Nature Cell Biology最新文献

α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells α-酮戊二酸促进幼年人胚胎干细胞的滋养外胚层诱导和成熟

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-04-23 DOI: 10.1038/s41556-025-01658-1

Karlien Van Nerum, Anne Wenzel, Lidia Argemi-Muntadas, Eleni Kafkia, Antar Drews, Ida Sophie Brun, Viktoria Lavro, Annina Roelofsen, Nikolaos Stamidis, Sandra Bages Arnal, Cheng Zhao, Simone di Sanzo, Moritz Völker-Albert, Sophie Petropoulos, Thomas Moritz, Jan Jakub Żylicz

{"title":"α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells","authors":"Karlien Van Nerum, Anne Wenzel, Lidia Argemi-Muntadas, Eleni Kafkia, Antar Drews, Ida Sophie Brun, Viktoria Lavro, Annina Roelofsen, Nikolaos Stamidis, Sandra Bages Arnal, Cheng Zhao, Simone di Sanzo, Moritz Völker-Albert, Sophie Petropoulos, Thomas Moritz, Jan Jakub Żylicz","doi":"10.1038/s41556-025-01658-1","DOIUrl":"https://doi.org/10.1038/s41556-025-01658-1","url":null,"abstract":"Development and lineage choice are driven by interconnected transcriptional, epigenetic and metabolic changes. Specific metabolites, such as α-ketoglutarate (αKG), function as signalling molecules affecting the activity of chromatin-modifying enzymes. However, how metabolism coordinates cell-state changes, especially in human pre-implantation development, remains unclear. Here we uncover that inducing naive human embryonic stem cells towards the trophectoderm lineage results in considerable metabolic rewiring, characterized by αKG accumulation. Elevated αKG levels potentiate the capacity of naive embryonic stem cells to specify towards the trophectoderm lineage. Moreover, increased αKG levels promote blastoid polarization and trophectoderm maturation. αKG supplementation does not affect global histone methylation levels; rather, it decreases acetyl-CoA availability, reduces histone acetyltransferase activity and weakens the pluripotency network. We propose that metabolism functions as a positive feedback loop aiding in trophectoderm fate induction and maturation, highlighting that global metabolic rewiring can promote specificity in cell fate decisions through intricate regulation of signalling and chromatin.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"17 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effects of embryonic origin, tissue cues and pathological signals on fibroblast diversity in humans 胚胎来源、组织线索和病理信号对人类成纤维细胞多样性的影响

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-04-22 DOI: 10.1038/s41556-025-01638-5

Marta Torregrossa, Lindsay Davies, Machens Hans-Günther, Jan C. Simon, Sandra Franz, Yuval Rinkevich

引用次数: 0

Metastatic medulloblastoma remodels the local leptomeningeal microenvironment to promote further metastatic colonization and growth 转移性髓母细胞瘤重塑局部脑膜微环境，促进进一步转移定植和生长

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-04-22 DOI: 10.1038/s41556-025-01660-7

Namal Abeysundara, Alexandra Rasnitsyn, Vernon Fong, Alexander Bahcheli, Randy Van Ommeren, Kyle Juraschka, Maria Vladoiu, Winnie Ong, Bryn Livingston, Pasqualino de Antonellis, Michelle Ly, Borja López Holgado, Olga Sirbu, Shahrzad Bahrampour, Hyun-Kee Min, Jerry Fan, Carolina Nor, Abhirami Visvanathan, Jiao Zhang, Hao Wang, Lei Qin, Ning Huang, Jonelle Pallotta, Tajana Douglas, Esta Mak, Haipeng Su, Karen Ng, Kevin Yang Zhang, Craig Daniels, Calixto-Hope G. Lucas, Charles G. Eberhart, Hailong Liu, Tao Jiang, Faiyaz Notta, Vijay Ramaswamy, Jüri Reimand, Marco Gallo, Jeremy N. Rich, Xiaochong Wu, Xi Huang, Michael D. Taylor

{"title":"Metastatic medulloblastoma remodels the local leptomeningeal microenvironment to promote further metastatic colonization and growth","authors":"Namal Abeysundara, Alexandra Rasnitsyn, Vernon Fong, Alexander Bahcheli, Randy Van Ommeren, Kyle Juraschka, Maria Vladoiu, Winnie Ong, Bryn Livingston, Pasqualino de Antonellis, Michelle Ly, Borja López Holgado, Olga Sirbu, Shahrzad Bahrampour, Hyun-Kee Min, Jerry Fan, Carolina Nor, Abhirami Visvanathan, Jiao Zhang, Hao Wang, Lei Qin, Ning Huang, Jonelle Pallotta, Tajana Douglas, Esta Mak, Haipeng Su, Karen Ng, Kevin Yang Zhang, Craig Daniels, Calixto-Hope G. Lucas, Charles G. Eberhart, Hailong Liu, Tao Jiang, Faiyaz Notta, Vijay Ramaswamy, Jüri Reimand, Marco Gallo, Jeremy N. Rich, Xiaochong Wu, Xi Huang, Michael D. Taylor","doi":"10.1038/s41556-025-01660-7","DOIUrl":"https://doi.org/10.1038/s41556-025-01660-7","url":null,"abstract":"Leptomeningeal metastases are the major source of morbidity and mortality for patients with medulloblastoma. The biology of the leptomeningeal metastases and the local tumour microenvironment are poorly characterized. Here we show that metastasis-associated meningeal fibroblasts (MB-MAFs) are transcriptionally distinct and signal extensively to tumour cells and the tumour microenvironment. Metastatic cells secrete platelet-derived growth factor (PDGF) ligands into the local microenvironment to chemotactically recruit meningeal fibroblasts. Meningeal fibroblasts are reprogrammed to become MB-MAFs, expressing distinct transcriptomes and secretomes, including bone morphogenetic proteins. Active bone morphogenetic protein signalling and co-implantation of tumour cells with MB-MAFs enhances the colonization of the leptomeninges by medulloblastoma cells and promotes the growth of established metastases. Furthermore, treatment of patient-derived xenograft mice with a PDGF-receptor-α neutralizing antibody enhances overall survival in vivo. Collectively, our results define a targetable intercellular communication cascade in the metastatic niche to treat leptomeningeal disease.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"31 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism 线粒体NADPH为线粒体脂肪酸合成和脂酰化提供燃料，为氧化代谢提供动力

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-04-21 DOI: 10.1038/s41556-025-01655-4

Dohun Kim, Rushendhiran Kesavan, Kevin Ryu, Trishna Dey, Austin Marckx, Cameron Menezes, Prakash P. Praharaj, Stewart Morley, Bookyong Ko, Mona H. Soflaee, Harrison J. Tom, Harrison Brown, Hieu S. Vu, Shih-Chia Tso, Chad A. Brautigam, Andrew Lemoff, Marcel Mettlen, Prashant Mishra, Feng Cai, Doug K. Allen, Gerta Hoxhaj

{"title":"Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism","authors":"Dohun Kim, Rushendhiran Kesavan, Kevin Ryu, Trishna Dey, Austin Marckx, Cameron Menezes, Prakash P. Praharaj, Stewart Morley, Bookyong Ko, Mona H. Soflaee, Harrison J. Tom, Harrison Brown, Hieu S. Vu, Shih-Chia Tso, Chad A. Brautigam, Andrew Lemoff, Marcel Mettlen, Prashant Mishra, Feng Cai, Doug K. Allen, Gerta Hoxhaj","doi":"10.1038/s41556-025-01655-4","DOIUrl":"https://doi.org/10.1038/s41556-025-01655-4","url":null,"abstract":"Nicotinamide adenine dinucleotide phosphate (NADPH) is a vital electron donor essential for macromolecular biosynthesis and protection against oxidative stress. Although NADPH is compartmentalized within the cytosol and mitochondria, the specific functions of mitochondrial NADPH remain largely unexplored. Here we demonstrate that NAD+ kinase 2 (NADK2), the principal enzyme responsible for mitochondrial NADPH production, is critical for maintaining protein lipoylation, a conserved lipid modification necessary for the optimal activity of multiple mitochondrial enzyme complexes, including the pyruvate dehydrogenase complex. The mitochondrial fatty acid synthesis (mtFAS) pathway utilizes NADPH for generating protein-bound acyl groups, including lipoic acid. By developing a mass-spectrometry-based method to assess mammalian mtFAS, we reveal that NADK2 is crucial for mtFAS activity. NADK2 deficiency impairs mtFAS-associated processes, leading to reduced cellular respiration and mitochondrial translation. Our findings support a model in which mitochondrial NADPH fuels the mtFAS pathway, thereby sustaining protein lipoylation and mitochondrial oxidative metabolism.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"35 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tumour interstitial fluid-enriched phosphoethanolamine suppresses T cell function 肿瘤间质液富集的磷酸乙醇胺抑制T细胞功能

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-04-21 DOI: 10.1038/s41556-025-01650-9

Yupeng Wang, Drew Wilfahrt, Patrick Jonker, Konstantinos Lontos, Chufan Cai, Benjamin Cameron, Bingxian Xie, Ronal M. Peralta, Emerson R. Schoedel, William G. Gunn, Roya AminiTabrizi, Hardik Shah, Dayana B. Rivadeneira, Alexander Muir, Greg M. Delgoffe

{"title":"Tumour interstitial fluid-enriched phosphoethanolamine suppresses T cell function","authors":"Yupeng Wang, Drew Wilfahrt, Patrick Jonker, Konstantinos Lontos, Chufan Cai, Benjamin Cameron, Bingxian Xie, Ronal M. Peralta, Emerson R. Schoedel, William G. Gunn, Roya AminiTabrizi, Hardik Shah, Dayana B. Rivadeneira, Alexander Muir, Greg M. Delgoffe","doi":"10.1038/s41556-025-01650-9","DOIUrl":"https://doi.org/10.1038/s41556-025-01650-9","url":null,"abstract":"Nutrient stress represents an important barrier for anti-tumour immunity, and tumour interstitial fluid often contains metabolites that hinder immune function. However, it is difficult to isolate the effects of tumour nutrient stress from other suppressive factors. Thus, we used a chemically defined cell culture medium based on the metabolomic profile of tumour interstitial fluid: tumour interstitial fluid medium (TIFM). Culture of CD8+ T cells in TIFM limited cell expansion and impaired CD8+ T cell effector functions upon restimulation, suggesting that tumour nutrient stress alone is sufficient to drive T cell dysfunction. We identified phosphoethanolamine (pEtn), a phospholipid intermediate, as a driver of T cell dysfunction. pEtn dampened T cell receptor signalling by depleting T cells of diacylglycerol required for T cell receptor signal transduction. The reduction of pEtn accumulation in tumours improved intratumoural T cell function and tumour control, suggesting that pEtn accumulation plays a dominant role in immunosuppression in the tumour microenvironment.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"37 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Metabolites in tumour interstitial fluid directly suppress T cells 肿瘤间质液中的代谢物直接抑制T细胞

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-04-21 DOI: 10.1038/s41556-025-01652-7

引用次数: 0

Author Correction: Combinatorial selective ER-phagy remodels the ER during neurogenesis 作者更正：组合选择性ER吞噬重塑了神经发生过程中的ER

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-04-15 DOI: 10.1038/s41556-025-01670-5

Melissa J. Hoyer, Cristina Capitanio, Ian R. Smith, Julia C. Paoli, Anna Bieber, Yizhi Jiang, Joao A. Paulo, Miguel A. Gonzalez-Lozano, Wolfgang Baumeister, Florian Wilfling, Brenda A. Schulman, J. Wade Harper

引用次数: 0

Targeting a key disulfide linkage to regulate RIG-I condensation and cytosolic RNA-sensing 靶向关键二硫键调节rig - 1缩合和胞质rna传感

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-04-14 DOI: 10.1038/s41556-025-01646-5

Bin Wang, Yongqiang Wang, Ting Pan, Lili Zhou, Yu Ran, Jing Zou, Xiaohua Yan, Zhenke Wen, Shixian Lin, Aiming Ren, Fangwei Wang, Zhuang Liu, Ting Liu, Huasong Lu, Bing Yang, Fangfang Zhou, Long Zhang

{"title":"Targeting a key disulfide linkage to regulate RIG-I condensation and cytosolic RNA-sensing","authors":"Bin Wang, Yongqiang Wang, Ting Pan, Lili Zhou, Yu Ran, Jing Zou, Xiaohua Yan, Zhenke Wen, Shixian Lin, Aiming Ren, Fangwei Wang, Zhuang Liu, Ting Liu, Huasong Lu, Bing Yang, Fangfang Zhou, Long Zhang","doi":"10.1038/s41556-025-01646-5","DOIUrl":"https://doi.org/10.1038/s41556-025-01646-5","url":null,"abstract":"Maintaining innate immune homeostasis is critical for preventing infections and autoimmune diseases but effective interventions are lacking. Here we identified C864–C869-mediated intermolecular disulfide-linkage formation as a critical step for human RIG-I activation that can be bidirectionally regulated to control innate immune homeostasis. The viral-stimulated C864–C869 disulfide linkage mediates conjugation of an SDS-resistant RIG-I oligomer, which prevents RIG-I degradation by E3 ubiquitin-ligase MIB2 and is necessary for RIG-I to perform liquid–liquid phase separation to compartmentalize downstream signalsome, thereby stimulating type I interferon signalling. The corresponding C865S ‘knock-in’ caused an oligomerization defect and liquid–liquid phase separation in mouse RIG-I, which inhibited innate immunity, resulting in increased viral load and mortality in mice. Using unnatural amino acids to generate covalent C864–C869 linkage and the development of an interfering peptide to block C864–C869 residues, we bidirectionally regulated RIG-I activities in human diseases. These findings provide in-depth insights on mechanism of RIG-I activation, allowing for the development of methodologies that hold promising implications in clinics.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"239 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Timing is everything 时机决定一切

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-04-11 DOI: 10.1038/s41556-025-01659-0

Angela R. Parrish

引用次数: 0

Peripheral neural stem cells from the neural tube contribute to multi-organ neurogenesis 来自神经管的外周神经干细胞有助于多器官神经发生

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-04-11 DOI: 10.1038/s41556-025-01649-2

引用次数: 0