https://hdl.handle.net/20.500.11811/662 2026-04-16T20:22:59Z https://hdl.handle.net/20.500.11811/13908 Kupffer cell programming by maternal obesity triggers fatty liver disease Huang, Hoa; Balzer, Nora R.; Seep, Lea; Splichalova, Iva; Blank-Stein, Nelli; Viola, Maria Francesca; Taveras, Eliana Franco; Acil, Kerim; Fink, Diana; Petrovic, Franzisca; Makdissi, Nikola; Bayar, Seyhmus; Mauel, Katharina; Radwaniak, Carolin; Zurkovic, Jelena; Kayvanjoo, Amir H.; Wunderling, Klaus; Jessen, Malin; Yaghmour, Mohamed H.; Kenner, Lukas; Ulas, Thomas; Grein, Stephan; Schultze, Joachim L.; Scott, Charlotte L.; Guilliams, Martin; Liu, Zhaoyuan; Ginhoux, Florent; Beyer, Marc D.; Thiele, Christoph; Meissner, Felix; Hasenauer, Jan; Wachten, Dagmar; Mass, Elvira Kupffer cells (KCs) are tissue-resident macrophages that colonize the liver early during embryogenesis. Upon liver colonization, KCs rapidly acquire a tissue-specific transcriptional signature, mature alongside the developing liver and adapt to its functions. Throughout development and adulthood, KCs perform distinct core functions that are essential for liver and organismal homeostasis, including supporting fetal erythropoiesis, postnatal erythrocyte recycling and liver metabolism. However, whether perturbations of macrophage core functions during development contribute to or cause disease at postnatal stages is poorly understood. Here, we utilize a mouse model of maternal obesity to perturb KC functions during gestation. We show that offspring exposed to maternal obesity develop fatty liver disease, driven by aberrant developmental programming of KCs that persists into adulthood. Programmed KCs promote lipid uptake by hepatocytes through apolipoprotein secretion. KC depletion in neonate mice born to obese mothers, followed by replenishment with naive monocytes, rescues fatty liver disease. Furthermore, genetic ablation of the gene encoding hypoxia-inducible factor-&alpha; (HIF1&alpha;) in macrophages during gestation prevents the metabolic programming of KCs from oxidative phosphorylation to glycolysis, thereby averting the development of fatty liver disease. These results establish developmental perturbation of KC functions as a causal factor in fatty liver disease in adulthood and position fetal-derived macrophages as critical intergenerational messengers within the concept of developmental origins of health and diseases. 2025-06-18T00:00:00Z https://hdl.handle.net/20.500.11811/13613 cOmicsArt Seep, Lea; Jost, Paul Jonas; Lisowski, Clivia; Huang, Hao; Grein, Stephan; Hermannsdottir, Hildigunnur; Kuellmer, Katharina; Fromme, Tobias; Klingenspor, Martin; Mass, Elvira; Kurts, Christian; Hasenauer, Jan <strong>Motivation:</strong> The availability of bulk-omic data is steadily increasing, necessitating collaborative efforts between experimental and computational researchers. While software tools with graphical user interfaces (GUIs) enable rapid and interactive data assessment, they are limited to pre-implemented methods, often requiring transitions to custom code for further adjustments. However, the most available tools lack GUI-independent reproducibility such as direct integration with R, resulting in very limited support for transition.<br /> <strong>Results:</strong> We introduce the customizable Omics Analysis and reporting tool—cOmicsArt. cOmicsArt aims to enhance collaboration through integration of GUI-based analysis with R. The GUI allows researchers to perform user-friendly exploratory and statistical analyses with interactive visualizations and automatic documentation. Downloadable R scripts and results ensure reproducibility and seamless integration with R, supporting both novice and experienced programmers by enabling easy customizations and serving as a foundation for more advanced analyses. This versatility also allows for usage in educational settings guiding students from GUI-based analysis to R Code. 2025-04-01T00:00:00Z https://hdl.handle.net/20.500.11811/13611 Phosphatidylcholine synthesis and remodeling in brain endothelial cells Yaghmour, Mohamed H.; Sajeevan, Theja; Thiele, Christoph; Kuerschner, Lars Mammalian cells synthesize hundreds of different variants of their prominent membrane lipid phosphatidylcholine (PC), all differing in the side chain composition. This batch is constantly remodeled by the Lands cycle, a metabolic pathway replacing one chain at a time. Using the alkyne lipid lyso-phosphatidylpropargylcholine (LpPC), a precursor and intermediate in PC synthesis and remodeling, we study both processes in brain endothelial bEND3 cells. A novel method for multiplexed sample analysis by mass spectrometry is developed that offers high throughput and molecular species resolution of the propargyl-labeled PC lipids. Their time-resolved profiles and kinetic parameters of metabolism demonstrate the plasticity of the PC pool and the acute handling of lipid influx in endothelial cells differs from that in hepatocytes. Side chain remodeling as a form of lipid cycling adapts the PC pool to the cell's need and maintains lipid homeostasis. We estimate that endothelial cells possess the theoretical capacity to remodel up to 99% of their PC pool within 3.5 h using the Lands cycle. However, PC species are not subjected stochastically to this remodeling pathway as different species containing duplets of saturated, omega-3, and omega-6 side chains show different decay kinetics. Our findings emphasize the essential function of Lands cycling for monitoring and adapting the side chain composition of PC in endothelial cells. 2025-04-01T00:00:00Z https://hdl.handle.net/20.500.11811/13610 Microglia and CD8⁺ T cell activation precede neuronal loss in a murine model of spastic paraplegia 15 Frolov, Aleksej; Huang, Hao; Schütz, Dagmar; Köhne, Maren; Blank-Stein, Nelli; Osei-Sarpong, Collins; Büttner, Maren; Elmzzahi, Tarek; Khundadze, Mukhran; Zahid, Marina; Reuter, Michael; Becker, Matthias; De Domenico, Elena; Bonaguro, Lorenzo; Kallies, Axel; Morrison, Helen; Hübner, Christian A.; Händler, Kristian; Stumm, Ralf; Mass, Elvira; Beyer, Marc D. In central nervous system (CNS) diseases characterized by late-onset neurodegeneration, the interplay between innate and adaptive immune responses remains poorly understood. This knowledge gap is exacerbated by the prolonged protracted disease course as it complicates the delineation of brain-resident and infiltrating cells. Here, we conducted comprehensive profiling of innate and adaptive immune cells in a murine model of spastic paraplegia 15 (SPG15), a complicated form of hereditary spastic paraplegia. Using fate-mapping of bone marrow–derived cells, we identified microgliosis accompanied by infiltration and local expansion of T cells in the CNS of <em>Spg15^−/−</em> mice. Single-cell analysis revealed an expansion of disease-associated microglia (DAM) and effector CD8⁺ T cells prior to neuronal loss. Analysis of potential cell–cell communication pathways suggested bidirectional interactions between DAM and effector CD8⁺ T cells, potentially contributing to disease progression in <em>Spg15^−/−</em> mice. In summary, we identified a shift in microglial phenotypes associated with the recruitment and expansion of T cells as a new characteristic of <em>Spg15</em>-driven neuropathology. 2025-04-23T00:00:00Z