Neural cells in the adult human central nervous system (CNS) display extensive transcriptional heterogeneity. How different layers of epigenetic regulation underpin this heterogeneity is poorly understood. Here we profile, at the single-nuclei epigenomic level, distinct regions of the adult human CNS, for chromatin accessibility and simultaneously for the histone modifications H3K27me3 and H3K27ac. We unveil a putative SOX10 enhancer and primed chromatin signatures at HOX loci in spinal-cord-derived human oligodendroglia (OLG) and astrocytes, but not microglia. These signatures in adult OLG were reminiscent of developmental profiles but were decoupled from robust gene expression. Moreover, using high-resolution Micro-C, we show that induced pluripotent stem-cell-derived human OLGs exhibit a HOX chromatin architecture compatible with the primed chromatin in adult OLGs, bearing a strong resemblance not only to OLG developmental architecture but also to high-grade pontine gliomas. Thus, epigenetic memory from developmental states in adult OLG not only enables them to promptly transcribe Hox family genes during regeneration but also makes them susceptible to gliomagenesis. Single-nucleus epigenomic maps of the adult human brain and spinal cord reveal that adult oligodendroglia retain developmental chromatin patterns, suggesting a molecular memory that may shape repair processes and cancer vulnerability.

Cannabis use continues to rise in Canada, prompting concerns due to its potential impact on immune function. This study investigated the effect of a cannabis joint extract (CJE) on natural killer (NK) cells and explored the mechanisms underlying its potential anti-inflammatory properties. Peripheral blood mononuclear cells (PBMCs) were exposed to varying concentrations of CJE to assess cytotoxicity. Flow cytometry was employed to evaluate oxidative stress, autophagy, mitochondrial membrane potential, caspase-3 activation, and DNA damage. Additionally, NK cell cytotoxicity, migration, and adhesion were analyzed. Data indicated that CJE exposure led to dose-dependent cytotoxicity in NK cells, primarily through apoptosis. Specifically, at a concentration of 3 μg/mL, CJE significantly increased reactive oxygen species (ROS), autophagy markers, caspase activation, and DNA damage, while reducing mitochondrial membrane potential. Moreover, CJE impaired NK cell-mediated killing of HeLa cells, though their migratory and adhesive abilities were unaffected. These findings evidence that cannabis can detrimentally affect NK cell viability and function via mechanisms involving autophagy and caspase-dependent apoptosis.

Predicting the efficacy and toxicity of mRNA vaccines remains challenging. We describe an in vitro human model that replicates immune responses to lipid nanoparticle (LNP)-based mRNA vaccines upon intramuscular injection. Vaccines are administered to human skeletal myoblasts and antigen-presenting cells (APCs). Non-amplifying mRNA (NAM) vaccines directly induce antigen expression in APCs, whereas self-amplifying mRNA (SAM) vaccines require muscle cell-APC contact. The transfer of APCs and soluble factors to a microfluidic human lymphoid follicle chip (LF Chip), to mimic lymphatic drainage, induces LF expansion, de novo immunoglobulin G (IgG) production against a naive antigen, and cytokine release, with responses varying by LNP type. Similar vaccination of LF chips with Moderna vaccine against SARS-CoV-2 spike recall antigen generates neutralizing antibodies and induces somatic hypermutation (SHM). These studies offer an all-human alternative for evaluating vaccine-induced immunity, limiting the need for non-human primates and accelerating vaccine development.