Biology subjects

Sontheimer, H.

Publications and source records attributed to Sontheimer, H..

5 recordsLinked to original sources

bioRxiv2021

Astrocyte plasticity ensures continued endfoot coverage of cerebral blood vessels and integrity of the blood brain barrier, with plasticity declining with normal aging.

Astrocytes extend endfeet that enwrap the vasculature. Disruptions to this association in disease coincide with breaches in blood-brain barrier (BBB) integrity, so we asked if the focal ablation of an astrocyte is sufficient to disrupt the BBB. 2Phatal ablation of astrocytes induced a plasticity response whereby surrounding astrocytes extended processes to cover vascular vacancies. This occurred prior to endfoot retraction in young mice yet occurred with significant delay in aged animals. Laser-stimulating replacement astrocytes showed them to induce constrictions in pre-capillary arterioles indicating that replacement astrocytes are functional. Inhibition of EGFR and pSTAT3 significantly reduced astrocyte replacement post-ablation yet without perturbations to BBB integrity. Identical endfoot replacement following astrocyte cell death due to reperfusion post-stroke supports the conclusion that astrocyte plasticity ensures continual vascular coverage so as to retain the BBB. Together, these studies uncover the ability of astrocytes to maintain cerebrovascular coverage via substitution from nearby cells and may represent a novel therapeutic target for vessel recovery post-stroke.

neuroscience↗

bioRxiv2021

Using zebrafish to elucidate glial-vascular interactions during CNS development

An emerging area of interest in Neuroscience is the cellular relationship between glia and blood vessels, as many of the presumptive support roles of glia require an association with the vasculature. These interactions are best studied in vivo and great strides have been made using mice to longitudinally image glial-vascular interactions. However, these methods are cumbersome for developmental studies, which could benefit from a more accessible system. Zebrafish (Danio rerio) are genetically tractable vertebrates, and given their translucency, are readily amenable for daily live imaging studies. We set out to examine whether zebrafish glia have conserved traits with mammalian glia regarding their ability to interact with and maintain the developing brain vasculature. We utilized transgenic zebrafish strains in which oligodendrocyte transcription factor 2 (olig2) and glial fibrillary acidic protein (gfap) identify different glial populations in the zebrafish brain and document their corresponding relationship with brain blood vessels. Our results demonstrate that olig2 and gfap zebrafish glia have distinct lineages and each interact with brain vessels as previously observed in mouse brain. Additionally, we manipulated these relationships through pharmacological and genetic approaches to distinguish the roles of these cell types during blood vessel development. olig2 glia use blood vessels as a pathway during their migration and Wnt signaling inhibition decreases their single-cell vessel co-option. By contrast, the ablation of gfap glia at the beginning of CNS angiogenesis impairs vessel development through a reduction in Vascular endothelial growth factor (Vegf), supporting a role for gfap glia during new brain vessel formation in zebrafish. This data suggests that zebrafish glia, akin to mammalian glia, have different lineages that show diverse interactions with blood vessels, and are a suitable model for elucidating glial-vascular relationships during vertebrate brain development.

developmental biology↗

bioRxiv2020

Spatially expandable fiber-based probes as a multifunctional deep brain interface

Understanding the cytoarchitecture and wiring of the brain requires improved methods to record and stimulate large groups of neurons with cellular specificity. This requires miniaturized neural interfaces that integrate into brain tissue without altering its properties. Existing neural interface technologies have been shown to provide high-resolution electrophysiological recording with high signal-to-noise ratio. However, with single implantation, the physical properties of these devices limit their access to one, small brain region. To overcome this limitation, we developed a platform that provides three-dimensional coverage of brain tissue through multisite multifunctional fiber-based neural probes guided in a helical scaffold. Chronic recordings from the spatially expandable fiber probes demonstrate the ability of these fiber probes capturing brain activities with a single-unit resolution for long observation times. Furthermore, using Thy1-ChR2-YFP mice we demonstrate the application of our probes in simultaneous recording and optical/chemical modulation of brain activities across distant regions. Similarly, varying electrographic brain activities from different brain regions were detected by our customizable probes in a mouse model of epilepsy, suggesting the potential of using these probes for the investigation of brain disorders such as epilepsy. Ultimately, this technique enables three-dimensional manipulation and mapping of brain activities across distant regions in the deep brain with minimal tissue damage, which can bring new insights for deciphering complex brain functions and dynamics in the near future.

bioengineering↗

bioRxiv2020

Fishing for contact: Modeling perivascular glioma invasion in the zebrafish brain.

Glioblastoma multiforme (GBM) is a highly invasive, central nervous system (CNS) cancer for which there is no a cure. Invading tumor cells evade treatment, limiting the efficacy of the current standard of care regimen. Understanding the underlying invasive behaviors that support tumor growth may allow for generation of novel GBM therapies. Zebrafish (Danio rerio) are attractive for genetics and live imaging, and have in recent years, emerged as a model system suitable for cancer biology research. While other groups have studied CNS tumors using zebrafish, few have concentrated on the invasive behaviors supporting the development of these diseases. Previous studies demonstrated that one of the main mechanisms of GBM invasion is perivascular invasion, i.e. single tumor cell migration along blood vessels. Here, we characterize phenotypes, methodology, and potential therapeutic avenues for utilizing zebrafish to model perivascular GBM invasion. Using patient derived xenolines or an adherent cell line, we demonstrate tumor expansion within the zebrafish brain. Within 24 hours post-intracranial injection, D54-MG-tdTomato glioma cells produce finger-like projections along the zebrafish brain vasculature. As few as 25 GBM cells were sufficient to promote single cell vessel co-option. Of note, these tumor-vessel interactions are CNS specific, and do not occur on pre-existing blood vessels when injected into the animals peripheral tissue. Tumor-vessel interactions increase over time and can be pharmacologically disrupted through inhibition of Wnt signaling. Therefore, zebrafish serve as a favorable model system to study perivascular glioma invasion, one of the deadly characteristics that make GBM so difficult to treat.

cancer biology↗

bioRxiv2020

Pericytes Directly Communicate with Emerging Endothelial Cells During Vasculogenesis

SummaryPericytes (PCs), cells that extend along capillaries to contribute stability and other critical functions to established vasculature, are attracting attention from various fields involving vascular-related pathologies. Here, we demonstrate primary evidence of PC communication with endothelial cells (ECs) prior to tube coalescence. Observations of apparent PCs during early embryogenesis urged development of a mouse embryonic stem cell line (DR-ESCs), enabling unique dual-reporter investigations into earliest PC-EC interactions. Live imaging of differentiating DR-ESCs corroborated emergence of a PC lineage, which preceded EC differentiation, and further revealed highly dynamic PC-EC interactions during coordinated vessel formation. We show direct PC-EC communication via cell microinjection and dye-transfer, and RNA-seq analysis indicates a PC-EC coupling mechanism via gap junction Connexin43 (Cx43), exclusively up-regulated throughout DR-ESC differentiation. High resolution imaging of embryonic and postnatal mouse vasculature substantiates Cx43 plaques at PC-EC borders. These findings indicate a new role for PCs during vasculogenesis via Cx43-mediated communication with ECs.Competing Interest StatementThe authors have declared no competing interest.View Full Text

developmental biology↗