Biology subjects

Hametner, S.

Publications and source records attributed to Hametner, S..

4 recordsLinked to original sources

bioRxiv2024

Aberrant iron deposition in the multiple sclerosis spinal cord relates to neurodegeneration

BackgroundIron accumulates in microglia-macrophages at the edge of multiple sclerosis (MS) lesions in the brain. Iron-rimmed brain lesions strongly predict disability accumulation, supporting iron metabolism is crucial in MS pathology. Little is known about iron distribution in the spinal cord. MethodsAutopsy cervical, thoracic and lumbar spinal cord samples from 9 controls and 46 MS donors of whom a subset (n=36) had mesiofrontal motor cortical tissue available for study, were labelled and systematically assessed for iron (DAB-enhanced Turnbull), myelin (PLP), axons (Palmgren silver), microglia-macrophages (TMEM119, Iba1, CD68), astroglia (GFAP), oligodendroglia (OLIG2), acute axonal injury (B-APP, SMI-32, NPY-1R) and oxidative stress (E06). MS lesional and non-lesional areas were considered. Total non-haem iron was quantified by inductively coupled plasma optical emission spectroscopy (ICP-OES). ResultsIn controls, iron predominantly localised to oligodendrocytes with total non-haem iron relating to total myelin fraction, which markedly differed in MS where iron accumulated in microglia-macrophages, subpial astrocytes, and axons in non-lesional areas. Iron laden microglia-macrophages were over-represented relative to total microglial-macrophages and displayed dysmorphic features. Iron-positive axons showed a disto-proximal gradient (highest at lumbar level) with a predilection for the corticospinal tracts. The extent of iron axon positivity related to smaller spinal cord area, lower total axonal counts, and greater oxidative stress. Iron positivity in each cellular compartment (i.e. subpial astrocytes, microglia-macrophage and axons) related to one-another and total non-haem iron correlated with axonal counts in MS. No iron-rimmed lesions were detected in the spinal cord unlike in cortical grey and subcortical white matter of the same cases where 22% and 80% of iron-rimmed lesions, respectively, were seen. ConclusionsDespite the conspicuous absence of iron-rimmed lesions in the MS spinal cord, we demonstrate widespread aberrant iron distribution in the MS spinal cord that relates to oxidative stress and neurodegeneration independent of demyelination. The distal cord predominant and corticospinal tract specific accumulation of iron in axons mirrors the pattern of length-dependent motoric disability commonly encountered in progressive MS. These findings implicate aberrant iron accumulation as a novel, clinically relevant, feature of MS spinal cord pathology.

neuroscience↗

bioRxiv2023

Single nucleus RNA sequencing reveals glial cell type-specific responses to ischemic stroke

Reactive neuroglia critically shape the brains response to ischemic stroke. However, their phenotypic heterogeneity impedes a holistic understanding of the cellular composition and microenvironment of the early ischemic lesion. Here we generated a single cell resolution transcriptomics dataset of the injured brain during the acute recovery from permanent middle cerebral artery occlusion. This approach unveiled infarction and subtype specific molecular signatures in oligodendrocyte lineage cells and astrocytes, which ranged among the most transcriptionally perturbed cell types in our dataset. Specifically, we characterized and compared infarction restricted proliferating oligodendrocyte precursor cells (OPCs), mature oligodendrocytes and heterogeneous reactive astrocyte populations. Our analyses unveiled unexpected commonalities in the transcriptional response of oligodendrocyte lineage cells and astrocytes to ischemic injury. Moreover, OPCs and reactive astrocytes were involved in a shared immuno-glial cross talk with stroke specific myeloid cells. In situ, osteopontin positive myeloid cells accumulated in close proximity to proliferating OPCs and reactive astrocytes, which expressed the osteopontin receptor CD44, within the perilesional zone specifically. In vitro, osteopontin increased the migratory capacity of OPCs. Collectively, our study highlights molecular cross talk events which might govern the cellular composition and microenvironment of infarcted brain tissue in the early stages of recovery.

neuroscience↗

bioRxiv2022

Spatial cell type mapping of multiple sclerosis lesions

Multiple sclerosis (MS) is a prototypic chronic-inflammatory disease of the central nervous system. After initial lesion formation during active demyelination, inflammation is gradually compartmentalized and restricted to specific tissue areas such as the lesion rim in chronic-active lesions. However, the cell type-specific and spatially restricted drivers of chronic tissue damage and lesion expansion are not well understood. Here, we investigated the properties of subcortical white matter lesions by creating a cell type-specific spatial map of gene expression across various inflammatory lesion stages in MS. An integrated analysis of single-nucleus and spatial transcriptomics data enabled us to uncover patterns of glial, immune and stromal cell subtype diversity, as well as to identify cell-cell communication and signaling signatures across lesion and non-lesion tissue areas in MS. Our results provide insights into the conversion of the tissue microenvironment from a homeostatic to a pathogenic or dysfunctional state underlying lesion progression in MS. We expect that this study will help identify spatially resolved cell type-specific biomarkers and therapeutic targets for future interventional trials in MS.

neuroscience↗

bioRxiv2020

Distributional changes in myelin-specific MRI markers uncover dynamics in the fornix following spatial navigation training

Increasing evidence implicates white matter (WM) dynamics supporting learning in the mature brain. Recent MRI studies, mostly using diffusion tensor MRI (DT-MRI), have demonstrated learning-induced WM changes at the microstructural level. However, while DT-MRI-derived measures have sensitivity to general WM microstructural changes, they lack compartmental specificity, making them difficult to relate to underlying cellular mechanisms, stymying deeper understanding of mechanisms supporting training-induced gains in performance. Gaining a deeper understanding demands a more detailed characterization of changes in specific WM sub-components. To this end, four microstructural MRI techniques were employed to study alterations in rat brains after 5-days of water maze training: DT-MRI; Composite Hindered and Restricted Model of Diffusion (CHARMED); magnetization transfer (MT) imaging; quantitative susceptibility mapping and R2*. The hypothesis tested here was that microstructural changes would be: (i) observed in tracts supporting spatial navigation, i.e., fornix and corpus callosum (CC); and (ii) more pronounced in the myelin-specific measures. Medians and distributions of microstructural parameters were derived along the fornix, CC and cingulum (as a comparison tract) using the tractometry approach. Summary measures were derived from different metrics using unsupervised data reduction. Significant pre-vs-post training differences were found in the medians of two principal components loading on: (i) anisotropy indices; and (ii) MT ratio. The most striking effect, however, was seen in the distributions of pre-vs-post training MT ratio in the fornix, consistent with the primary hypothesis, and highlighting the value of this alternative to the standard approach (i.e., comparing means/medians of DT-MRI parameters) for studying neuroplasticity in vivo. Significance statementRecent MRI-studies have demonstrated that white matter (WM) dynamics support learning, even in the mature brain. However, most studies are based on diffusion tensor MRI (DT-MRI) measures, which although providing sensitivity to WM microstructural changes, do not provide a direct translation to the underlying cellular mechanisms making interpretation difficult. Using alternative quantitative MRI approaches, this study provided more specific subcomponent microstructural insights into the brains WM response to water-maze training. We show that myelin-specific MR measures show more marked changes than axonal-specific and DT-MRI measures, in WM tracts responsible for spatial navigation. The results promote adoption of these alternative approaches to DT-MRI for studying neuroplasticity in vivo.

neuroscience↗