Biology subjects

Morton, L.

Publications and source records attributed to Morton, L..

4 recordsLinked to original sources

bioRxiv2023

Spatio-temporal dynamics of microglia phenotype in human and murine cSVD: impact of acute and chronic hypertensive states

Vascular risk factors such as chronic hypertension are well established major modifiable factors for the development of cerebral small vessel disease (cSVD). In the present study, our focus was the investigation of cSVD-related phenotypic changes in microglia in human disease and in the spontaneously hypertensive stroke-prone rat (SHRSP) model of cSVD. Our examination of cortical microglia in human post-mortem cSVD cortical tissue revealed distinct morphological microglial features specific to cSVD. We identified enlarged somata, an increase in the territory occupied by thickened microglial processes, and an expansion in the number of vascular-associated microglia. In parallel, we characterized microglia in a rodent model of hypertensive cSVD along different durations of arterial hypertension, i.e., early chronic and late chronic hypertension. Microglial somata were already enlarged in early hypertension, whereas at late-stage chronic hypertension they further exhibited elongat ed branches, thickened processes, and a reduced ramification index, mirroring the findings in human cSVD. An unbiased multidimensional flow cytometric analysis revealed phenotypic heterogeneit y among microglia cells within the hippocampus and cortex. At early-stage hypertension, hippocampal microglia exhibited upregulated CD11b/c, P2Y12R, CD200R, and CD86 surface markers. Detailed analysis of cell subpopulations revealed a unique microglial subset expressing CD11b/c, CD163, and CD86 exclusively in early hypertension. Notably, even at early-stage hypertension, microglia displayed a higher association with cerebral blood vessels. We identified several profound clusters of microglia expressing distinct marker profiles at late chronic hypertensive states. We further detected a temporal hypertension-related disturbances in blood-brain barrier integrity, accompanied by increased recruitment of leukocytes to the brain parenchyma in early hypertension. In summary, our findings demonstrate a higher vulnerability of the hippocampus, stage-specific microglial signatures based on morphological features, and cell surface protein expression in response to chronic arterial hypertension. These results indicate the diversity within microglia sub-populations and implicate the subtle involvement of microglia in cSVD pathogenesis.

neuroscience↗

bioRxiv2023

Vascular and neural transcriptomics reveal stage-dependent pathways to inflammation and cognitive dysfunction in a rat model of hypertension

Chronic arterial hypertension causes cerebral microvascular dysfunction and doubles dementia risk in aging. However, cognitive health preservation by therapeutic blood pressure lowering alone is limited and depends on disease duration, the degree of irreversible tissue damage and whether microvascular function can be restored. This study aimed to understand molecular and cellular temporo-spatial pathomechanisms in the course of hypertension. We investigated the effects of initial, early chronic and late chronic hypertension in the frontal brain of rats by applying behavioral tests, histopathology, immunofluorescence, FACS, microvascular/neural tissue RNA sequencing as well as 18F-FDG PET imaging. Chronic hypertension caused frontal brain-specific behavioral deficits. Our results highlight stage-dependent responses to continuous microvascular stress and wounding by hypertension. Early responses included a fast recruitment of activated microglia to the blood vessels, immigration of peripheral immune cells, blood-brain-barrier leakage and an energy-demanding hypermetabolic state. Vascular adaptation mechanisms were observed in later stages and included angiogenesis and vessel wall strengthening by upregulation of cellular adhesion molecules and extracellular matrix. Additionally, we identified late chronic accumulation of Igfbp-5 in the brains of hypertensive rats, which is also a signature of Alzheimers dementia and attenuates protective Igf-1 signaling. Our study advances the knowledge of involved pathomechanisms and highlights the stage-dependent nature of hypertensive pathobiology. This groundwork might be helpful for basic and clinical research to identify stage-dependent markers in the human disease course, investigate stage-dependent interventions besides blood pressure lowering and better understand the relationship between poor vascular health and neurodegenerative diseases.

neuroscience↗

bioRxiv2022

Spatially resolved human kidney multi-omics single cell atlas highlights the key role of the fibrotic microenvironment in kidney disease progression

Kidneys possess one of the most intricate three-dimensional cellular structures in the body, yet the spatial and molecular principles of kidney health and disease remain inadequately understood. Here, we have generated high-quality datasets for 81 samples, including single cell (sc), single nuclear (sn), spot level (Visium) and single cell resolution (CosMx) spatial (sp)-RNA expression, and sn open chromatin, capturing cells from healthy, diabetic, and hypertensive diseased human kidneys. By combining the snRNA, snATAC and scRNA sequencing we identify cell types and map these cell types to their locations within the tissue. Unbiased deconvolution of the spatial data identifies 4 distinct spatial microenvironments: glomerular, immune, tubule and fibrotic. We describe the complex, heterogenous cellular and spatial organization of human microenvironments in health and disease. Further, we find that the fibrotic microenvironment spatial gene signature is not only able to molecularly classify human kidneys, but it also offers an improved prognosis prediction compared to traditional histopathological analysis. We provide a comprehensive spatially resolved molecular roadmap of the human kidney and the fibrotic process, demonstrating the clinical utility of spatial transcriptomics.

genetics↗

bioRxiv2022

Initial and ongoing tobacco smoking elicits vascular damage and distinct inflammatory response linked to neurodegeneration

Tobacco smoking is strongly linked to vascular damage contributing to the development of hypertension, atherosclerosis, as well as an increased risk for neurodegeneration. Still, the contribution of the innate immune system to the development of vascular damage upon chronic tobacco use before the onset of clinical symptoms is not fully elucidated. Notably, our data provide evidence that a single acute exposure to tobacco in never smokers elicits a secretion of extracellular vesicles by endothelial cells expressing CD105 and CD49e, granting further recognition of early preclinical biomarker of vascular damage. Further, we investigated the effects of smoking on the immune system of healthy asymptomatic chronic smokers compared to never-smokers and focused on the innate immune system. Our data reveal a distinct immune landscape representative for early stages of vascular damage before tobacco smoking related disease develop in clinically asymptomatic chronic smokers. These results indicate a dysregulated immuno-vascular axis in chronic tobacco smokers that are considered healthy individuals. The distinct alterations are characterized by increased CD36 expression by blood monocyte subsets, neutrophilia, increased plasma IL-18 and reduced levels of IL-33, IL-10 and IL-8. Further, the detection of lower circulating BDNF and elevated sTREM2, specific markers for neurodegeneration, suggests a considerable pre-clinical impact of tobacco smoking on CNS function in clinically healthy individuals. These findings provide further insight into the initial and ongoing effects of tobacco smoking and the potential vascular damage contributing to the progression of neurodegenerative disorders, specifically cerebrovascular dysfunction and dementia.

immunology↗