Biology subjects

Baydyuk, M.

Publications and source records attributed to Baydyuk, M..

4 recordsLinked to original sources

bioRxiv2024

Dissecting the evolving cellular landscape of a remyelinating microenvironment

Demyelination, or the loss of myelin in the central nervous system (CNS) is a hallmark of multiple sclerosis (MS) and occurs in various forms of CNS injury and neurodegenerative diseases. The regeneration of myelin, or remyelination, occurs spontaneously following demyelination. The lysophosphatidylcholine (LPC)-induced focal demyelination model enables investigations into the mechanisms of remyelination, providing insight into the molecular basis underlying an evolving remyelinating microenvironment over a tractable time course. Here, we present a detailed analysis using high-resolution single nucleus RNA sequencing to investigate gene expression dynamics across multiple cell populations involved in the remyelination process. We examine three specific time points following focal demyelinating injury in mice, and by delineating activation states within the heterogeneous cell populations of demyelinated lesions, we highlight changes in gene expression within subclusters of each cell population from the early stages of injury response to the initiation and maintenance of remyelination. Our findings reveal how shifts in microglial, astrocytic and fibroblast activities within lesions are associated with efficient oligodendrocyte differentiation during remyelination.

neuroscience↗

bioRxiv2023

Differential effects of IL4I1 protein on lymphocytes from healthy and multiple sclerosis patients

Multiple sclerosis (MS) is a chronic inflammatory disease characterized by immune mediated demyelination of the central nervous system, resulting in extensive neurological deficit and remyelination impairment. We have previously found that interleukin-four induced one (IL4I1) protein modulates CNS inflammation and enhances remyelination in mouse models of experimental demyelination. However, it remained unclear if IL4I1 regulates lymphocyte activity in MS. To assess the therapeutic potential of IL4I1 in MS, we investigated the impact of IL4I1 treatment on human lymphocytes from peripheral blood mononuclear cells (PBMCs) obtained from healthy individuals and MS patients. We found that IL4I1 increased the relative densities of Th2 and regulatory T-cells, while reducing Th17 cell density in healthy control samples. Furthermore, IL4I1-treated lymphocytes promoted CNS remyelination when grafted into demyelinated spinal cord lesions in mice. We found that baseline endogenous IL4I1 expression was reduced in people with MS. However, unlike healthy controls, IL4I1 treatment had no significant effect on IL17 or TOB1 expression in lymphocytes derived from MS patients. These results suggest that IL4I1 skews CD4+ T-cells to a regulatory state in healthy human lymphocytes, which may be essential for promoting remyelination. However, IL4I1 appears unable to exert its influence on lymphocytes in MS, indicating that impaired IL4I1-mediated activity may underlie MS pathology.

neuroscience↗

bioRxiv2023

PKC modulator bryostatin-1 therapeutically targets CNS innate immunity to attenuate neuroinflammation and promote remyelination

In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining the balance between myelin repair and demyelination/neurodegeneration. Phagocytic and regenerative functions of these CNS innate immune cells support remyelination, whereas chronic and maladaptive inflammatory activation promotes lesion expansion and disability, particularly in the progressive forms of MS. No currently approved drugs convincingly target microglia and macrophages within the CNS, contributing to the critical lack of therapies promoting remyelination and slowing progression in MS. Here, we found that the protein kinase C (PKC)-modulating drug bryostatin-1 (bryo-1), a CNS-penetrant compound with an established human safety profile, produces a shift in microglia and CNS macrophage transcriptional programs from pro-inflammatory to regenerative phenotypes, both in vitro and in vivo. Treatment of microglia with bryo-1 prevented the activation of neurotoxic astrocytes while stimulating scavenger pathways, phagocytosis, and secretion of factors that promote oligodendrocyte differentiation. In line with these findings, systemic treatment with bryo-1 augmented remyelination following a focal demyelinating injury in vivo. Our results demonstrate the potential of bryo-1 and functionally related PKC modulators as myelin regenerative and neuroprotective agents in MS and other neurologic diseases through therapeutic targeting of microglia and CNS-associated macrophages. One Sentence SummaryPKC modulation in CNS innate immune cells favors the activation of a beneficial phenotype that promotes myelin regeneration and neuroprotection.

neuroscience↗

bioRxiv2020

EphA7 Isoforms Differentially Regulate Cortical Dendrite Development

The shape of a neuron reflects its cellular function and ultimately, how it operates in neural circuits. Dendrites receive and integrate incoming signals, including excitatory input onto dendritic spines, so understanding how dendritic development proceeds is fundamental for discerning neural function. Using loss- and gain-of-function paradigms, we previously demonstrated that EphA7 receptor signaling during cortical development impacts dendrites in two ways: restricting growth early and promoting spine formation later. Here, the molecular basis for this shift in EphA7 function is defined. Expression analyses reveal that both full-length (EphA7-FL) and truncated (EphA7-T1; lacking kinase domain) isoforms of EphA7 are expressed in the developing cortex, with peak expression of EphA7-FL overlapping with dendritic elaboration and highest levels of EphA7-T1 coinciding with spine formation. Overexpression studies in cultured neurons demonstrate that EphA7-FL inhibits both dendritic growth and spine formation, while EphA7-T1 increases spine density. Furthermore, signaling downstream of EphA7 varies during development; in vivo inhibition of kinase-dependent mTOR by rapamycin in EphA7 mutant neurons rescues the dendritic branching, but not the dendritic spine phenotypes. Finally, interaction and signaling modulation was examined. In cells in culture, direct interaction between EphA7-FL and EphA7-T1 is demonstrated which results in EphA7- T1-based modulation of EphA7-FL phosphorylation. In vivo, both isoforms are colocalized to cortical synapses and levels of phosphorylated EphA7-FL decrease as EphA7-T1 levels rise. Thus, the phenotypes of EphA7 during cortical dendrite development are explained by divergent functions of two variants of the receptor.

neuroscience↗