Biology subjects

Kruse, L.

Publications and source records attributed to Kruse, L..

4 recordsLinked to original sources

bioRxiv2023

Highly oxidized albumin is mainly cleared by mouse liver sinusoidal endothelial cells via the receptors stabilin-1 and -2

BackgroundOxidized albumin (oxHSA) is elevated in several pathological conditions, especially those involving the liver, such as decompensated cirrhosis, acute on chronic liver failure and liver mediated renal failure. Patient derived oxidized albumin was previously shown to be an inflammatory mediator in cultured endothelial cells and leukocytes. The removal from circulation of oxidized albumins is therefore essential for maintenance of homeostasis. Normal serum levels of oxidized albumin are low, implying it is constantly eliminated. Liver sinusoidal endothelial cells (LSEC) are prominent scavenger cells in the body, specializing in the removal of macromolecules e.g. hyaluronan, denatured collagen, modified albumins, bacterial endotoxin (LPS) and oxidized lipoprotein. Given that oxidized albumin is mainly cleared by the liver, we hypothesize the LSEC are the site of uptake in the liver. Furthermore the stabilins -1 and -2 are the most prominent candidates for oxHSA uptake receptors, given their expression pattern and uptake of other ligands. MethodsIn vivo biodistribution, hepatocellular distribution and in vitro uptake studies on isolated liver cell populations or receptor expressing cell lines. ResultsIn vivo oxHSA was cleared rapidly (t1/2 <90seconds) by the liver (47% of uptake) and distributed to mainly the LSEC. In in vitro studies LSEC endocytosed oxHSA much more than other cell populations isolated from the liver. Furthermore, it was shown that the uptake was mediated by the stabilins, by inhibiting uptake in LSEC with other stabilin ligands and showing uptake in HEK cells overexpressing stabilin-1 or 2. oxHSA also inhibited the uptake of other stabilin ligands. ConclusionsLSEC and their stabilins are vital for the clearance of oxidized albumin, and therefore play a pivotal role in maintaining homeostasis.

molecular biology↗

bioRxiv2023

Effect of caffeine and other xanthines on liver sinusoidal endothelial cell ultrastructure

Xanthines such as caffeine and theobromine are among the most consumed psychoactive stimulants in the world, either as natural components of coffee, tea and chocolate, or as food additives. The present study assessed if xanthines affect liver sinusoidal endothelial cells (LSEC). Cultured primary rat LSEC were challenged with xanthines at concentrations typically obtained from normal consumption of xanthine-containing beverages, food or medicines; and at higher concentrations below the in vitro toxic limit. The fenestrated morphology of LSEC were examined with scanning electron and structured illumination microscopy. All xanthine challenges had no toxic effects on LSEC ultrastructure as judged by LSEC fenestration morphology, or function as determined by endocytosis studies. All xanthines in high concentrations (150 g/mL) increased fenestration frequency but at physiologically relevant concentrations, only theobromine (8 g/mL) showed an effect. LSEC porosity was influenced only by high caffeine doses which also shifted the fenestration distribution towards smaller pores. Moreover, a dose-dependent increase in fenestration number was observed after caffeine treatment. If these compounds induce similar changes in vivo, age-related reduction of LSEC porosity can be reversed by oral treatment with theobromine or with other xanthines using targeted delivery.

cell biology↗

bioRxiv2022

Signature morpho-electric properties of diverse GABAergic interneurons in the human neocortex

Human cortical interneurons have been challenging to study due to high diversity and lack of mature brain tissue platforms and genetic targeting tools. We employed rapid GABAergic neuron viral labeling plus unbiased Patch-seq sampling in brain slices to define the signature morpho-electric properties of GABAergic neurons in the human neocortex. Viral targeting greatly facilitated sampling of the SST subclass, including primate specialized double bouquet cells which mapped to two SST transcriptomic types. Multimodal analysis uncovered an SST neuron type with properties inconsistent with original subclass assignment; we instead propose reclassification into PVALB subclass. Our findings provide novel insights about functional properties of human cortical GABAergic neuron subclasses and types and highlight the essential role of multimodal annotation for refinement of emerging transcriptomic cell type taxonomies. One Sentence SummaryViral genetic labeling of GABAergic neurons in human ex vivo brain slices paired with Patch-seq recording yields an in-depth functional annotation of human cortical interneuron subclasses and types and highlights the essential role of multimodal functional annotation for refinement of emerging transcriptomic cell type taxonomies.

neuroscience↗

bioRxiv2022

Morpho-electric and transcriptomic divergence of the layer 1 interneuron repertoire in human versus mouse neocortex

Neocortical layer 1 (L1) is a site of convergence between pyramidal neuron dendrites and feedback axons where local inhibitory signaling can profoundly shape cortical processing. Evolutionary expansion of human neocortex is marked by distinctive pyramidal neuron types with extensive branching in L1, but whether L1 interneurons are similarly diverse is underexplored. Using patch-seq recordings from human neurosurgically resected tissues, we identified four transcriptomically defined subclasses, unique subtypes within those subclasses and additional types with no mouse L1 homologue. Compared with mouse, human subclasses were more strongly distinct from each other across all modalities. Accompanied by higher neuron density and more variable cell sizes compared with mouse, these findings suggest L1 is an evolutionary hotspot, reflecting the increasing demands of regulating the expanding human neocortical circuit. One Sentence SummaryUsing transcriptomics and morpho-electric analyses, we describe innovations in human neocortical layer 1 interneurons.

neuroscience↗