NMDAR-rich OPC state. Our findings highlight a possible mechanism for the pro-remyelinating action of clemastine and metformin, and suggest that OPC states can be modulated as a strategy to promote myelin repair.


Assuntos
Metformina , Células Precursoras de Oligodendrócitos , Células Precursoras de Oligodendrócitos/metabolismo , Clemastina , Receptores de N-Metil-D-Aspartato/metabolismo , Metformina/farmacologia , Metformina/metabolismo , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Diferenciação Celular/fisiologia
4.
eNeuro ; 11(3)2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38351133

RESUMO

The subependymal zone (SEZ), also known as the subventricular zone (SVZ), constitutes a neurogenic niche that persists during postnatal life. In humans, the neurogenic potential of the SEZ declines after the first year of life. However, studies discovering markers of stem and progenitor cells highlight the neurogenic capacity of progenitors in the adult human SEZ, with increased neurogenic activity occurring under pathological conditions. In the present study, the complete cellular niche of the adult human SEZ was characterized by single-nucleus RNA sequencing, and compared between four youth (age 16-22) and four middle-aged adults (age 44-53). We identified 11 cellular clusters including clusters expressing marker genes for neural stem cells (NSCs), neuroblasts, immature neurons, and oligodendrocyte progenitor cells. The relative abundance of NSC and neuroblast clusters did not differ between the two age groups, indicating that the pool of SEZ NSCs does not decline in this age range. The relative abundance of oligodendrocyte progenitors and microglia decreased in middle-age, indicating that the cellular composition of human SEZ is remodeled between youth and adulthood. The expression of genes related to nervous system development was higher across different cell types, including NSCs, in youth as compared with middle-age. These transcriptional changes suggest ongoing central nervous system plasticity in the SEZ in youth, which declined in middle-age.


Assuntos
Células-Tronco Neurais , Células Precursoras de Oligodendrócitos , Adulto , Pessoa de Meia-Idade , Adolescente , Humanos , Adulto Jovem , RNA-Seq , Neurônios , Ventrículos Laterais/metabolismo , Neurogênese/fisiologia
5.
CNS Neurosci Ther ; 30(1): e14552, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38287523

RESUMO

AIMS: Multiple sclerosis (MS) is a chronic neurological disease that currently lacks effective curative treatments. There is a need to find effective therapies, especially to reverse the progressive demyelination and neuronal damage. Oligodendrocytes form the myelin sheath around axons in the central nervous system (CNS) and oligodendrocyte precursor cells (OPCs) undergo mechanisms that enable spontaneously the partial repair of damaged lesions. The aim of this study was to discover small molecules with potential effects in demyelinating diseases, including (re)myelinating properties. METHODS: Recently, it has been shown how LRRK2 inhibition promotes oligodendrogliogenesis and therefore an efficient repair or myelin damaged lesions. Here we explored small molecules inhibiting LRRK2 as potential enhancers of primary OPCs proliferation and differentiation, and their potential impact on the clinical score of experimental autoimmune encephalomyelitys (EAE) mice, a validated model of the most frequent clinical form of MS, relapsing-remitting MS. RESULTS: One of the LRRK2 inhibitors presented in this study promoted the proliferation and differentiation of OPC primary cultures. When tested in the EAE murine model of MS, it exerted a statistically significant reduction of the clinical burden of the animals, and histological evidence revealed how the treated animals presented a reduced lesion area in the spinal cord. CONCLUSIONS: For the first time, a small molecule with LRRK2 inhibition properties presented (re)myelinating properties in primary OPCs cultures and potentially in the in vivo murine model. This study provides an in vivo proof of concept for a LRRK2 inhibitor, confirming its potential for the treatment of MS.


Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Células Precursoras de Oligodendrócitos , Camundongos , Animais , Encefalomielite Autoimune Experimental/patologia , Células Precursoras de Oligodendrócitos/patologia , Modelos Animais de Doenças , Bainha de Mielina/patologia , Oligodendroglia/patologia , Diferenciação Celular , Benzotiazóis/farmacologia , Benzotiazóis/uso terapêutico , Camundongos Endogâmicos C57BL
6.
Nat Neurosci ; 27(2): 219-231, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38216650

RESUMO

In the nervous system, only one type of neuron-glial synapse is known to exist: that between neurons and oligodendrocyte precursor cells (OPCs), yet their composition, assembly, downstream signaling and in vivo functions remain largely unclear. Here, we address these questions using in vivo microscopy in zebrafish spinal cord and identify postsynaptic molecules PSD-95 and gephyrin in OPCs. The puncta containing these molecules in OPCs increase during early development and decrease upon OPC differentiation. These puncta are highly dynamic and frequently assemble at 'hotspots'. Gephyrin hotspots and synapse-associated Ca2+ activity in OPCs predict where a subset of myelin sheaths forms in differentiated oligodendrocytes. Further analyses reveal that spontaneous synaptic release is integral to OPC Ca2+ activity, while evoked synaptic release contributes only in early development. Finally, disruption of the synaptic genes dlg4a/dlg4b, gphnb and nlgn3b impairs OPC differentiation and myelination. Together, we propose that neuron-OPC synapses are dynamically assembled and can predetermine myelination patterns through Ca2+ signaling.


Assuntos
Bainha de Mielina , Células Precursoras de Oligodendrócitos , Animais , Bainha de Mielina/fisiologia , Peixe-Zebra , Oligodendroglia/fisiologia , Neurônios/fisiologia , Diferenciação Celular/fisiologia
8.
Immunology ; 171(4): 618-633, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38243672

RESUMO

Oligodendrocyte progenitor cells (OPCs) were regarded for years solely for their regenerative role; however, their immune-modulatory roles have gained much attention recently, particularly in the context of multiple sclerosis (MS). Despite extensive studies on OPCs, there are limited data elucidating the interactions between their intrinsic regenerative and immune functions, as well as their relationship with the inflamed central nervous system (CNS) environment, a key factor in MS pathology. We examined the effects of pro-inflammatory cytokines, represented by interferon (IFN)-γ and tumour necrosis factor (TNF)-α, as well as anti-inflammatory cytokines, represented by interleukin (IL)-4 and IL-10, on OPC differentiation and immune characteristics. Using primary cultures, enzyme-linked immunosorbent assay and immunofluorescence stainings, we assessed differentiation capacity, phagocytic activity, major histocompatibility complex (MHC)-II expression, and cytokine secretion. We observed that the anti-inflammatory milieu (IL4 and IL10) reduced both OPC differentiation and immune functions. Conversely, exposure to TNF-α led to intact differentiation, increased phagocytic activity, high levels of MHC-II expression, and cytokines secretion. Those effects were attributed to signalling via TNF-receptor-2 and counteracted the detrimental effects of IFN-γ on OPC differentiation. Our findings suggest that a pro-regenerative, permissive inflammatory environment is needed for OPCs to execute both regenerative and immune-modulatory functions.


Assuntos
Esclerose Múltipla , Células Precursoras de Oligodendrócitos , Humanos , Células Precursoras de Oligodendrócitos/metabolismo , Citocinas/metabolismo , Diferenciação Celular , Esclerose Múltipla/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Imunidade , Anti-Inflamatórios/farmacologia , Oligodendroglia
9.
Neurochem Res ; 49(3): 670-683, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38015410

RESUMO

White matter dysplasia (WMD) in preterm infants due to intrauterine inflammation is caused by excessive apoptosis of oligodendrocyte precursor cells (OPCs). In recent years, studies have found that excessive autophagy and apoptosis are highly interconnected and important in infection and inflammatory diseases in general. Therefore, in this study, we aimed to confirm whether regulation of autophagy by using the Akt phosphorylation agonist SC79 can inhibit abnormal apoptosis of OPCs and promote myelin maturation and white matter development in neonatal rats with WMD. We investigated the effect of inflammation on oligodendrocyte development in P0 neonatal rats by intracerebellar injection of LPS, and collected brain tissue at P2 and P5. Immunohistochemical and immunofluorescence staining were used to evaluate white matter damage, while immunofluorescence staining, terminal deoxynucleotidyl transferase dUTP nick end labeling analysis (TUNEL), and western blotting were used to evaluate autophagy and apoptosis. First, we observed that white matter development was arrested and white matter fiber maturation was impaired in LPS-inflicted pups compared with those in the sham-operated group. Second, treatment with SC79 reduced the levels of LC3II, caspase 3, caspase 9, and Bax/Bcl-2 and increased the levels of p62, p-Akt, and p-mTOR in the brain tissue of neonatal rats. Finally, SC79 treatment inhibited OPC apoptosis by increasing the binding of Beclin 1 to Bcl-2, which promoted OPC differentiation and maturation. However, the opposite results were observed after rapamycin administration. Taken together, our results suggest that SC79 can inhibit the abnormal apoptosis of OPCs caused by excessive autophagy through the Akt/mTOR pathway and that SC79 is a potential therapeutic agent for WMD in preterm infants.


Assuntos
Células Precursoras de Oligodendrócitos , Substância Branca , Humanos , Recém-Nascido , Ratos , Animais , Substância Branca/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Lipopolissacarídeos/farmacologia , Recém-Nascido Prematuro , Apoptose , Serina-Treonina Quinases TOR/metabolismo , Autofagia , Inflamação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
10.
Artigo em Inglês | MEDLINE | ID: mdl-38052500

RESUMO

Oligodendrocyte precursor cells (OPCs) are a central nervous system resident population of glia with a distinct molecular identity and an ever-increasing list of functions. OPCs generate oligodendrocytes throughout development and across the life span in most regions of the brain and spinal cord. This process involves a complex coordination of molecular checkpoints and biophysical cues from the environment that initiate the differentiation and integration of new oligodendrocytes that synthesize myelin sheaths on axons. Outside of their progenitor role, OPCs have been proposed to play other functions including the modulation of axonal and synaptic development and the participation in bidirectional signaling with neurons and other glia. Here, we review OPC identity and known functions and discuss recent findings implying other roles for these glial cells in brain physiology and pathology.


Assuntos
Células Precursoras de Oligodendrócitos , Bainha de Mielina/fisiologia , Oligodendroglia/fisiologia , Axônios/fisiologia , Neurônios/fisiologia
11.
Acta Biomater ; 174: 297-313, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38096960

RESUMO

The transcription factor Olig2 is highly expressed throughout oligodendroglial development and is needed for the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes and remyelination. Although Olig2 overexpression in OPCs is a possible therapeutic target for enhancing myelin repair in ischemic stroke, achieving Olig2 overexpression in vivo remains a formidable technological challenge. To address this challenge, we employed lipid nanoparticle (LNP)-mediated delivery of Olig2 synthetically modified messenger RNA (mRNA) as a viable method for in vivo Olih2 protein overexpression. Specifically, we developed CD140a-targeted LNPs loaded with Olig2 mRNA (C-Olig2) to achieve targeted Olig2 protein expression within PDGFRα+ OPCs, with the goal of promoting remyelination for ischemic stroke therapy. We show that C-Olig2 promotes the differentiation of PDGFRα+ OPCs derived from mouse neural stem cells into mature oligodendrocytes in vitro, suggesting that mRNA-mediated Olig2 overexpression is a rational approach to promote oligodendrocyte differentiation and remyelination. Furthermore, when C-Olig2 was administered to a murine model of ischemic stroke, it led to improvements in blood‒brain barrier (BBB) integrity, enhanced remyelination, and rescued learning and cognitive deficits. Our comprehensive analysis, which included bulk RNA sequencing (RNA-seq) and single-nucleus RNA-seq (snRNA-seq), revealed upregulated biological processes related to learning and memory in the brains of mice treated with C-Olig2 compared to those receiving empty LNPs (Mock). Collectively, our findings highlight the therapeutic potential of multifunctional nanomedicine targeting mRNA expression for ischemic stroke and suggest that this approach holds promise for addressing various brain diseases. STATEMENT OF SIGNIFICANCE: While Olig2 overexpression in OPCs represents a promising therapeutic avenue for enhancing remyelination in ischemic stroke, in vivo strategies for achieving Olig2 expression pose considerable technological challenges. The delivery of mRNA via lipid nanoparticles is considered aa viable approach for in vivo protein expression. In this study, we engineered CD140a-targeted LNPs loaded with Olig2 mRNA (C-Olig2) with the aim of achieving specific Olig2 overexpression in mouse OPCs. Our findings demonstrate that C-Olig2 promotes the differentiation of OPCs into oligodendrocytes in vitro, providing evidence that mRNA-mediated Olig2 overexpression is a rational strategy to foster remyelination. Furthermore, the intravenous administration of C-Olig2 into a murine model of ischemic stroke not only improved blood-brain barrier integrity but also enhanced remyelination and mitigated learning and cognitive deficits. These results underscore the promising therapeutic potential of multifunctional nanomedicine targeting mRNA expression in the context of ischemic stroke.


Assuntos
AVC Isquêmico , Células Precursoras de Oligodendrócitos , Camundongos , Animais , Fator de Transcrição 2 de Oligodendrócitos , AVC Isquêmico/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Modelos Animais de Doenças , Bainha de Mielina , Diferenciação Celular/genética , Oligodendroglia , Isquemia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
12.
Biol Chem ; 405(1): 31-41, 2024 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-37950644

RESUMO

Growth cones of oligodendrocyte progenitor cells (OPCs) are challenging to investigate with conventional light microscopy due to their small size. Especially substructures such as filopodia, lamellipodia and their underlying cytoskeleton are difficult to resolve with diffraction limited microscopy. Light microscopy techniques, which surpass the diffraction limit such as stimulated emission depletion microscopy, often require expensive setups and specially trained personnel rendering them inaccessible to smaller research groups. Lately, the invention of expansion microscopy (ExM) has enabled super-resolution imaging with any light microscope without the need for additional equipment. Apart from the necessary resolution, investigating OPC growth cones comes with another challenge: Imaging the topography of membranes, especially label- and contact-free, is only possible with very few microscopy techniques one of them being scanning ion conductance microscopy (SICM). We here present a new imaging workflow combining SICM and ExM, which enables the visualization of OPC growth cone nanostructures. We correlated SICM recordings and ExM images of OPC growth cones captured with a conventional widefield microscope. This enabled the visualization of the growth cones' membrane topography as well as their underlying actin and tubulin cytoskeleton.


Assuntos
Microscopia , Células Precursoras de Oligodendrócitos , Microscopia/métodos , Cones de Crescimento , Citoesqueleto , Microtúbulos
13.
Nat Commun ; 14(1): 8122, 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38065932

RESUMO

Oligodendrocyte precursor cells (OPCs) generate oligodendrocytes, contributing to myelination and myelin repair. OPCs contact axons and respond to neuronal activity, but how the information relayed by the neuronal activity translates into OPC Ca2+ signals, which in turn influence their fate, remains unknown. We generated transgenic mice for concomitant monitoring of OPCs Ca2+ signals and cell fate using 2-photon microscopy in the somatosensory cortex of awake-behaving mice. Ca2+ signals in OPCs mainly occur within processes and confine to Ca2+ microdomains. A subpopulation of OPCs enhances Ca2+ transients while mice engaged in exploratory locomotion. We found that OPCs responsive to locomotion preferentially differentiate into oligodendrocytes, and locomotion-non-responsive OPCs divide. Norepinephrine mediates locomotion-evoked Ca2+ increases in OPCs by activating α1 adrenergic receptors, and chemogenetic activation of OPCs or noradrenergic neurons promotes OPC differentiation. Hence, we uncovered that for fate decisions OPCs integrate Ca2+ signals, and norepinephrine is a potent regulator of OPC fate.


Assuntos
Cálcio , Células Precursoras de Oligodendrócitos , Camundongos , Animais , Células Precursoras de Oligodendrócitos/fisiologia , Norepinefrina/farmacologia , Camundongos Transgênicos , Bainha de Mielina/fisiologia , Oligodendroglia/fisiologia , Diferenciação Celular/fisiologia , Córtex Cerebral
14.
Sci Rep ; 13(1): 21959, 2023 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-38081969

RESUMO

Oligodendrocyte progenitor cells (OPC) are the main proliferative cells in the healthy adult brain. They produce new myelinating oligodendrocytes to ensure physiological myelin remodeling and regeneration after various pathological insults. Growing evidence suggests that OPC have other functions. Here, we aimed to develop an experimental model that allows the specific ablation of OPC at the adult stage to unravel possible new functions. We generated a transgenic mouse expressing a floxed human diphtheria toxin receptor under the control of the PDGFRa promoter, crossed with an Olig2Cre mouse to limit the recombination to the oligodendrocyte lineage in the central nervous system. We determined a diphtheria toxin dose to substantially decrease OPC density in the cortex and the corpus callosum without triggering side toxicity after a few daily injections. OPC density was normalized 7 days post-treatment, showing high repopulation capacity from few surviving OPC. We took advantage of this strong but transient depletion to show that OPC loss was associated with behavioral impairment, which was restored by OPC recovery, as well as disruption of the excitation/inhibition balance in the sensorimotor cortex, reinforcing the hypothesis of a neuromodulatory role of OPC in the adult brain.


Assuntos
Células Precursoras de Oligodendrócitos , Camundongos , Animais , Humanos , Bainha de Mielina , Camundongos Transgênicos , Oligodendroglia/patologia , Encéfalo/patologia , Diferenciação Celular/fisiologia
15.
Transl Neurodegener ; 12(1): 52, 2023 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-37964328

RESUMO

Oligodendrocyte progenitor cells (OPCs) play pivotal roles in myelin formation and phagocytosis, communicating with neighboring cells and contributing to the integrity of the blood-brain barrier (BBB). However, under the pathological circumstances of Alzheimer's disease (AD), the brain's microenvironment undergoes detrimental changes that significantly impact OPCs and their functions. Starting with OPC functions, we delve into the transformation of OPCs to myelin-producing oligodendrocytes, the intricate signaling interactions with other cells in the central nervous system (CNS), and the fascinating process of phagocytosis, which influences the function of OPCs and affects CNS homeostasis. Moreover, we discuss the essential role of OPCs in BBB formation and highlight the critical contribution of OPCs in forming CNS-protective barriers. In the context of AD, the deterioration of the local microenvironment in the brain is discussed, mainly focusing on neuroinflammation, oxidative stress, and the accumulation of toxic proteins. The detrimental changes disturb the delicate balance in the brain, impacting the regenerative capacity of OPCs and compromising myelin integrity. Under pathological conditions, OPCs experience significant alterations in migration and proliferation, leading to impaired differentiation and a reduced ability to produce mature oligodendrocytes. Moreover, myelin degeneration and formation become increasingly active in AD, contributing to progressive neurodegeneration. Finally, we summarize the current therapeutic approaches targeting OPCs in AD. Strategies to revitalize OPC senescence, modulate signaling pathways to enhance OPC differentiation, and explore other potential therapeutic avenues are promising in alleviating the impact of AD on OPCs and CNS function. In conclusion, this review highlights the indispensable role of OPCs in CNS function and their involvement in the pathogenesis of AD. The intricate interplay between OPCs and the AD brain microenvironment underscores the complexity of neurodegenerative diseases. Insights from studying OPCs under pathological conditions provide a foundation for innovative therapeutic strategies targeting OPCs and fostering neurodegeneration. Future research will advance our understanding and management of neurodegenerative diseases, ultimately offering hope for effective treatments and improved quality of life for those affected by AD and related disorders.


Assuntos
Doença de Alzheimer , Células Precursoras de Oligodendrócitos , Humanos , Doença de Alzheimer/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Qualidade de Vida , Oligodendroglia/metabolismo , Diferenciação Celular
16.
PLoS One ; 18(11): e0294583, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37983226

RESUMO

In this study, we investigated the role of glutamate delta 1 receptor (GluD1) in oligodendrocyte progenitor cell (OPC)-mediated myelination during basal (development) and pathophysiological (cuprizone-induced demyelination) conditions. Initially, we sought to determine the expression pattern of GluD1 in OPCs and found a significant colocalization of GluD1 puncta with neuron-glial antigen 2 (NG2, OPC marker) in the motor cortex and dorsal striatum. Importantly, we found that the ablation of GluD1 led to an increase in the number of myelin-associated glycoprotein (MAG+) cells in the corpus callosum and motor cortex at P40 without affecting the number of NG2+ OPCs, suggesting that GluD1 loss selectively facilitates OPC differentiation rather than proliferation. Further, deletion of GluD1 enhanced myelination in the corpus callosum and motor cortex, as indicated by increased myelin basic protein (MBP) staining at P40, suggesting that GluD1 may play an essential role in the developmental regulation of myelination during the critical window period. In contrast, in cuprizone-induced demyelination, we observed reduced MBP staining in the corpus callosum of GluD1 KO mice. Furthermore, cuprizone-fed GluD1 KO mice showed more robust motor deficits. Collectively, our results demonstrate that GluD1 plays a critical role in OPC regulation and myelination in normal and demyelinating conditions.


Assuntos
Doenças Desmielinizantes , Células Precursoras de Oligodendrócitos , Camundongos , Animais , Bainha de Mielina/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Cuprizona , Ácido Glutâmico/metabolismo , Camundongos Knockout , Oligodendroglia/metabolismo , Diferenciação Celular/fisiologia , Corpo Caloso/metabolismo , Receptores de Glutamato/metabolismo , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/metabolismo , Camundongos Endogâmicos C57BL
18.
Cell Rep ; 42(10): 113272, 2023 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-37858465

RESUMO

Remyelination after white matter injury (WMI) often fails in diseases such as multiple sclerosis because of improper recruitment and repopulation of oligodendrocyte precursor cells (OPCs) in lesions. How OPCs elicit specific intracellular programs in response to a chemically and mechanically diverse environment to properly regenerate myelin remains unclear. OPCs construct primary cilia, specialized signaling compartments that transduce Hedgehog (Hh) and G-protein-coupled receptor (GPCR) signals. We investigated the role of primary cilia in the OPC response to WMI. Removing cilia from OPCs genetically via deletion of Ift88 results in OPCs failing to repopulate WMI lesions because of reduced proliferation. Interestingly, loss of cilia does not affect Hh signaling in OPCs or their responsiveness to Hh signals but instead leads to dysfunctional cyclic AMP (cAMP)-dependent cAMP response element-binding protein (CREB)-mediated transcription. Because inhibition of CREB activity in OPCs reduces proliferation, we propose that a GPCR/cAMP/CREB signaling axis initiated at OPC cilia orchestrates OPC proliferation during development and in response to WMI.


Assuntos
Células Precursoras de Oligodendrócitos , Substância Branca , Células Precursoras de Oligodendrócitos/metabolismo , Cílios/metabolismo , Substância Branca/metabolismo , Proteínas Hedgehog/metabolismo , Oligodendroglia/metabolismo , Bainha de Mielina/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proliferação de Células , Diferenciação Celular/fisiologia
19.
J Neurochem ; 167(4): 571-581, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37874764

RESUMO

In the central nervous system, microglia are responsible for removing infectious agents, damaged/dead cells, and amyloid plaques by phagocytosis. Other cell types, such as astrocytes, are also recently recognized to show phagocytotic activity under some conditions. Oligodendrocyte precursor cells (OPCs), which belong to the same glial cell family as microglia and astrocytes, may have similar functions. However, it remains largely unknown whether OPCs exhibit phagocytic activity against foreign materials like microglia. To answer this question, we examined the phagocytosis activity of OPCs using primary rat OPC cultures. Since innate phagocytosis activity could trigger cell death pathways, we also investigated whether participating in phagocytosis activity may lead to OPC cell death. Our data shows that cultured OPCs phagocytosed myelin-debris-rich lysates prepared from rat corpus callosum, without progressing to cell death. In contrast to OPCs, mature oligodendrocytes did not show phagocytotic activity against the bait. OPCs also exhibited phagocytosis towards lysates of rat brain cortex and cell membrane debris from cultured astrocytes, but the percentage of OPCs that phagocytosed beta-amyloid was much lower than the myelin debris. We then conducted RNA-seq experiments to examine the transcriptome profile of OPC cultures and found that myelination- and migration-associated genes were downregulated 24 h after phagocytosis. On the other hand, there were a few upregulated genes in OPCs 24 h after phagocytosis. These data confirm that OPCs play a role in debris removal and suggest that OPCs may remain in a quiescent state after phagocytosis.


Assuntos
Células Precursoras de Oligodendrócitos , Ratos , Animais , Células Precursoras de Oligodendrócitos/fisiologia , Diferenciação Celular/fisiologia , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Fagocitose/genética , Células Cultivadas
20.
Neurobiol Dis ; 187: 106315, 2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-37783234

RESUMO

G protein-coupled receptor 17 (GPR17) and the WNT pathway are critical players of oligodendrocyte (OL) differentiation acting as essential timers in developing brain to achieve fully-myelinating cells. However, whether and how these two systems are related to each other is still unknown. Of interest, both factors are dysregulated in developing and adult brain diseases, including white matter injury and cancer, making the understanding of their reciprocal interactions of potential importance for identifying new targets and strategies for myelin repair. Here, by a combined pharmacological and biotechnological approach, we examined regulatory mechanisms linking WNT signaling to GPR17 expression in OLs. We first analyzed the relative expression of mRNAs encoding for GPR17 and the T cell factor/Lymphoid enhancer-binding factor-1 (TCF/LEF) transcription factors of the canonical WNT/ß-CATENIN pathway, in PDGFRα+ and O4+ OLs during mouse post-natal development. In O4+ cells, Gpr17 mRNA level peaked at post-natal day 14 and then decreased concomitantly to the physiological uprise of WNT tone, as shown by increased Lef1 mRNA level. The link between WNT signaling and GPR17 expression was further reinforced in vitro in primary PDGFRα+ cells and in Oli-neu cells. High WNT tone impaired OL differentiation and drastically reduced GPR17 mRNA and protein levels. In Oli-neu cells, WNT/ß-CATENIN activation repressed Gpr17 promoter activity through both putative WNT response elements (WRE) and upregulation of the inhibitor of DNA-binding protein 2 (Id2). We conclude that the WNT pathway influences OL maturation by repressing GPR17, which could have implications in pathologies characterized by dysregulations of the OL lineage including multiple sclerosis and oligodendroglioma.


Assuntos
Células Precursoras de Oligodendrócitos , Via de Sinalização Wnt , Camundongos , Animais , beta Catenina/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas do Tecido Nervoso/genética , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Diferenciação Celular/fisiologia , Oligodendroglia/metabolismo , RNA Mensageiro/metabolismo
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