Biology subjects

Groh, A. M.

Publications and source records attributed to Groh, A. M..

3 recordsLinked to original sources

bioRxiv2025

An MRI-informed histo-molecular analysis implicates ependymal cells in the pathogenesis of periventricular pathology in multiple sclerosis

It is now widely recognized that the cerebrospinal fluid (CSF)-adjacent brain surfaces - namely the subpial cortical region and the ependyma-adjacent periventricular region - are uniquely susceptible to a distinct, diffuse form of pathology in multiple sclerosis. So-called surface-in gradients of pathology predict future disease relapses independent of classical white matter lesions and are thought to occur as a result of cytotoxic factors in the CSF. Given the underlying mechanisms driving surface-in gradients appear to be distinct, they represent a novel treatment target. However, exactly how cytotoxic factor entry into the brain is regulated at these CSF-facing borders is not understood, particularly at the ventricular interface. Indeed, although studies have indicated that ependymal cells may be damaged in MS, there has yet to be a comprehensive assessment of cell health in the disease. We employed ultra-high-field MRI-guided immunohistochemistry, electron microscopy, and multiomic single nucleus RNA/ATAC sequencing to deeply phenotype human ependymal cells in MS. Our data revealed that ependymal cell pathology is a direct correlate of periventricular surface-in gradients of pathology in MS, and that the immune-responsive, reactive state assumed by ependymal cells is associated with widespread transporter and junctional protein gene dysregulation. We then further defined the gene regulatory networks underpinning the MS ependymal state, predicted ligands known to be enriched in MS CSF that could drive the emergence of this state, and tested one candidate in vivo. We found that IFN{gamma} increased murine ependymal permeability and that conditional knockout of ependymal interferon gamma receptor 1 (Ifngr1) was sufficient to reverse this effect. Our data directly implicate ependymal cell dysregulation in the emergence of periventricular pathology in MS. More widely, we denote the modulatory capacity of CSF ligands on ependymal cell function and how this may influence the inflammatory status of the periventricular region. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/633055v2_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@d76aadorg.highwire.dtl.DTLVardef@9cb480org.highwire.dtl.DTLVardef@e4805org.highwire.dtl.DTLVardef@19a50b4_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

A subset of human choroid plexus epithelial cells exhibit mitochondrial eccentricity and distinct expression of the pigmentation-associated enzyme TYRP1

For decades, ultrastructural evaluation of epithelial cells in diverse organ systems has demonstrated the existence of two subtypes identified by stark differences in cytoplasmic electron density - so-called light and dark epithelial cells. Choroid plexus (CP) epithelial cells are key regulators of CSF homeostasis and are one of many specialized epithelial linings that exhibit this bimodal phenotype. Despite longstanding acknowledgement, it has been difficult to assess the potential significance of adult human light and dark CP epithelial cells due to a lack of characterization beyond electron microscopy (EM). We present the first transcriptomic analysis of adult human CP epithelial cells and denote the existence of four epithelial subpopulations, one of which is defined by elevated expression of TYRP1 - a melanocyte-associated tyrosine-related protein involved in cellular pigmentation and proliferation. TYRP1-high cells also downregulate genes related to cilia function (which is consistent with observations of dark cell identity in organoids) and upregulate genes associated with pathways related to cell cycling, stress, and iron regulation. Our data provide an explanation of the molecular underpinning of adult human light and dark cell identity and serve as a resource for investigations of epithelial heterogeneity in the CP and other organs where dark cells are found.

neuroscience↗

bioRxiv2024

An integrative layer-resolved atlas of the adult human meninges

The human meninges are a dynamic tri-layered brain border that plays a key role in brain development, CSF homeostasis, immune regulation, and higher-level brain function. The meninges have also been implicated in central nervous system (CNS) pathologies such as infection, autoimmunity, and brain trauma. To understand how the meningeal microenvironment is altered under pathological conditions it is necessary to have a complete understanding of its normotypic cellular architecture and function. To date, there is no complete atlas of the normotypic adult human meninges. By surgically extracting each human meningeal layer during surgery, we generated the first layer-resolved map of all meningeal cell types via an integration of whole cell single cell RNA sequencing, multiplexed error-robust fluorescence in situ hybridization (MERFISH), and protein immunolabelling. Since fibroblasts play key roles in meningeal homeostasis yet remain less well-characterised than other meningeal cell types, we deeply phenotyped these cells in all layers. We identified 10 fibroblast subpopulations with unique predicted functions that localise to distinct neuroanatomical niches. Fibroblast interaction analysis in the dura and subarachnoid space (SAS) uncovered novel interactions with vascular cell populations mediated by insulin growth factor signaling. Together, these data serve as a comprehensive resource for future investigations of meningeal function in the healthy and diseased brain.

neuroscience↗