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THE JOURNAL OF BIOLOGICAL CHEMISTRY: The Biochemical Behavior of LeadL I. Influence of Calcium, Phosphorus, and Vitamin D on Lead in Blood and Bone

The present study characterizes the 3D anatomy of meningeal lymphatic vasculature and associated CSF drainage by postmortem light-sheet imaging in mice and by real-time magnetic resonance imaging in humans, demonstrating conserved lymphatic circuitries in contact with dural venous sinuses.

/pdf/conserved-meningeal-lymphatic-drainage-circuits-in-mice-and-34p2qm7x.pdf

Conserved meningeal lymphatic drainage circuits in mice and humans

Oligodendrocytes are the critical cell types giving rise to the myelin nerve sheath enabling efficient nerve transmission in the central nervous system (CNS). Oligodendrocyte precursor cells differentiate into mature oligodendrocytes and are maintained throughout life. Deficits in the generation, proliferation, or differentiation of these cells or their maintenance have been linked to neurological disorders ranging from developmental disorders to neurodegenerative diseases and limit repair after CNS injury. Understanding the regulation of these processes is critical for achieving proper myelination during development, preventing disease, or recovering from injury. Many of the key factors underlying these processes are epigenetic regulators that enable the fine tuning or reprogramming of gene expression during development and regeneration in response to changes in the local microenvironment. These include chromatin remodelers, histone-modifying enzymes, covalent modifiers of DNA methylation, and RNA modification–mediated mechanisms. In this review, we will discuss the key components in each of these classes which are responsible for generating and maintaining oligodendrocyte myelination as well as potential targeted approaches to stimulate the regenerative program in developmental disorders and neurodegenerative diseases.

Epigenetic regulation of oligodendrocyte myelination in developmental disorders and neurodegenerative diseases

The glioma tumor microenvironment plays a crucial role in the development, occurrence, and treatment of gliomas. Glioma-associated macrophages (GAMs) are the most widely infiltrated immune cells in the tumor microenvironment (TME) and one of the major cell populations that exert immune functions. GAMs typically originate from two cell types-brain-resident microglia (BRM) and bone marrow-derived monocytes (BMDM), depending on a variety of cytokines for recruitment and activation. GAMs mainly contain two functionally and morphologically distinct activation types- classically activated M1 macrophages (antitumor/immunostimulatory) and alternatively activated M2 macrophages (protumor/immunosuppressive). GAMs have been shown to affect multiple biological functions of gliomas, including promoting tumor growth and invasion, angiogenesis, energy metabolism, and treatment resistance. Both M1 and M2 macrophages are highly plastic and can polarize or interconvert under various malignant conditions. As the relationship between GAMs and gliomas has become more apparent, GAMs have long been one of the promising targets for glioma therapy, and many studies have demonstrated the therapeutic potential of this target. Here, we review the origin and activation of GAMs in gliomas, how they regulate tumor development and response to therapies, and current glioma therapeutic strategies targeting GAMs.

Origin, activation, and targeted therapy of glioma-associated macrophages

A simple self-assembly nanomicelle based on brain tumor-targeting peptide-mediated siRNA delivery for glioma immunotherapy via intranasal administration.

SLIT2 is a secreted polypeptide that guides migration of cells expressing ROBO1&2 receptors. Herein, we investigated SLIT2/ROBO signaling effects in gliomas. In patients with glioblastoma (GBM), SLIT2 expression increased with malignant progression and correlated with poor survival and immunosuppression. Knockdown of SLIT2 in mouse glioma cells and patient derived GBM xenografts reduced tumor growth and synergized with immunotherapy to prolong survival. Tumor cell SLIT2 knockdown inhibited macrophage invasion and promoted a cytotoxic gene expression profile, which improved tumor vessel function and enhanced efficacy of chemotherapy and immunotherapy. Mechanistically, SLIT2 promoted microglia/macrophage chemotaxis and tumor-supportive polarization via ROBO1&2-mediated PI3Kγ activation. Macrophage Robo1&2 deletion and systemic SLIT2 trap delivery mimicked SLIT2 knockdown effects on tumor growth and the tumor microenvironment (TME), revealing SLIT2 signaling through macrophage ROBOs as a novel regulator of the GBM microenvironment and a potential immunotherapeutic target for brain tumors.

https://biorxiv.org/content/10.1101/2021.04.12.438457v1.full.pdf

SLIT2-ROBO signaling in tumor-associated microglia/macrophages drives glioblastoma immunosuppression and vascular dysmorphia

DNA methylation is critical for oligodendrocyte development. The role of the converse process, DNA demethylation regulated by Ten-Eleven-Translocation (TET) dioxygenases, in oligodendrocyte homeostasis, myelination and remyelination however remains elusive. Here, we identify a genome-wide and locus-specific DNA hydroxymethylation landscape shift during oligodendrocyte progenitor cell (OPC) differentiation. Tet1 ablation results in defects in oligodendrocyte development and myelination in the developing brain, while impairing remyelination after demyelination in adult brains. Transcriptomic and DNA hydroxymethylation analyses reveal a TET1-regulated epigenetic program for oligodendrocyte differentiation and identify a set of target genes associated with Ca2+ homeostasis. Tet1-deficient OPCs exhibited reduced [Ca2+] oscillations, while activation of calcium channels partially restores the differentiation defect of Tet1-deficient OPCs. Moreover, dysregulated oligodendrocyte homeostasis caused by Tet1-deficiency impairs action potential propagation and synaptic transmission. Thus, our results suggest that stage-specific TET1-mediated epigenetic programming of oligodendrocyte homeostasis is required for proper myelination and repair as well as neuronal physiology in cell-autonomous and non-cell-autonomous mechanisms, respectively.

/pdf/tet1-mediated-oligodendrocyte-homeostasis-regulates-23wsbizujf.pdf

TET1-mediated Oligodendrocyte Homeostasis Regulates Myelination and Synaptic Functions

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SLIT2-ROBO signaling in tumor-associated microglia/macrophages drives glioblastoma immunosuppression and vascular dysmorphia

TET1-mediated Oligodendrocyte Homeostasis Regulates Myelination and Synaptic Functions