Biology subjects

Derks, R. J. E.

Publications and source records attributed to Derks, R. J. E..

3 recordsLinked to original sources

bioRxiv2025

Normothermic human kidney preservation drives iron accumulation and ferroptosis

Ex vivo normothermic machine perfusion has been proposed to protect deceased donor organs, promoting metabolic recovery and allowing quality assessment. However, its benefits for preserving deceased donor kidneys remain ambiguous. We postulate that the use of red blood cells (RBCs) as oxygen carriers and associated secondary hemolysis may in fact cause renal injury, offsetting potential advantages. During 48-hour normothermic perfusion of seven human deceased donor kidneys, we observed progressive hemolysis, leading to iron accumulation in perfusate, tissue, and urine. Untargeted lipidomic analysis revealed profound increases in oxidized phospholipid species in perfused kidneys, pointing towards iron-dependent cell death known as ferroptosis. Next, in twelve additional human kidney perfusions, we demonstrate that either dialysis-based free hemoglobin removal or cell-free perfusion attenuates hemolysis-driven iron accumulation, phospholipid peroxidation, and acute kidney injury. Our findings highlight the pathological role of hemolysis and iron on the kidney, urging restraint in the clinical application of RBC-based kidney perfusion.

physiology↗

bioRxiv2024

The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4

Lipid changes in the brain have been implicated in many neurodegenerative diseases including Alzheimers Disease (AD), Parkinsons disease and Amyotrophic Lateral Sclerosis. To facilitate comparative lipidomic research across brain-diseases we established a data commons named the Neurolipid Atlas, that we have pre-populated with novel human, mouse and isogenic induced pluripotent stem cell (iPSC)-derived lipidomics data for different brain diseases. We show that iPSC-derived neurons, microglia and astrocytes display distinct lipid profiles that recapitulate in vivo lipotypes. Leveraging multiple datasets, we show that the AD risk gene ApoE4 drives cholesterol ester (CE) accumulation in human astrocytes recapitulating CE accumulation measured in the human AD brain. Multi-omic interrogation of iPSC-derived astrocytes revealed that cholesterol plays a major role in astrocyte interferon-dependent pathways such as the immunoproteasome and major histocompatibility complex (MHC) class I antigen presentation. We show that through enhanced cholesterol esterification ApoE4 suppresses immune activation of astrocytes. Our novel data commons, available at neurolipidatlas.com, provides a user-friendly tool and knowledge base for a better understanding of lipid dyshomeostasis in neurodegenerative diseases.

neuroscience↗

bioRxiv2021

Generating heterokaryotic cells via bacterial cell-cell fusion

Cell-cell fusion is fundamentally important for tissue repair, virus transmission, and genetic recombination, among other functions. Fusion has been mainly studied in eukaryotic cells and lipid vesicles, while cell-cell fusion in bacteria is less well characterized, due to the cell wall acting as a fusion-limiting barrier. Here we use cell wall-deficient bacteria to investigate the dynamics of cell fusion in bacteria that replicate without their cell wall. Stable, replicating cells containing differently labeled chromosomes were successfully obtained from fusion. We find that the rate of cell-cell fusion depends on the fluidity of cell membranes. Furthermore, we show that not only the efficiency but also the specificity of cell-cell fusion can be controlled via a pair of synthetic membrane-associated lipopeptides. Our results provide a molecular handle to understand and control cell-cell fusion to generate heterokaryotic cells, which was an important step in the evolution of protocells and of increasing importance for the design of synthetic cells.

microbiology↗