Biology subjects

Skarica, M.

Publications and source records attributed to Skarica, M..

3 recordsLinked to original sources

bioRxiv2023

VEGF-C promotes brain-derived fluid drainage, confers neuroprotection, and improves stroke outcomes

Meningeal lymphatic vessels promote tissue clearance and immune surveillance in the central nervous system (CNS). Vascular endothelium growth factor-C (VEGF-C) is essential for meningeal lymphatic development and maintenance and has therapeutic potential for treating neurological disorders, including ischemic stroke. We have investigated the effects of VEGF-C overexpression on brain fluid drainage, single cell transcriptome in the brain, and stroke outcomes in adult mice. Intra-cerebrospinal fluid administration of an adeno-associated virus expressing VEGF-C (AAV-VEGF-C) increases the CNS lymphatic network. Post-contrast T1 mapping of the head and neck showed that deep cervical lymph node size and drainage of CNS-derived fluids were increased. Single nuclei RNA sequencing revealed a neuro-supportive role of VEGF-C via upregulation of calcium and brain-derived neurotrophic factor (BDNF) signaling pathways in brain cells. In a mouse model of ischemic stroke, AAV-VEGF-C pretreatment reduced stroke injury and ameliorated motor performances in the subacute stage. AAV-VEGF-C thus promotes CNS-derived fluid and solute drainage, confers neuroprotection, and reduces ischemic stroke damage. Short abstractIntrathecal delivery of VEGF-C increases the lymphatic drainage of brain-derived fluids confers neuroprotection, and improves neurological outcomes after ischemic stroke.

neuroscience↗

bioRxiv2020

Primate-specific response of astrocytes to stroke limits peripheral macrophage infiltration

Reactive astrocytes play critical roles after brain injuries but their precise function in stroke is not well defined. Here, we utilized single nuclei transcriptomics to characterize astrocytes after ischemic stroke in nonhuman primate (NHP) marmoset monkey primary visual cortex. We identified 19 putative subtypes of astrocytes from injured and uninjured brain hemispheres and observed nearly complete segregation between stroke and control astrocyte clusters. We then screened for genes that might be limiting stroke recovery and discovered that one neurite-outgrowth inhibitory protein, NogoA, previously associated with oligodendrocytes but not astrocytes, was expressed in numerous reactive astrocyte subtypes. NogoA upregulation on reactive astrocytes was confirmed in vivo for NHP and human, but not observed to the same extent in rodent. Further in vivo and in vitro studies determined that NogoA mediated an anti-inflammatory response which limits deeper infiltration of peripheral macrophages from the lesion during the subacute post-stroke period. Specifically, these findings are relevant to the development of NogoA-targeting therapies shortly after ischemic stroke. Our findings have uncovered the complexity and species specificity of astrocyte responses, which need to be considered more when investigating novel therapeutics for brain injury.

neuroscience↗

bioRxiv2020

Molecular Diversity Among Adult Hippocampal and Entorhinal Cells

The hippocampal-entorhinal system is comprised of functionally distinct subregions collectively critical for cognition, and selectively vulnerable to aging and pathological processes. To gain insights into neuronal and non-neuronal populations within this system, we performed single-nucleus transcriptional profiling from five human hippocampal-entorhinal subregions. We found that transcriptomic diversity of excitatory neurons across these subregions reflected the molecular transition from three-layered archicortex to six-layered neocortex. Additionally, mRNA and protein for DCX, an immature neuron marker, were clearly detected in some cells, but not in dentate granule cells, the cell-type predicted to be generated in adult neurogenesis. We also found that previously functionally uncharacterized METTL7B was enriched in human and non-human primate neuronal subtypes less vulnerable to initial Alzheimers disease pathology. Proteomic and biochemical assays revealed METTL7B interacts with Alzheimers disease-related proteins, including APP, and its overexpression reduced amyloid-beta generation. These results reveal cell type-specific molecular properties relevant for hippocampal-entorhinal physiology and dysfunction.

neuroscience↗