Mikolaj Opielka, Krzysztof Urbanowicz, Klaudia Konieczna-Wolska, Elisabeth Müller, Oliwier Krajewski, Maureen Feucherolles, Qiuqin Zhou, Michal Bienkowski, Gilles Frache, Carsten Hopf, Lucas Schirmer, Aleksandra Rutkowska, Ryszard T Smolenski
{"title":"空间脂质组学揭示小鼠脑内脱髓鞘和再脱髓鞘动力学。","authors":"Mikolaj Opielka, Krzysztof Urbanowicz, Klaudia Konieczna-Wolska, Elisabeth Müller, Oliwier Krajewski, Maureen Feucherolles, Qiuqin Zhou, Michal Bienkowski, Gilles Frache, Carsten Hopf, Lucas Schirmer, Aleksandra Rutkowska, Ryszard T Smolenski","doi":"10.1016/j.jlr.2025.100912","DOIUrl":null,"url":null,"abstract":"<p><p>Myelin pathology in demyelinating diseases is accompanied by lipid remodeling that remains challenging to characterize at spatial level using traditional mass spectrometry. We developed an optimized AP-MALDI-Orbitrap MSI pipeline, incorporating sample preparation improvements and mass recalibration, to investigate lipid dynamics in the cuprizone (CPZ) mouse model of demyelination. Dual-modality, untargeted lipid profiling was performed to map spatially resolved lipid alterations during demyelination and spontaneous remyelination in two key brain areas of male mice: corpus callosum (CC) and cortex (Ctx), with lipid identifications benchmarked against 4D-LC-TIMS-MS/MS. Demyelinated regions were identified using Black Gold II staining. Using 1 ppm mass tolerance, we annotated 154 and 133 lipids at the sum-composition level in CC and Ctx, respectively, with 60% validated by LC-MS/MS. Spatial lipid profiling revealed CPZ-induced alterations in sphingolipids, sulfatides, and glycerophospholipids, supported by reanalysis of a published snRNA-seq dataset from a mouse CPZ model. Long-chain ceramides (Cer) and hexosylceramides (HexCer) were reduced in demyelinated regions, with partial, region-specific recovery during remyelination. Short-chain sulfatides (SHexCer), sphingomyelins (SM) and seminolipids transiently increased in the CC during demyelination, while long-chain sulfatides decreased in both CC and Ctx. Additionally, we observed demyelination-induced upregulation of polyunsaturated glycerophospholipids in CC and phosphatidylinositols (PI) in cortex. Lipid subclass changes emerged as reliable markers of both demyelination and remyelination in the mouse brain. Region-specific alterations in lipid metabolism provide new insights into the processes of de- and remyelination. Notably, remyelinated fibers have a distinct lipid profile compared to intact myelin, suggesting that lipid-based therapeutic strategies could improve myelin repair.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100912"},"PeriodicalIF":4.1000,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Spatial lipidomics reveals demyelination and remyelination dynamics in the mouse brain.\",\"authors\":\"Mikolaj Opielka, Krzysztof Urbanowicz, Klaudia Konieczna-Wolska, Elisabeth Müller, Oliwier Krajewski, Maureen Feucherolles, Qiuqin Zhou, Michal Bienkowski, Gilles Frache, Carsten Hopf, Lucas Schirmer, Aleksandra Rutkowska, Ryszard T Smolenski\",\"doi\":\"10.1016/j.jlr.2025.100912\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Myelin pathology in demyelinating diseases is accompanied by lipid remodeling that remains challenging to characterize at spatial level using traditional mass spectrometry. We developed an optimized AP-MALDI-Orbitrap MSI pipeline, incorporating sample preparation improvements and mass recalibration, to investigate lipid dynamics in the cuprizone (CPZ) mouse model of demyelination. Dual-modality, untargeted lipid profiling was performed to map spatially resolved lipid alterations during demyelination and spontaneous remyelination in two key brain areas of male mice: corpus callosum (CC) and cortex (Ctx), with lipid identifications benchmarked against 4D-LC-TIMS-MS/MS. Demyelinated regions were identified using Black Gold II staining. Using 1 ppm mass tolerance, we annotated 154 and 133 lipids at the sum-composition level in CC and Ctx, respectively, with 60% validated by LC-MS/MS. Spatial lipid profiling revealed CPZ-induced alterations in sphingolipids, sulfatides, and glycerophospholipids, supported by reanalysis of a published snRNA-seq dataset from a mouse CPZ model. Long-chain ceramides (Cer) and hexosylceramides (HexCer) were reduced in demyelinated regions, with partial, region-specific recovery during remyelination. Short-chain sulfatides (SHexCer), sphingomyelins (SM) and seminolipids transiently increased in the CC during demyelination, while long-chain sulfatides decreased in both CC and Ctx. Additionally, we observed demyelination-induced upregulation of polyunsaturated glycerophospholipids in CC and phosphatidylinositols (PI) in cortex. Lipid subclass changes emerged as reliable markers of both demyelination and remyelination in the mouse brain. Region-specific alterations in lipid metabolism provide new insights into the processes of de- and remyelination. 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Spatial lipidomics reveals demyelination and remyelination dynamics in the mouse brain.
Myelin pathology in demyelinating diseases is accompanied by lipid remodeling that remains challenging to characterize at spatial level using traditional mass spectrometry. We developed an optimized AP-MALDI-Orbitrap MSI pipeline, incorporating sample preparation improvements and mass recalibration, to investigate lipid dynamics in the cuprizone (CPZ) mouse model of demyelination. Dual-modality, untargeted lipid profiling was performed to map spatially resolved lipid alterations during demyelination and spontaneous remyelination in two key brain areas of male mice: corpus callosum (CC) and cortex (Ctx), with lipid identifications benchmarked against 4D-LC-TIMS-MS/MS. Demyelinated regions were identified using Black Gold II staining. Using 1 ppm mass tolerance, we annotated 154 and 133 lipids at the sum-composition level in CC and Ctx, respectively, with 60% validated by LC-MS/MS. Spatial lipid profiling revealed CPZ-induced alterations in sphingolipids, sulfatides, and glycerophospholipids, supported by reanalysis of a published snRNA-seq dataset from a mouse CPZ model. Long-chain ceramides (Cer) and hexosylceramides (HexCer) were reduced in demyelinated regions, with partial, region-specific recovery during remyelination. Short-chain sulfatides (SHexCer), sphingomyelins (SM) and seminolipids transiently increased in the CC during demyelination, while long-chain sulfatides decreased in both CC and Ctx. Additionally, we observed demyelination-induced upregulation of polyunsaturated glycerophospholipids in CC and phosphatidylinositols (PI) in cortex. Lipid subclass changes emerged as reliable markers of both demyelination and remyelination in the mouse brain. Region-specific alterations in lipid metabolism provide new insights into the processes of de- and remyelination. Notably, remyelinated fibers have a distinct lipid profile compared to intact myelin, suggesting that lipid-based therapeutic strategies could improve myelin repair.
期刊介绍:
The Journal of Lipid Research (JLR) publishes original articles and reviews in the broadly defined area of biological lipids. We encourage the submission of manuscripts relating to lipids, including those addressing problems in biochemistry, molecular biology, structural biology, cell biology, genetics, molecular medicine, clinical medicine and metabolism. Major criteria for acceptance of articles are new insights into mechanisms of lipid function and metabolism and/or genes regulating lipid metabolism along with sound primary experimental data. Interpretation of the data is the authors’ responsibility, and speculation should be labeled as such. Manuscripts that provide new ways of purifying, identifying and quantifying lipids are invited for the Methods section of the Journal. JLR encourages contributions from investigators in all countries, but articles must be submitted in clear and concise English.