The roles of neural stem cells in myelin regeneration and repair therapy after spinal cord injury

Stem Cell Research & Therapy, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 8, 2024

Abstract Spinal cord injury (SCI) is a complex tissue that results in wide range of physical deficits, including permanent or progressive disabilities sensory, motor and autonomic functions. To date, limitations current clinical treatment options can leave SCI patients with lifelong disabilities. There an urgent need to develop new therapies for reconstructing the damaged spinal neuron-glia network restoring connectivity supraspinal pathways. Neural stem cells (NSCs) possess ability self-renew differentiate into neurons neuroglia, oligodendrocytes, which are responsible formation maintenance myelin sheath regeneration demyelinated axons. For these properties, NSCs considered be promising cell source rebuilding neural circuits promoting regeneration. Over past decade, transplantation has been extensively tested variety preclinical models SCI. This review aims highlight pathophysiology promote understanding role repair therapy advances pathological mechanism, pre-clinical studies, as well trials via NSC therapeutic strategy. Understanding mastering frontier updates will pave way establishing novel strategies improve quality recovery from

Language: Английский

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Glial Cells as Key Regulators in Neuroinflammatory Mechanisms Associated with Multiple Sclerosis

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9588 - 9588

Published: Sept. 4, 2024

Even though several highly effective treatments have been developed for multiple sclerosis (MS), the underlying pathological mechanisms and drivers of disease not fully elucidated. In recent years, there has a growing interest in studying neuroinflammation context glial cell involvement as is increasing evidence their central role progression. Although communication proper function underlies brain homeostasis maintenance, effects an MS remain complex controversial. this review, we aim to provide overview contribution cells, oligodendrocytes, astrocytes, microglia pathology during both activation orchestration inflammatory mechanisms, well synergistic repair restoration function. Additionally, discuss how understanding may new therapeutic targets either limit progression or facilitate repair.

Language: Английский

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Myeloid cell-associated aromatic amino acid metabolism facilitates CNS myelin regeneration

npj Regenerative Medicine, Journal Year: 2024, Volume and Issue: 9(1)

Published: Jan. 2, 2024

Abstract Regulation of myeloid cell activity is critical for successful myelin regeneration (remyelination) in demyelinating diseases, such as multiple sclerosis (MS). Here, we show aromatic alpha-keto acids (AKAs) generated from the amino acid oxidase, interleukin-4 induced 1 (IL4I1), promote efficient remyelination mouse models MS. During remyelination, cells upregulated expression IL4I1. Conditionally knocking out IL4I1 impaired efficiency. Mice lacking exhibited a reduction AKAs, phenylpyruvate, indole-3-pyruvate, and 4-hydroxyphenylpyruvate, remyelinating lesions. Decreased AKA levels were also observed people with MS, particularly progressive phase when impaired. Oral administration AKAs modulated cell-associated inflammation, promoted oligodendrocyte maturation, enhanced mice focal demyelinated Transcriptomic analysis revealed treatment shift metabolic pathways aryl hydrocarbon receptor Our results suggest metabolism via produces lesions to enable remyelination. Increasing or targeting related may serve strategy facilitate inflammatory conditions.

Language: Английский

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The missing hallmark of health: psychosocial adaptation

Cell Stress, Journal Year: 2024, Volume and Issue: 8, P. 21 - 50

Published: Jan. 1, 2024

The eight biological hallmarks of health that we initially postulated (Cell. 2021 Jan 7;184(1):33-63) include features spatial compartmentalization (integrity barriers, containment local perturbations), maintenance homeostasis over time (recycling & turnover, integration circuitries, rhythmic oscillations) and an array adequate responses to stress (homeostatic resilience, hormetic regulation, repair regeneration). These affect all somatic strata the human body (molecules, organelles, cells, supracellular units, organs, organ systems, systemic circuitries meta-organism). Here postulate mental socioeconomic factors must be added this 8×8 matrix as additional hallmark (“psychosocial adaptation”) stratum interactions”), hence building a 9×9 matrix. Potentially, perturbation each affects psychosocial vice versa. Finally, discuss (patho)physiological bases these interactions their implications for improvement.

Language: Английский

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The interplay of inflammation and remyelination: rethinking MS treatment with a focus on oligodendrocyte progenitor cells

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: July 12, 2024

Multiple sclerosis (MS) therapeutic goals have traditionally been dichotomized into two distinct avenues: immune-modulatory-centric interventions and pro-regenerative strategies. Oligodendrocyte progenitor cells (OPCs) were regarded for many years solely in concern to their potential generate oligodendrocytes myelin the central nervous system (CNS). However, accumulating data elucidate multifaceted roles of OPCs, including immunomodulatory functions, positioning them as cardinal constituents CNS's immune landscape.

Language: Английский

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Innate immune training restores pro-reparative myeloid functions to promote remyelination in the aged central nervous system

Immunity, Journal Year: 2024, Volume and Issue: 57(9), P. 2173 - 2190.e8

Published: July 24, 2024

The reduced ability of the central nervous system to regenerate with increasing age limits functional recovery following demyelinating injury. Previous work has shown that myelin debris can overwhelm metabolic capacity microglia, thereby impeding tissue regeneration in aging, but underlying mechanisms are unknown. In a model demyelination, we found substantial number genes were not effectively activated aged myeloid cells displayed epigenetic modifications associated restricted chromatin accessibility. Ablation two class I histone deacetylases microglia was sufficient restore mice remyelinate lesioned tissue. We used Bacillus Calmette-Guerin (BCG), live-attenuated vaccine, train innate immune and detected reprogramming brain-resident restoration clearance lesion recovery. Our results provide insight into aging-associated decline function how this decay be prevented by reprogramming.

Language: Английский

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Assessing disease progression and treatment response in progressive multiple sclerosis

Nature Reviews Neurology, Journal Year: 2024, Volume and Issue: 20(10), P. 573 - 586

Published: Sept. 9, 2024

Language: Английский

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Remyelination in the Central Nervous System

Cold Spring Harbor Perspectives in Biology, Journal Year: 2024, Volume and Issue: 16(3), P. a041371 - a041371

Published: Feb. 5, 2024

Robin J.M. Franklin1, Benedetta Bodini2,3 and Steven A. Goldman4,5 1Altos Labs Cambridge Institute of Science, CB21 6GH, United Kingdom 2Sorbonne Université, Paris Brain Institute, CNRS, INSERM, 75013, France 3Saint-Antoine Hospital, APHP, 75012, 4Center for Translational Neuromedicine, University Rochester Medical Center, Rochester, New York 14642, USA 5University Copenhagen Faculty Medicine, 2200, Denmark Correspondence: rfranklin{at}altoslabs.com

Language: Английский

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Mechanisms of Demyelination and Remyelination Strategies for Multiple Sclerosis

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(7), P. 6373 - 6373

Published: March 28, 2023

All currently licensed medications for multiple sclerosis (MS) target the immune system. Albeit promising preclinical results demonstrated disease amelioration and remyelination enhancement via modulating oligodendrocyte lineage cells, most drug candidates showed only modest or no effects in human clinical trials. This might be due to fact that is a sophistically orchestrated process calls interplay between neurons, central nervous system (CNS) resident innate peripheral infiltrates this may somewhat differ humans rodent models used research. To ensure successful remyelination, recruitment activation/repression of each cell type should regulated highly organized spatio-temporal manner. As result, targeting one single pathway population have difficulty restoring optimal microenvironment at lesion sites remyelination. Therefore, when exploring new MS, it instrumental consider not on all CNS populations but also time administration during progression. In review, we describe dysregulated mechanisms relevant disruption their coordination as causes failure, providing an overview complex sites.

Language: Английский

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Mechanosensitive channel of large conductance enhances the mechanical stretching-induced upregulation of glycolysis and oxidative metabolism in Schwann cells

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Feb. 1, 2024

Abstract Background Physical exercise directly stretching the peripheral nerve promotes regeneration; however, its action mechanism remains elusive. Our present study aimed to investigate effects of mechanosensitive channel large conductance (MscL) activated by mechanical on cultured Schwann cells (SCs) and explore possible mechanism. Methods Primary SCs from neonatal mice at 3–5 days age were derived transfected with lentivirus vector expressing a mutant version MscL, MscL-G22S. We first detected cell viability calcium ion (Ca 2+ ) influx in MscL-G22S-expressing low-intensity controls. Proteomic energy metabolomics analyses performed comprehensive MscL-G22S activation SCs. Measurement glycolysis- oxidative phosphorylation-related molecules ATP production respectively further validate Finally, roles phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target rapamycin (mTOR) signaling pathway metabolism modulation was investigated. Results Mechanical stretching-induced significantly increased Ca into Both proteomic targeted analysis indicated upregulation as main MscL-G22S-activation MscL-G22S-activated showed significant glycolysis phosphorylation when alone had only mild than those without stimuli. caused PI3K/AKT/mTOR HIF-1α/c-Myc. Inhibition PI3K abolished activation-induced HIF-1α/c-Myc reduced levels substrates mitochondrial activity. Conclusion activates promote energic substrates, which may be applied enhance regeneration via glia-axonal metabolic coupling.

Language: Английский

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