Biology subjects

Lambrichts, I.

Publications and source records attributed to Lambrichts, I..

3 recordsLinked to original sources

bioRxiv2025

Human Myelin Spheres for In Vitro Oligodendrocyte Maturation, Myelination and Neurological Disease Modeling

Demyelinating diseases, such as multiple sclerosis, damage the protective myelin sheaths of the central nervous system. The development of effective therapies has been hampered by the lack of models that accurately replicate human myelin biology. Here we present a novel method to generate human myelin spheres (MyS) by coculturing of hPSC-derived neuronal and oligodendrocyte precursor cells, to create myelinated neurons. Using multimodal analyses including confocal and (electron)microscopy, single-nuclei transcriptomics, lipidomics, and electrophysiology, we demonstrate myelination in MyS as early as six weeks into coculture. These myelinated structures mature over time into multilamellar and compacted myelin sheaths with lipid compositions and transcriptomic profiles mirror the temporal dynamics of in vivo human oligodendrocyte development and neuronal myelination, resembling those of late fetal/postnatal oligodendrocytes. By employing lysolecithin-induced demyelination and Rabies virus infection experiments, we demonstrate the potential of MyS as an innovative, physiologically relevant platform for studying myelin-related neurodegeneration and neuroinfection.

neuroscience↗

bioRxiv2023

Defective Schwann cell lipid metabolism alters plasma membrane dynamics in Charcot-Marie-Tooth disease 1A

Duplication of PMP22 causes Charcot-Marie-Tooth disease type 1A (CMT1A) and is known to disrupt the lipid metabolism in myelinating Schwann cells by unknown mechanisms. By using two CMT1A mouse models overexpressing human PMP22, we discovered that PMP22 dose-dependently downregulates genes that are involved in lipid and cholesterol metabolism. Lipidomic analysis on CMT1A mouse sciatic nerves confirmed lipid metabolic abnormalities primarily associated with cholesterol and sphingolipids. We observed similar lipidomic profiles and downregulation of genes associated with lipid metabolism in human CMT1A patient induced pluripotent stem cell-derived Schwann cell precursors (iPSC-SCPs). We confirmed these findings by demonstrating altered lipid raft dynamics and plasma membrane fluidity in CMT1A iPSC-SCPs. Additionally, we identified impaired cholesterol incorporation in the plasma membrane due to altered lipid storage homeostasis in CMT1A iPSC-SCPs, which could be modulated by changing the lipid composition of the cell culture medium. These findings suggest that PMP22 plays a role in regulating the lipid composition of the plasma membrane and lipid storage homeostasis. Targeting lipid metabolism may hold promise as a potential treatment for CMT1A patients. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/535224v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@17d4e84org.highwire.dtl.DTLVardef@1adce4forg.highwire.dtl.DTLVardef@1c3e1eborg.highwire.dtl.DTLVardef@12525da_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPMP22 copy number causes a dose-dependent suppression of cholesterol and lipid biosynthesis in peripheral nerves of CMT1A mice C_LIO_LILipid composition is altered in the sciatic nerves of CMT1A mice and in the membranes of patient derived iPSC-SCPs, with a significant reduction in sphingolipids C_LIO_LICMT1A iPSC-SCPs show decreased plasma membrane lipids required for regulating lipid raft dynamics, membrane fluidity, and membrane order C_LIO_LILipid storage misregulation is key in the pathogenesis of CMT1A C_LI

neuroscience↗

bioRxiv2022

Extracellular vesicle-associated cholesterol dictates the regenerative functions of macrophages in the brain

Macrophages play major roles in the pathophysiology of various neurological disorders, being involved in seemingly opposing processes such as lesion progression and resolution. Yet, the molecular mechanisms that drive their harmful and benign effector functions remain poorly understood. Here, we demonstrate that extracellular vesicles (EVs) secreted by repair-associated macrophages (RAMs) enhance remyelination ex vivo and in vivo by promoting the differentiation of oligodendrocyte precursor cells (OPCs). Guided by lipidomic analysis and applying cholesterol depletion and enrichment strategies, we find that EVs released by RAMs show markedly elevated cholesterol levels and that cholestserol abundance controls their reparative impact on OPC maturation and remyelination. Mechanistically, EV-associated cholesterol was found to promote OPC differentiation through direct membrane fusion. Collectively, our findings highlight that EVs are essential for cholesterol trafficking in the brain and that changes in cholesterol abundance dictate the reparative impact of EVs released by macrophages in the brain, potentially having broad implications for therapeutic strategies aimed at promoting repair in neurodegenerative disorders.

neuroscience↗