TNFR2 signaling in oligodendrocyte precursor cells suppresses their immune-inflammatory function and detrimental microglia activation in CNS demyelinating disease.

Multiple Sclerosis (MS) is a chronic degenerative disease of the central nervous system (CNS) characterized by inflammation, demyelination, and progressive neurodegeneration. These processes, combined with the failure of reparative remyelination initiated by oligodendrocyte precursor cells (OPCs), lead to irreversible neurological impairment. The cytokine tumor necrosis factor (TNF) has been implicated in CNS repair via activation of its cognate receptor TNFR2 in glia. Here, we demonstrate the important role of TNFR2 in regulating OPC function in vivo during demyelinating disease, and that TNFR2 expressed in OPCs modulates OPC-microglia interactions. In PdgfrαCreERT:Tnfrsf1bfl/fl:Eyfp mice with selective TNFR2 ablation in OPCs, we observed an earlier onset and disease peak in experimental autoimmune encephalomyelitis (EAE). This was associated with accelerated immune cell infiltration and increased microglia activation in the spinal cord. Similarly, PdgfrαCreERT:Tnfrsf1bfl/fl:Eyfp mice showed rapid and increased microglia reactivity compared to control mice in the corpus callosum after cuprizone-induced demyelination, followed by chronic reduction in the number of mature myelinating oligodendrocytes (OLs). With EAE and cuprizone models combined, we uncovered that TNFR2 does not have a cell autonomous role in OPC differentiation, but may be important for survival of newly formed mature OLs. Finally, using an in vitro approach, we demonstrated that factors released by Tnfrsf1b ablated OPCs drove microglia to develop an exacerbated "foamy" phenotype when incubated with myelin-rich spinal cord homogenate, aberrantly increasing lysosomal lipid accumulation. Together, our data indicate that TNFR2 signaling in OPCs is protective by dampening their immune-inflammatory activation and by suppressing neurotoxic microglia reactivity. This suggests that boosting TNFR2 activation or its downstream cascades could be an effective strategy to restore OPC reparative capacity in neuroimmune and demyelinating disease.

Single-cell and spatial transcriptome assays reveal heterogeneity in gliomas through stress responses and pathway alterations.

Background: Glioma is a highly heterogeneous malignancy of the central nervous system. This heterogeneity is driven by various molecular processes, including neoplastic transformation, cell cycle dysregulation, and angiogenesis. Among these biomolecular events, inflammation and stress pathways in the development and driving factors of glioma heterogeneity have been reported. However, the mechanisms of glioma heterogeneity under stress response remain unclear, especially from a spatial aspect. Methods: This study employed single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to explore the impact of oxidative stress response genes in oligodendrocyte precursor cells (OPCs). Our analysis identified distinct pathways activated by oxidative stress in two different types of gliomas: high- and low- grade (HG and LG) gliomas. Results: In HG gliomas, oxidative stress induced a metabolic shift from oxidative phosphorylation to glycolysis, promoting cell survival by preventing apoptosis. This metabolic reprogramming was accompanied by epithelial-to-mesenchymal transition (EMT) and an upregulation of stress response genes. Furthermore, SCENIC (Single-Cell rEgulatory Network Inference and Clustering) analysis revealed that oxidative stress activated the AP1 transcription factor in HG gliomas, thereby enhancing tumor cell survival and proliferation. Conclusion: Our findings provide a novel perspective on the mechanisms of oxidative stress responses across various grades of gliomas. This insight enhances our comprehension of the evolutionary processes and heterogeneity within gliomas, potentially guiding future research and therapeutic strategies.

Calibration transfer between NIR instruments using optimally predictive calibration subsets.

In this study, a new approach for the selection of informative standardization samples from the original calibration set for the transfer of a calibration model between NIR instruments is proposed and evaluated. First, a calibration model is developed, after variable selection by the Final Complexity Adapted Models (FCAM) method, using the significance of the PLS regression coefficients (FCAM-SIG) as selection criterion. Then, the resulting model is used for the selection of the best fitting subset of calibration samples with optimally predictive ability, called the optimally predictive calibration subset (OPCS). Next, the standardization samples are selected from the OPCS. The spectra on the slave instruments are transferred to corresponding spectra on the master instrument by the widely used Piecewise Direct Standardization (PDS) method. Thereafter, for the test set on the slave instrument, a 3D response surface plot is drawn for the root mean squared error of prediction (RMSEP) as a function of the number of OPCS samples and window sizes used for the PDS method. Finally, the smallest set of calibration samples, in combination with the optimal window size, providing the optimal RMSEP, is selected as standardization set. The proposed OPCS approach for the selection of standardization samples is tested on two real-life NIR data sets providing 13 X-y combinations to model. The results show that the obtained numbers of OPCS-based standardization samples are statistically significantly lower than those obtained with the widely used representative sample selection method of Kennard and Stone, while the predictive performances are similar.

Preventing production of new oligodendrocytes impairs remyelination and sustains behavioural deficits after demyelination.

Damage to oligodendrocytes (OLs) and myelin sheaths (demyelination) has been shown to be associated with numerous neurological and psychiatric disorders. Remyelination is a rare and reliable regenerative response that occurs in the central nervous system (CNS). It is generally believed that OL progenitor cells (OPCs) are the cell source to generate new OLs to remyelinate the demyelinated axons. However, several recent studies have argued that pre-existing mature OLs that survive within the demyelinated area are responsible for remyelination. Here, by conditional knock-out (KO) of a transcription factor gene that is essential for OPC differentiation, namely myelin regulatory factor (Myrf), to block the production of adult new OLs and examined its effect on remyelination after cuprizone (CPZ)-induced demyelination. We found that OPCs specific Myrf cKO mice show dramatic impairment in remyelination after 4 weeks of recovery from 5 weeks of CPZ diet and they leave over significant behavioral deficits such as anxiety-like behavior, decreased motor skills, and impaired memory compared to control mice that have recovered for the same time. Our data support the idea that OPCs are the major cell sources for myelin regeneration, suggesting that targeting the activation of OPCs and promoting their differentiation to boost new OLs production is critical for therapeutic intervention for demyelinating diseases such as multiple sclerosis (MS).

Fucoidan improving spinal cord injury recovery: Modulating microenvironment and promoting remyelination.

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.

Translating Molecular Approaches to Oligodendrocyte-Mediated Neurological Circuit Modulation.

The central nervous system (CNS) exhibits remarkable adaptability throughout life, enabled by intricate interactions between neurons and glial cells, in particular, oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs). This adaptability is pivotal for learning and memory, with OLs and OPCs playing a crucial role in neural circuit development, synaptic modulation, and myelination dynamics. Myelination by OLs not only supports axonal conduction but also undergoes adaptive modifications in response to neuronal activity, which is vital for cognitive processing and memory functions. This review discusses how these cellular interactions and myelin dynamics are implicated in various neurocircuit diseases and disorders such as epilepsy, gliomas, and psychiatric conditions, focusing on how maladaptive changes contribute to disease pathology and influence clinical outcomes. It also covers the potential for new diagnostics and therapeutic approaches, including pharmacological strategies and emerging biomarkers in oligodendrocyte functions and myelination processes. The evidence supports a fundamental role for myelin plasticity and oligodendrocyte functionality in synchronizing neural activity and high-level cognitive functions, offering promising avenues for targeted interventions in CNS disorders.

Isolating pollen signals from laser diode aerosol Optical Particle Counter (OPC) data through positive matrix factorization (PMF) and Unmix receptor models.

Pollen, a significant natural bioaerosol and allergen for sensitized individuals, is expected to increase in prevalence due to climate change. Mitigating allergy symptoms involves avoiding pollen exposure and pre-medication, emphasizing the importance of real-time knowledge of localized ambient air pollen concentrations. Laser diode Optical Particle Counters (OPCs) are commonly used for monitoring particle number concentrations in ambient air. This study explores the hypothesis that OPCs can monitor pollen but may struggle to distinguish them from other particles. We aimed to isolate the pollen signal from collective particle number concentrations using source apportionment models, specifically Positive Matrix Factorization (PMF) and Unmix, applied to multiple bin OPC data. The pollen signals isolated using PMF show slightly better correlation values than those isolated using Unmix. PMF-derived pollen signals exhibit strong correlations with Holoptelea (r = 0.64) and total pollen (r = 0.54) concentrations, while a moderate correlation is observed with Poaceae (r = 0.47). Exclusion of low pollen events strengthens correlations for Holoptelea and Poaceae to very strong (r = 0.87) and strong (r = 0.67), respectively. Although both model types effectively isolate the pollen signal, metrics suggest that Unmix has the potential for more accurate predictions of both moderate and extreme pollen events simultaneously. The Mean Absolute Error (MAE), Root Mean Square Error (RMSE), and Relative Root Mean Square Error (RRMSE) metrics for Holoptelea are 46.2 grains m-3, 72.4 grains m-3, and 15.3; for Poaceae, 3.9 grains m-3, 4.9 grains m-3, and 13.0; and for total pollen, 43.5 grains m-3, 72.1 grains m-3, and 14.1. This study represents a significant development in the use of source apportionment models and ambient OPCs for real-time pollen monitoring, offering a cost-effective alternative to conventional automated pollen sensors. Despite challenges, the proposed methodology provides a practical and accessible solution for pollen monitoring, contributing to the advancement of bioaerosol monitoring technologies.

The Genomic Intersection of Oligodendrocyte Dynamics in Schizophrenia and Aging Unravels Novel Pathological Mechanisms and Therapeutic Potentials.

Schizophrenia is a significant worldwide health concern, affecting over 20 million individuals and contributing to a potential reduction in life expectancy by up to 14.5 years. Despite its profound impact, the precise pathological mechanisms underlying schizophrenia continue to remain enigmatic, with previous research yielding diverse and occasionally conflicting findings. Nonetheless, one consistently observed phenomenon in brain imaging studies of schizophrenia patients is the disruption of white matter, the bundles of myelinated axons that provide connectivity and rapid signalling between brain regions. Myelin is produced by specialised glial cells known as oligodendrocytes, which have been shown to be disrupted in post-mortem analyses of schizophrenia patients. Oligodendrocytes are generated throughout life by a major population of oligodendrocyte progenitor cells (OPC), which are essential for white matter health and plasticity. Notably, a decline in a specific subpopulation of OPC has been identified as a principal factor in oligodendrocyte disruption and white matter loss in the aging brain, suggesting this may also be a factor in schizophrenia. In this review, we analysed genomic databases to pinpoint intersections between aging and schizophrenia and identify shared mechanisms of white matter disruption and cognitive dysfunction.

Functional myelin in cognition and neurodevelopmental disorders.

In vertebrates, oligodendrocytes (OLs) are glial cells of the central nervous system (CNS) responsible for the formation of the myelin sheath that surrounds the axons of neurons. The myelin sheath plays a crucial role in the transmission of neuronal information by promoting the rapid saltatory conduction of action potentials and providing neurons with structural and metabolic support. Saltatory conduction, first described in the peripheral nervous system (PNS), is now generally recognized as a universal evolutionary innovation to respond quickly to the environment: myelin helps us think and act fast. Nevertheless, the role of myelin in the central nervous system, especially in the brain, may not be primarily focused on accelerating conduction speed but rather on ensuring precision. Its principal function could be to coordinate various neuronal networks, promoting their synchronization through oscillations (or rhythms) relevant for specific information processing tasks. Interestingly, myelin has been directly involved in different types of cognitive processes relying on brain oscillations, and myelin plasticity is currently considered to be part of the fundamental mechanisms for memory formation and maintenance. However, despite ample evidence showing the involvement of myelin in cognition and neurodevelopmental disorders characterized by cognitive impairments, the link between myelin, brain oscillations, cognition and disease is not yet fully understood. In this review, we aim to highlight what is known and what remains to be explored to understand the role of myelin in high order brain processes.

Oligodendrocyte progenitor cells' fate after neonatal asphyxia-Puzzling implications for the development of hypoxic-ischemic encephalopathy.

Premature birth or complications during labor can cause temporary disruption of cerebral blood flow, often followed by long-term disturbances in brain development called hypoxic-ischemic (HI) encephalopathy. Diffuse damage to the white matter is the most frequently detected pathology in this condition. We hypothesized that oligodendrocyte progenitor cell (OPC) differentiation disturbed by mild neonatal asphyxia may affect the viability, maturation, and physiological functioning of oligodendrocytes. To address this issue, we studied the effect of temporal HI in the in vivo model in P7 rats with magnetic resonance imaging (MRI), microscopy techniques and biochemical analyses. Moreover, we recreated the injury in vitro performing the procedure of oxygen-glucose deprivation on rat neonatal OPCs to determine its effect on cell viability, proliferation, and differentiation. In the in vivo model, MRI evaluation revealed changes in the volume of different brain regions, as well as changes in the directional diffusivity of water in brain tissue that may suggest pathological changes to myelinated neuronal fibers. Hypomyelination was observed in the cortex, striatum, and CA3 region of the hippocampus. Severe changes to myelin ultrastructure were observed, including delamination of myelin sheets. Interestingly, shortly after the injury, an increase in oligodendrocyte proliferation was observed, followed by an overproduction of myelin proteins 4 weeks after HI. Results verified with the in vitro model indicate, that in the first days after damage, OPCs do not show reduced viability, intensively proliferate, and overexpress myelin proteins and oligodendrocyte-specific transcription factors. In conclusion, despite the increase in oligodendrocyte proliferation and myelin protein expression after HI, the production of functional myelin sheaths in brain tissue is impaired. Presented study provides a detailed description of oligodendrocyte pathophysiology developed in an effect of HI injury, resulting in an altered CNS myelination. The described models may serve as useful tools for searching and testing effective of effective myelination-supporting therapies for HI injuries.

Microglia-derived exosomes modulate myelin regeneration via miR-615-5p/MYRF axis.

Demyelination and failure of remyelination in the central nervous system (CNS) characterize a number of neurological disorders. Spontaneous remyelination in demyelinating diseases is limited, as oligodendrocyte precursor cells (OPCs), which are often present in demyelinated lesions in abundance, mostly fail to differentiate into oligodendrocytes, the myelinating cells in the CNS. In addition to OPCs, the lesions are assembled numbers of activated resident microglia/infiltrated macrophages; however, the mechanisms and potential role of interactions between the microglia/macrophages and OPCs are poorly understood. Here, we generated a transcriptional profile of exosomes from activated microglia, and found that miR-615-5p was elevated. miR-615-5p bound to 3'UTR of myelin regulator factor (MYRF), a crucial myelination transcription factor expressed in oligodendrocyte lineage cells. Mechanistically, exosomes from activated microglia transferred miR-615-5p to OPCs, which directly bound to MYRF and inhibited OPC maturation. Furthermore, an effect of AAV expressing miR-615-5p sponge in microglia was tested in experimental autoimmune encephalomyelitis (EAE) and cuprizone (CPZ)-induced demyelination model, the classical mouse models of multiple sclerosis. miR-615-5p sponge effectively alleviated disease progression and promoted remyelination. This study identifies miR-615-5p/MYRF as a new target for the therapy of demyelinating diseases.

EAAT3 impedes oligodendrocyte remyelination in chronic cerebral hypoperfusion-induced white matter injury.

BACKGROUND: Chronic cerebral hypoperfusion-induced demyelination causes progressive white matter injury, although the pathogenic pathways are unknown. METHODS: The Single Cell Portal and PanglaoDB databases were used to analyze single-cell RNA sequencing experiments to determine the pattern of EAAT3 expression in CNS cells. Immunofluorescence (IF) was used to detect EAAT3 expression in oligodendrocytes and oligodendrocyte progenitor cells (OPCs). EAAT3 levels in mouse brains were measured using a western blot at various phases of development, as well as in traumatic brain injury (TBI) and intracerebral hemorrhage (ICH) mouse models. The mouse bilateral carotid artery stenosis (BCAS) model was used to create white matter injury. IF, Luxol Fast Blue staining, and electron microscopy were used to investigate the effect of remyelination. 5-Ethynyl-2-Deoxy Uridine staining, transwell chamber assays, and IF were used to examine the effects of OPCs' proliferation, migration, and differentiation in vivo and in vitro. The novel object recognition test, the Y-maze test, the rotarod test, and the grid walking test were used to examine the impact of behavioral modifications. RESULTS: A considerable amount of EAAT3 was expressed in OPCs and mature oligodendrocytes, according to single-cell RNA sequencing data. During multiple critical phases of mouse brain development, there were no substantial changes in EAAT3 levels in the hippocampus, cerebral cortex, or white matter. Furthermore, neither the TBI nor ICH models significantly affected the levels of EAAT3 in the aforementioned brain areas. The chronic white matter injury caused by BCAS, on the other hand, resulted in a strikingly high level of EAAT3 expression in the oligodendroglia and white matter. Correspondingly, blocking EAAT3 assisted in the recovery of cognitive and motor impairment as well as the restoration of cerebral blood flow following BCAS. Furthermore, EAAT3 suppression was connected to improved OPCs' survival and proliferation in vivo as well as faster OPCs' proliferation, migration, and differentiation in vitro. Furthermore, this study revealed that the mTOR pathway is implicated in EAAT3-mediated remyelination. CONCLUSIONS: Our findings provide the first evidence that abnormally high levels of oligodendroglial EAAT3 in chronic cerebral hypoperfusion impair OPCs' pro-remyelination actions, hence impeding white matter repair and functional recovery. EAAT3 inhibitors could be useful in the treatment of ischemia demyelination.

Oligodendrocyte progenitor cell-specific delivery of lipid nanoparticles loaded with Olig2 synthetically modified messenger RNA for ischemic stroke therapy.

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.

Contribution of Oligodendrocytes, Microglia, and Astrocytes to Myelin Debris Uptake in an Explant Model of Inflammatory Demyelination in Rats.

The internalization and degradation of myelin in glia contributes to the resolution of neuroinflammation and influences disease progression. The identification of a three-dimensional experimental model to study myelin processing under neuroinflammation will offer a novel approach for studying treatment strategies favoring inflammation resolution and neuroprotection. Here, by using a model of neuroinflammation in hippocampal explants, we show that myelin debris accumulated immediately after insult and declined at 3 days, a time point at which tentative repair processes were observed. Olig2+ oligodendrocytes upregulated the LRP1 receptor and progressively increased MBP immunoreactivity both at peri-membrane sites and within the cytosol. Oligodendrocyte NG2+ precursors increased in number and immunoreactivity one day after insult, and moderately internalized MBP particles. Three days after insult MBP was intensely coexpressed by microglia and, to a much lesser extent, by astrocytes. The engulfment of both MBP+ debris and whole MBP+ cells contributed to the greatest microglia response. In addition to improving our understanding of the spatial-temporal contribution of glial scarring to myelin uptake under neuroinflammation, our findings suggest that the exposure of hippocampal explants to LPS + IFN-γ-induced neuroinflammation may represent a valuable demyelination model for studying both the extrinsic and intrinsic myelin processing by glia under neuroinflammation.

Evaluation of BCAS1-positive immature oligodendrocytes after cerebral ischemic stroke and SVD.

Ischemic cerebrovascular disease is an important cause of physical disability and dementia. Oligodendrocytes (OLGs), which differentiate from oligodendrocyte precursor cells (OPCs), are crucial for remyelination of the damaged brain and functional recovery. Breast carcinoma amplified sequence 1 (BCAS1) has recently been shown to be highly expressed in newly formed pre-myelinating oligodendrocytes (pre-mOLGs), while its expression level is reduced in mature OLGs. In this study, we analyzed BCAS1 expression by immunohistochemical analysis of human post-mortem brain tissue from six stroke patients (death within 2 months after stroke onset) and eight small vessel disease (SVD) patients. Control post-mortem brain tissue was from eight age-matched patients without any obvious central nervous system (CNS) pathology. The Olig2 expression in the area corresponding to the same section of the BCAS1-stained slice was analyzed to determine the total oligodendrocyte lineage. The percentage of differentiating OPCs in the oligodendrocyte lineage was calculated as the ratio of BCAS1+ to Olig2+ cells (BCAS1+/Olig2+). The stroke and SVD cases showed demyelination with decreased expression of myelin basic protein (MBP, a mature OLG marker). The stroke cases showed significantly increased numbers of early-stage BCAS1+ cells with an immature morphology and Olig2+ cells (pan-oligodendrocyte lineages) in the peri-infarct areas in both the cortex and white matter, but showed no increase in the number of late-stage BCAS1+ cells with a mature morphology. In contrast, the SVD cases showed no significant increase in Olig2+ and BCAS1+ cells. These results indicated that remyelination dysfunction could be attributed to insufficient maturation of OPCs in stroke and impaired recruitment of OPCs in SVD.

Generation of Oligodendrocytes from Human Pluripotent and Embryonic Stem Cells.

Oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes (OLs) can be generated using human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs). By manipulating culture conditions, pluripotent cell types are serially guided through intermediary cell types, developing first into neural progenitor cells (NPCs) then OPCs before maturing as CNS-specific OLs. This procedure is conducted under adherent, feeder-free conditions to derive mature OLs in as few as 28 days.

Brain matters: unveiling the distinct contributions of region, age, and sex to glia diversity and CNS function.

The myelinated white matter tracts of the central nervous system (CNS) are essential for fast transmission of electrical impulses and are often differentially affected in human neurodegenerative diseases across CNS region, age and sex. We hypothesize that this selective vulnerability is underpinned by physiological variation in white matter glia. Using single nucleus RNA sequencing of human post-mortem white matter samples from the brain, cerebellum and spinal cord and subsequent tissue-based validation we found substantial glial heterogeneity with tissue region: we identified region-specific oligodendrocyte precursor cells (OPCs) that retain developmental origin markers into adulthood, distinguishing them from mouse OPCs. Region-specific OPCs give rise to similar oligodendrocyte populations, however spinal cord oligodendrocytes exhibit markers such as SKAP2 which are associated with increased myelin production and we found a spinal cord selective population particularly equipped for producing long and thick myelin sheaths based on the expression of genes/proteins such as HCN2. Spinal cord microglia exhibit a more activated phenotype compared to brain microglia, suggesting that the spinal cord is a more pro-inflammatory environment, a difference that intensifies with age. Astrocyte gene expression correlates strongly with CNS region, however, astrocytes do not show a more activated state with region or age. Across all glia, sex differences are subtle but the consistent increased expression of protein-folding genes in male donors hints at pathways that may contribute to sex differences in disease susceptibility. These findings are essential to consider for understanding selective CNS pathologies and developing tailored therapeutic strategies.

Targeting Pericytes for Functional Recovery in Ischemic Stroke.

Pericytes surrounding endothelial cells in the capillaries are emerging as an attractive cell resource, which can show a large variety of functions in ischemic stroke, including preservation of the blood-brain barrier, regulation of immune function, and support for cerebral vasculature. These functions have been fully elucidated in previous studies. However, in recent years, increasing evidence has shown that pericytes play an important role in neurological recovery after ischemic stroke due to their regenerative function which can be summarized in two aspects according to current discoveries, one is that pericytes are thought to be multipotential themselves, and the other is that pericytes can promote the differentiation of oligodendrocyte progenitor cells (OPCs). Considering the neuroprotective treatment for stroke has not been much progressed in recent years, new therapies targeting pericytes may be a future direction. Here, we will review the beneficial effects of pericytes in ischemic stroke from two directions: the barrier and vascular functions and the regenerative functions of pericytes.

Correlation Between Toxic Elements and Pesticide Residues in Medicinal Herbs Available in Pharmaceutical Market.

The use of medicinal plants for self-medication of minor health conditions has become a widespread practice in contemporary society. Few consumes, however, question the contamination of these products with toxic factors resulting from the planet's increasingly polluted environment. This paper presents the levels of five toxic elements (As, Cr, Pb, Cd, and Hg) and nine organochlorine pesticides (hexachlorobenzene (HCB), lindane, heptachor, aldrin, dieldrin, endrin, p,p'DDE, p,p'DDD, and p,p'DDT) in 14 brands of regularly consumed medicinal products in Romania. The toxic elements content was determined using energy-dispersive X-ray fluorescence (EDXRF) technique, and organochlorine pesticide residues (OPCs) were quantified using gas-chromatographic method, equipped with electron capture detector (GC-ECD). The results show that in the case of Cr, Cd, and Hg, the concentrations exceeded the limit values established by World Health Organisation (WHO) for raw herbal material. The higher level of OPCs (such as p,p'DDD, p,p'DDT, aldrin, and dieldrin) was found in the samples of Hypericum perforatum-St. John's wort, Crataegus monogyna-hawthorn, and Epilobium parviflorum-hoary willowherb. The correlations between the content of toxic elements and pesticides were determined by statistical analysis. Hierarchical clustering technique was used to detect natural grouping between the toxic elements and pesticides. For herb samples, four clusters were identified, the strongest correlated cluster consisting of Pb, HCB, Cr, and Hg. A further analysis within this cluster suggested that Cr levels are statistically different from the rest of the elements.