Biology subjects

Abeln, M.

Publications and source records attributed to Abeln, M..

4 recordsLinked to original sources

bioRxiv2025

Platelets Link Coagulation and Complement in Regulating Placental Vascular Development

During early pregnancy, maternal blood surrounds the embryo before the placenta is fully developed, requiring tight regulation of maternal blood flow into the placental vasculature. We identify placental microthrombi (PMTs) as essential structures guiding this process. PMTs contain platelets, coagulation factors, and complement proteins, and their formation depends on maternal platelet activation by thrombin through the protease-activated receptor PAR4. Deficiency of PAR4 abolished PMTs and caused excessive bleeding at the implantation site. C3 deficiency also led to increased bleeding events, indicating that complement activation contributes to thrombosis in the placental circulation. Conversely, dysregulated complement activation in CMP-sialic acid synthase-deficient (Cmas-/-) mice led to widespread thrombosis and failed placental development. Strikingly, platelet activation via PAR4 was necessary to localize complement activation to trophoblast surfaces, thereby coupling coagulation and complement in PMT formation. Depletion of maternal platelets mitigated complement-driven thromboinflammation in Cmas-/- pregnancies, restoring placental growth. These findings uncover a critical cooperation between platelets, coagulation, and complement in establishing maternal blood flow to the placenta. Successful pregnancy therefore requires not only activation but also tight regulation of these systems to balance necessary PMT formation with the prevention of pathological thrombosis. Graphical abstract(Created in BioRender. Tiede, A. (2025) https://BioRender.com/l6zeezr) O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/675525v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@c04354org.highwire.dtl.DTLVardef@844863org.highwire.dtl.DTLVardef@ac7ba5org.highwire.dtl.DTLVardef@1e9be32_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Multi-omic analysis reveals the unique glycan landscape of the blood-brain barrier glycocalyx

The blood-brain barrier (BBB) glycocalyx is the dense layer of glycans and glycoconjugates that coats the luminal surface of the central nervous system (CNS) vasculature. Despite being the first point of contact between the blood and brain, not much is known about the BBB glycocalyx. Here, we performed a multi-omic investigation of the BBB glycocalyx which revealed a unique glycan landscape characterized by enrichment of sialic acid, chondroitin sulfate, and hyaluronan. We found that the BBB glycocalyx was thicker than glycocalyces in the peripheral vasculature and that hyaluronan was the major contributor to its ultrastructure. Using endothelial RNA sequencing, we found potential genetic determinants for these differences, including BBB enrichment of genes involved in sialic acid addition and peripheral enrichment of Tmem2 and Hyal2, the only known cell-surface hyaluronidases. Glycocalyx degradation and increases in vascular permeability are widely associated with inflammation. However, we found that the BBB glycocalyx remains largely unchanged in neuroinflammation during the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and that its degradation is not sufficient to alter BBB permeability in health. Moreover, we showed that CNS endothelial sialic acid removal delays onset of EAE, indicating that BBB glycocalyx sialic acid may contribute to the progression of neuroinflammation. These findings underscore the unique and robust nature of the BBB glycocalyx and provide targets and tools for future studies into its role in health and neuroinflammation.

molecular biology↗

bioRxiv2023

Tumor sialylation is a barrier against CD8 T cell-mediated anti-tumor responses and anti-PD-1 resistance in breast cancer

Breast cancer is the most common cancer among women. However, the use of immune checkpoint inhibitors, that have revolutionized treatment of multiple cancers, unfortunately remain largely ineffective in most breast cancer patients. Here, we report the most comprehensive glycoproteome map in breast tumor cells, pointing to a key role of sialic acid modifications in mammary cancer. Genetic and pharmacologic inhibition of sialylation repolarizes the tumor microenvironment, leading to a reduction in myeloid-derived suppressor cells and a significant increase in Tcf7+ memory and CD8+ effector T cells. Mechanistically, sialylation controls cell surface expression of MHC class I and PD-1-ligand on the tumor cells. Functionally, in vivo interference with sialylation on breast cancer cells licenses CD8+ T cells to effectively kill the tumors. In multiple immunotherapy-resistant breast tumor models, we also show that the abrogation of sialylation sensitizes to anti-PD-1 immune checkpoint therapy. We further demonstrate that hyper-sialylation occurs in over half of human breast cancers tested and correlates with poor T cell infiltration. Our results establish sialylation as a central immunoregulator in breast cancer, orchestrating multiple pathways of immune evasion. Targeting tumor sialylation licenses immunologically inert mammary tumors to be efficiently eliminated by anti-cancer immunity and sensitizes to immune checkpoint therapy.

cancer biology↗

bioRxiv2022

The monosialoganglioside GM1a protects trophoblasts, erythrocytes and endothelial cells against complement attack

The complement system is a part of the innate immune system in the fluid phase and efficiently eliminates pathogens. However, its activation requires tight regulation on the host cell surface in order not to compromise cellular viability. Previously, we showed that loss of placental cell surface sialylation in mice in vivo leads to a maternal complement attack at the fetal-maternal interface, ultimately resulting in loss of pregnancy. To gain insight into the regulatory function of sialylation in complement activation, we here generated trophoblast stem cells devoid of sialylation, which also revealed complement sensitivity and cell death in vitro. Glycolipid-analysis by xCGE-LIF allowed us to identify the monosialoganglioside GM1a as a key element of cell surface complement regulation. Exogenously administered GM1a integrated into the plasma membrane of trophoblasts, dramatically increased binding of complement factor H and was sufficient to protect the cells from complement attack and cell death. Furthermore, GM1a treatment rescued sensitized human erythrocytes and endothelial cells from complement attack in a concentration dependent manner. This study demonstrates for the first time the complement regulatory potential of exogenously administered gangliosides and paves the way for sialoglycotherapeutics as a novel substance class for membrane-targeted complement regulators. Key pointsO_LIThe naturally occurring sialic acid containing glycosphingolipid GM1a is a potent regulator of complement activation on mammalian trophoblast, erythrocyte and endothelial cell surfaces. C_LIO_LIIncorporated GM1a recruits complement factor H and thus could represent a novel membrane-targeted complement therapeutic. C_LI

biochemistry↗