Pub Date : 2025-11-28DOI: 10.1038/s41556-025-01809-4
Ruofei Li, Yingying Li, Su Wu, Zhifen Zhou, Xinyu Hou, Ping Yang, Jun Zhu, Ying Xia, Wenchao Wu, Ran Feng, Qiuyuan Gao, Kunling Huang, Yi Liu, Jianfei Zheng, Xiaoqin Zhong, Hui Huang, Cheng Chang, Wenbin Ma, Zhou Songyang, Feng Liu
Nuclear condensates (NCs) are membraneless organelles that enable spatial and functional compartmentalization in the nucleus. Yet, the components and functional co-organization of NCs have been poorly studied. Here, we used PhastID to explore the proximal interactome of 18 NCs in HeLa cells. Our data revealed the organizational flow of gene control among these NCs. Crucially, we developed an algorithm to dissect the intricate internal relations of NCs. This algorithm led to key discoveries: the identification of an uncharacterized BUD13 condensate, and the recognition of specific co-organizations between nuclear gems and Cajal bodies for telomerase maturation, and between nuclear gems and histone locus bodies for histone gene pre-mRNA processing. We also created a global reference map to understand NC dynamics under stresses and how disease-related mutations differentially affect NC interactomes. Overall, our work provides a proximal proteome-based atlas for human NCs, substantially advancing our spatiotemporal understanding of nuclear biological events. Li, Li, Wu et al. use a proteomics approach, PhastID to identify protein components of nuclear condensates (NCs). They reveal crosstalk between NCs, the dynamics of condensate components and identify an NC formed by BUD13.
{"title":"Proximal proteomics reveals a landscape of human nuclear condensates","authors":"Ruofei Li, Yingying Li, Su Wu, Zhifen Zhou, Xinyu Hou, Ping Yang, Jun Zhu, Ying Xia, Wenchao Wu, Ran Feng, Qiuyuan Gao, Kunling Huang, Yi Liu, Jianfei Zheng, Xiaoqin Zhong, Hui Huang, Cheng Chang, Wenbin Ma, Zhou Songyang, Feng Liu","doi":"10.1038/s41556-025-01809-4","DOIUrl":"10.1038/s41556-025-01809-4","url":null,"abstract":"Nuclear condensates (NCs) are membraneless organelles that enable spatial and functional compartmentalization in the nucleus. Yet, the components and functional co-organization of NCs have been poorly studied. Here, we used PhastID to explore the proximal interactome of 18 NCs in HeLa cells. Our data revealed the organizational flow of gene control among these NCs. Crucially, we developed an algorithm to dissect the intricate internal relations of NCs. This algorithm led to key discoveries: the identification of an uncharacterized BUD13 condensate, and the recognition of specific co-organizations between nuclear gems and Cajal bodies for telomerase maturation, and between nuclear gems and histone locus bodies for histone gene pre-mRNA processing. We also created a global reference map to understand NC dynamics under stresses and how disease-related mutations differentially affect NC interactomes. Overall, our work provides a proximal proteome-based atlas for human NCs, substantially advancing our spatiotemporal understanding of nuclear biological events. Li, Li, Wu et al. use a proteomics approach, PhastID to identify protein components of nuclear condensates (NCs). They reveal crosstalk between NCs, the dynamics of condensate components and identify an NC formed by BUD13.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2198-2213"},"PeriodicalIF":19.1,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145611569","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}
Pub Date : 2025-11-27DOI: 10.1038/s41556-025-01821-8
Isabella M. Alves, Christina Marie Termini
Haematopoietic stem cells (HSCs) are used in a variety of cellular therapies, but our ability to support these cells ex vivo remains technically challenging. A new study discovers that inhibiting ferroptosis promotes HSC expansion ex vivo and applies these findings to HSC transplant and gene editing approaches.
{"title":"Blocking ferroptosis to expand human HSCs","authors":"Isabella M. Alves, Christina Marie Termini","doi":"10.1038/s41556-025-01821-8","DOIUrl":"10.1038/s41556-025-01821-8","url":null,"abstract":"Haematopoietic stem cells (HSCs) are used in a variety of cellular therapies, but our ability to support these cells ex vivo remains technically challenging. A new study discovers that inhibiting ferroptosis promotes HSC expansion ex vivo and applies these findings to HSC transplant and gene editing approaches.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2041-2042"},"PeriodicalIF":19.1,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609478","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}
Pub Date : 2025-11-26DOI: 10.1038/s41556-025-01811-w
Musu Yuan, Kaitian Jin, Hanying Yan, Amelia Schroeder, Chunyu Luo, Sicong Yao, Bernhard Dumoulin, Jonathan Levinsohn, Tianhao Luo, Jean R. Clemenceau, Inyeop Jang, Minji Kim, Yunhe Liu, Minghua Deng, Emma E. Furth, Parker Wilson, Anupma Nayak, Idania Lubo, Luisa Maren Solis Soto, Linghua Wang, Jeong Hwan Park, Katalin Susztak, Tae Hyun Hwang, Mingyao Li
Spatial omics technologies have transformed biomedical research by enabling high-resolution molecular profiling while preserving the native tissue architecture. These advances provide unprecedented insights into tissue structure and function. However, the high cost and time-intensive nature of spatial omics experiments necessitate careful experimental design, particularly in selecting regions of interest (ROIs) from large tissue sections. Currently, ROI selection is performed manually, which introduces subjectivity, inconsistency and a lack of reproducibility. Previous studies have shown strong correlations between spatial molecular patterns and histological features, suggesting that readily available and cost-effective histology images can be leveraged to guide spatial omics experiments. Here we present Smart Spatial omics (S2-omics), an end-to-end workflow that automatically selects ROIs from histology images with the goal of maximizing molecular information content in the ROIs. Through comprehensive evaluations across multiple spatial omics platforms and tissue types, we demonstrate that S2-omics enables systematic and reproducible ROI selection and enhances the robustness and impact of downstream biological discovery. Yuan et al. present S2-omics, an end-to-end workflow that automatically identifies regions of interest in histology images to maximize molecular information capture in spatial omics experiments.
{"title":"Smart spatial omics (S2-omics) optimizes region of interest selection to capture molecular heterogeneity in diverse tissues","authors":"Musu Yuan, Kaitian Jin, Hanying Yan, Amelia Schroeder, Chunyu Luo, Sicong Yao, Bernhard Dumoulin, Jonathan Levinsohn, Tianhao Luo, Jean R. Clemenceau, Inyeop Jang, Minji Kim, Yunhe Liu, Minghua Deng, Emma E. Furth, Parker Wilson, Anupma Nayak, Idania Lubo, Luisa Maren Solis Soto, Linghua Wang, Jeong Hwan Park, Katalin Susztak, Tae Hyun Hwang, Mingyao Li","doi":"10.1038/s41556-025-01811-w","DOIUrl":"10.1038/s41556-025-01811-w","url":null,"abstract":"Spatial omics technologies have transformed biomedical research by enabling high-resolution molecular profiling while preserving the native tissue architecture. These advances provide unprecedented insights into tissue structure and function. However, the high cost and time-intensive nature of spatial omics experiments necessitate careful experimental design, particularly in selecting regions of interest (ROIs) from large tissue sections. Currently, ROI selection is performed manually, which introduces subjectivity, inconsistency and a lack of reproducibility. Previous studies have shown strong correlations between spatial molecular patterns and histological features, suggesting that readily available and cost-effective histology images can be leveraged to guide spatial omics experiments. Here we present Smart Spatial omics (S2-omics), an end-to-end workflow that automatically selects ROIs from histology images with the goal of maximizing molecular information content in the ROIs. Through comprehensive evaluations across multiple spatial omics platforms and tissue types, we demonstrate that S2-omics enables systematic and reproducible ROI selection and enhances the robustness and impact of downstream biological discovery. Yuan et al. present S2-omics, an end-to-end workflow that automatically identifies regions of interest in histology images to maximize molecular information capture in spatial omics experiments.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2225-2238"},"PeriodicalIF":19.1,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01811-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1038/s41556-025-01804-9
Alberto Minetti, Omid Omrani, Christiane Brenner, Feyza Cansiz, Shinya Imada, Jonas Rösler, Saleh Khawaled, Gabriele Allies, Sven W. Meckelmann, Nadja Gebert, Ivonne Heinze, Norman Rahnis, Jing Lu, Katrin Spengler, Mahdi Rasa, Emilio Cirri, Regine Heller, Ömer Yilmaz, Alpaslan Tasdogan, Francesco Neri, Alessandro Ori
Ageing dampens the regenerative potential of intestinal epithelium across species including humans, yet the underlying causes remain elusive. Here we characterized the temporal dynamics of regeneration following injury induced by 5-fluorouracil, a commonly used chemotherapeutic agent, using proteomic and metabolomic profiling of intestinal tissues together with functional assays. The comparison of regeneration dynamics in mice of different ages revealed the emergence of proteostasis stress and increased levels of polyamines following injury exclusively in old epithelia. We show that delayed regeneration is an intrinsic feature of aged epithelial cells that display reduced protein synthesis and the accumulation of ubiquitylated proteins. The inhibition of the polyamine pathway in vivo further delays regeneration in old mice, whereas its activation by dietary intervention or supplementation of polyamines is sufficient to enhance the regenerative capacity of aged intestines. Our findings highlight the promising epithelial targets for interventions aimed at tackling the decline in tissue repair mechanisms associated with ageing. Minetti, Omrani et al. report that delayed intestinal regeneration results from protein homeostasis stress and can be improved by modulation of the polyamine pathway dynamics.
{"title":"Polyamines sustain epithelial regeneration in aged intestines by modulating protein homeostasis","authors":"Alberto Minetti, Omid Omrani, Christiane Brenner, Feyza Cansiz, Shinya Imada, Jonas Rösler, Saleh Khawaled, Gabriele Allies, Sven W. Meckelmann, Nadja Gebert, Ivonne Heinze, Norman Rahnis, Jing Lu, Katrin Spengler, Mahdi Rasa, Emilio Cirri, Regine Heller, Ömer Yilmaz, Alpaslan Tasdogan, Francesco Neri, Alessandro Ori","doi":"10.1038/s41556-025-01804-9","DOIUrl":"10.1038/s41556-025-01804-9","url":null,"abstract":"Ageing dampens the regenerative potential of intestinal epithelium across species including humans, yet the underlying causes remain elusive. Here we characterized the temporal dynamics of regeneration following injury induced by 5-fluorouracil, a commonly used chemotherapeutic agent, using proteomic and metabolomic profiling of intestinal tissues together with functional assays. The comparison of regeneration dynamics in mice of different ages revealed the emergence of proteostasis stress and increased levels of polyamines following injury exclusively in old epithelia. We show that delayed regeneration is an intrinsic feature of aged epithelial cells that display reduced protein synthesis and the accumulation of ubiquitylated proteins. The inhibition of the polyamine pathway in vivo further delays regeneration in old mice, whereas its activation by dietary intervention or supplementation of polyamines is sufficient to enhance the regenerative capacity of aged intestines. Our findings highlight the promising epithelial targets for interventions aimed at tackling the decline in tissue repair mechanisms associated with ageing. Minetti, Omrani et al. report that delayed intestinal regeneration results from protein homeostasis stress and can be improved by modulation of the polyamine pathway dynamics.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2063-2077"},"PeriodicalIF":19.1,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01804-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1038/s41556-025-01806-7
Srivarsha Rajshekar, Omar Adame-Arana, Gaurav Bajpai, Serafin U. Colmenares, Hannah Papoi, Lucy D. Brennan, Shingo Tsukamoto, Samuel Safran, Gary H. Karpen
Nucleoli are surrounded by pericentromeric heterochromatin (PCH), reflecting a conserved spatial association between the two largest biomolecular condensates in eukaryotic nuclei. Nucleoli are the sites of ribosome synthesis, whereas the repeat-rich PCH is essential for chromosome segregation, genome stability and transcriptional silencing, yet the mechanisms for their co-assembly are unclear. Here we use high-resolution live imaging during Drosophila embryogenesis and reveal that de novo establishment of PCH–nucleolar associations is highly dynamic, as PCH transitions from extending along the nuclear edge to surrounding the nucleolus. Elimination of the nucleolus by removing the ribosomal RNA genes disrupted this process causing increased PCH compaction, followed by its reorganization into a toroidal structure. Furthermore, in embryos lacking ribosomal RNA genes, nucleolar proteins were redistributed into new bodies or ‘neocondensates’, including enrichment in the PCH toroidal hole. Combining these in vivo observations with molecular dynamics simulations based on multiphase wetting theory revealed that nucleolar–PCH associations can be mediated by a hierarchy of interaction strengths between PCH, nucleoli and proteins with dual affinities for both compartments. We validate this model by identifying such a protein, a DEAD-box RNA helicase called Pitchoune, and show that modulation of its affinity for either nucleolar or PCH components alters nucleolar–PCH organization. Together, this study unveils a dynamic programme for establishing nucleolar–PCH associations during animal development and demonstrates how interaction hierarchies and dual-affinity molecular linkers co-organize compositionally distinct condensates. Rajshekar et al. show that a hierarchy of affinities layers pericentromeric heterochromatin around nucleoli, with the RNA helicase Pitchoune (DDX18) acting as a key dual-affinity linker in Drosophila melanogaster.
{"title":"Hierarchical interactions between nucleolar and heterochromatin condensates are mediated by a dual-affinity protein","authors":"Srivarsha Rajshekar, Omar Adame-Arana, Gaurav Bajpai, Serafin U. Colmenares, Hannah Papoi, Lucy D. Brennan, Shingo Tsukamoto, Samuel Safran, Gary H. Karpen","doi":"10.1038/s41556-025-01806-7","DOIUrl":"10.1038/s41556-025-01806-7","url":null,"abstract":"Nucleoli are surrounded by pericentromeric heterochromatin (PCH), reflecting a conserved spatial association between the two largest biomolecular condensates in eukaryotic nuclei. Nucleoli are the sites of ribosome synthesis, whereas the repeat-rich PCH is essential for chromosome segregation, genome stability and transcriptional silencing, yet the mechanisms for their co-assembly are unclear. Here we use high-resolution live imaging during Drosophila embryogenesis and reveal that de novo establishment of PCH–nucleolar associations is highly dynamic, as PCH transitions from extending along the nuclear edge to surrounding the nucleolus. Elimination of the nucleolus by removing the ribosomal RNA genes disrupted this process causing increased PCH compaction, followed by its reorganization into a toroidal structure. Furthermore, in embryos lacking ribosomal RNA genes, nucleolar proteins were redistributed into new bodies or ‘neocondensates’, including enrichment in the PCH toroidal hole. Combining these in vivo observations with molecular dynamics simulations based on multiphase wetting theory revealed that nucleolar–PCH associations can be mediated by a hierarchy of interaction strengths between PCH, nucleoli and proteins with dual affinities for both compartments. We validate this model by identifying such a protein, a DEAD-box RNA helicase called Pitchoune, and show that modulation of its affinity for either nucleolar or PCH components alters nucleolar–PCH organization. Together, this study unveils a dynamic programme for establishing nucleolar–PCH associations during animal development and demonstrates how interaction hierarchies and dual-affinity molecular linkers co-organize compositionally distinct condensates. Rajshekar et al. show that a hierarchy of affinities layers pericentromeric heterochromatin around nucleoli, with the RNA helicase Pitchoune (DDX18) acting as a key dual-affinity linker in Drosophila melanogaster.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2102-2115"},"PeriodicalIF":19.1,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01806-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-21DOI: 10.1038/s41556-025-01808-5
Guanghui Xu, Yuhan Chen, Laura M. Martins, En Li, Fuxi Wang, Tulio Magana, Junlin Ruan, Julie A. Law
DNA methylation is maintained by forming self-reinforcing connections with other repressive chromatin modifications, resulting in stably silenced genes and transposons. However, these mechanisms fail to explain how new methylation patterns are generated. In Arabidopsis, CLASSY3 targets the RNA-directed DNA methylation machinery to different loci in reproductive tissues, generating distinct epigenomes via unknown mechanism(s). Here we discovered that several different REPRODUCTIVE MERISTEM (REM) transcription factors are required for methylation at CLASSY3 targets specific to anther or ovule tissues. We designate these factors as REM INSTRUCTS METHYLATION (RIMs) and demonstrate that disruption of their DNA-binding domains, or the motifs they recognize, blocks RNA-directed DNA methylation. Furthermore, we demonstrate that mis-expression of RIM12 is sufficient to initiate siRNA production at ovule targets in anthers. These findings reveal a critical role for genetic information in targeting DNA methylation in reproductive tissues, expanding our understanding of how methylation is regulated to include inputs from both genetic and epigenetic information. Xu et al. identify REPRODUCTIVE MERISTEM transcription factors that are required for RNA-directed DNA methylation at CLASSY3 target loci in male and female reproductive tissues of Arabidopsis.
{"title":"Transcription factors instruct DNA methylation patterns in plant reproductive tissues","authors":"Guanghui Xu, Yuhan Chen, Laura M. Martins, En Li, Fuxi Wang, Tulio Magana, Junlin Ruan, Julie A. Law","doi":"10.1038/s41556-025-01808-5","DOIUrl":"10.1038/s41556-025-01808-5","url":null,"abstract":"DNA methylation is maintained by forming self-reinforcing connections with other repressive chromatin modifications, resulting in stably silenced genes and transposons. However, these mechanisms fail to explain how new methylation patterns are generated. In Arabidopsis, CLASSY3 targets the RNA-directed DNA methylation machinery to different loci in reproductive tissues, generating distinct epigenomes via unknown mechanism(s). Here we discovered that several different REPRODUCTIVE MERISTEM (REM) transcription factors are required for methylation at CLASSY3 targets specific to anther or ovule tissues. We designate these factors as REM INSTRUCTS METHYLATION (RIMs) and demonstrate that disruption of their DNA-binding domains, or the motifs they recognize, blocks RNA-directed DNA methylation. Furthermore, we demonstrate that mis-expression of RIM12 is sufficient to initiate siRNA production at ovule targets in anthers. These findings reveal a critical role for genetic information in targeting DNA methylation in reproductive tissues, expanding our understanding of how methylation is regulated to include inputs from both genetic and epigenetic information. Xu et al. identify REPRODUCTIVE MERISTEM transcription factors that are required for RNA-directed DNA methylation at CLASSY3 target loci in male and female reproductive tissues of Arabidopsis.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2116-2127"},"PeriodicalIF":19.1,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01808-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-18DOI: 10.1038/s41556-025-01814-7
Lucrezia della Volpe, Andrew J. Lee, Mateusz Antoszewski, Amy A. Deik, Ksenia R. Safina, Teng Gao, Chun-Jie Guo, Tianyi Ye, Peng Lyu, Jorge D. Martin-Rufino, Nicole Castano, Jonathan Good, Yaniris Molina-Aponte, Jiawei Zhao, Clary B. Clish, Peter van Galen, Vijay G. Sankaran
Improved ex vivo expansion of human haematopoietic stem cells (HSCs) would considerably advance transplantation and genome-engineered therapies, yet existing culture methods still allow substantial HSC loss. Here we show that this attrition is driven largely by ferroptosis, a metabolically regulated, iron-dependent cell-death pathway, and that it can be blocked to augment HSC expansion. Inhibiting ferroptosis with liproxstatin-1 or ferrostatin-1 markedly increases the expansion of cord blood and adult HSCs consistently across donors in both widely used serum-free cultures and recently reported chemically defined conditions. The expanded cells retain phenotypic and molecular stem cell identity and mediate improved durable, multilineage engraftment in xenotransplanted mice without genotoxicity or aberrant haematopoiesis. Mechanistically, ferroptosis blockade is accompanied by upregulated ribosome biogenesis and cholesterol synthesis, increasing levels of 7-dehydrocholesterol—a potent endogenous ferroptosis inhibitor that itself promotes HSC expansion. Crucially, this approach enhances yields of therapeutically genome-modified HSCs, paving a path for clinical applications. della Volpe et al. augment the ex vivo expansion potential of human haematopoietic stem cells (HSCs) by inhibiting ferroptosis with liproxstatin-1 or ferrostatin-1. Treated HSCs have enhanced in vivo repopulation capacity.
{"title":"Inhibiting ferroptosis enhances ex vivo expansion of human haematopoietic stem cells","authors":"Lucrezia della Volpe, Andrew J. Lee, Mateusz Antoszewski, Amy A. Deik, Ksenia R. Safina, Teng Gao, Chun-Jie Guo, Tianyi Ye, Peng Lyu, Jorge D. Martin-Rufino, Nicole Castano, Jonathan Good, Yaniris Molina-Aponte, Jiawei Zhao, Clary B. Clish, Peter van Galen, Vijay G. Sankaran","doi":"10.1038/s41556-025-01814-7","DOIUrl":"10.1038/s41556-025-01814-7","url":null,"abstract":"Improved ex vivo expansion of human haematopoietic stem cells (HSCs) would considerably advance transplantation and genome-engineered therapies, yet existing culture methods still allow substantial HSC loss. Here we show that this attrition is driven largely by ferroptosis, a metabolically regulated, iron-dependent cell-death pathway, and that it can be blocked to augment HSC expansion. Inhibiting ferroptosis with liproxstatin-1 or ferrostatin-1 markedly increases the expansion of cord blood and adult HSCs consistently across donors in both widely used serum-free cultures and recently reported chemically defined conditions. The expanded cells retain phenotypic and molecular stem cell identity and mediate improved durable, multilineage engraftment in xenotransplanted mice without genotoxicity or aberrant haematopoiesis. Mechanistically, ferroptosis blockade is accompanied by upregulated ribosome biogenesis and cholesterol synthesis, increasing levels of 7-dehydrocholesterol—a potent endogenous ferroptosis inhibitor that itself promotes HSC expansion. Crucially, this approach enhances yields of therapeutically genome-modified HSCs, paving a path for clinical applications. della Volpe et al. augment the ex vivo expansion potential of human haematopoietic stem cells (HSCs) by inhibiting ferroptosis with liproxstatin-1 or ferrostatin-1. Treated HSCs have enhanced in vivo repopulation capacity.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2214-2224"},"PeriodicalIF":19.1,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01814-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-17DOI: 10.1038/s41556-025-01810-x
August F. Williams, David A. G. Gervasio, Claire E. Turkal, Anna E. Stuhlfire, Michael X. Wang, Brandon E. Mauch, Rhea Plawat, Ariel H. Nguyen, Michelle H. Paw, Mehrshad Hairani, Cooper P. Lathrop, Sophie H. Harris, Jennifer L. Page, Matthew J. Hangauer
Oncogene-targeted cancer therapies can provide deep responses but frequently suffer from acquired resistance. Therapeutic approaches to treat tumours that have acquired drug resistance are complicated by continual tumour evolution and multiple co-occurring resistance mechanisms. Rather than treating resistance after it emerges, it may be possible to prevent it by inhibiting the adaptive processes that initiate resistance, but these are poorly understood. Here we report that residual cancer persister cells that survive oncogene-targeted therapy are growth arrested by drug stress-induced intrinsic type I interferon signalling. To escape growth arrest, persister cells leverage apoptotic machinery to transcriptionally suppress interferon-stimulated genes (ISGs). Mechanistically, persister cells sublethally engage apoptotic caspases to activate DNA endonuclease DNA fragmentation factor B (also known as caspase-activated DNase), which induces DNA damage, mutagenesis and stress response factor activating transcription factor 3 (ATF3). ATF3 limits activator protein 1-mediated ISG expression sufficiently to allow persister cell regrowth. Persister cells deficient in DNA fragmentation factor B or ATF3 exhibit high ISG expression and are consequently unable to regrow. Therefore, sublethal apoptotic stress paradoxically promotes the regrowth of residual cancer cells that survive drug treatment. Williams et al. report a growth arrest mechanism in residual cancer persister cells through targeted therapy-induced upregulation of type I interferon signalling, which is negatively regulated by apoptotic DNA endonuclease DFFB to allow tumour relapse.
{"title":"DNA fragmentation factor B suppresses interferon to enable cancer persister cell regrowth","authors":"August F. Williams, David A. G. Gervasio, Claire E. Turkal, Anna E. Stuhlfire, Michael X. Wang, Brandon E. Mauch, Rhea Plawat, Ariel H. Nguyen, Michelle H. Paw, Mehrshad Hairani, Cooper P. Lathrop, Sophie H. Harris, Jennifer L. Page, Matthew J. Hangauer","doi":"10.1038/s41556-025-01810-x","DOIUrl":"10.1038/s41556-025-01810-x","url":null,"abstract":"Oncogene-targeted cancer therapies can provide deep responses but frequently suffer from acquired resistance. Therapeutic approaches to treat tumours that have acquired drug resistance are complicated by continual tumour evolution and multiple co-occurring resistance mechanisms. Rather than treating resistance after it emerges, it may be possible to prevent it by inhibiting the adaptive processes that initiate resistance, but these are poorly understood. Here we report that residual cancer persister cells that survive oncogene-targeted therapy are growth arrested by drug stress-induced intrinsic type I interferon signalling. To escape growth arrest, persister cells leverage apoptotic machinery to transcriptionally suppress interferon-stimulated genes (ISGs). Mechanistically, persister cells sublethally engage apoptotic caspases to activate DNA endonuclease DNA fragmentation factor B (also known as caspase-activated DNase), which induces DNA damage, mutagenesis and stress response factor activating transcription factor 3 (ATF3). ATF3 limits activator protein 1-mediated ISG expression sufficiently to allow persister cell regrowth. Persister cells deficient in DNA fragmentation factor B or ATF3 exhibit high ISG expression and are consequently unable to regrow. Therefore, sublethal apoptotic stress paradoxically promotes the regrowth of residual cancer cells that survive drug treatment. Williams et al. report a growth arrest mechanism in residual cancer persister cells through targeted therapy-induced upregulation of type I interferon signalling, which is negatively regulated by apoptotic DNA endonuclease DFFB to allow tumour relapse.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2143-2151"},"PeriodicalIF":19.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01810-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-17DOI: 10.1038/s41556-025-01836-1
Dario F. De Jesus, Zijie Zhang, Natalie K. Brown, Xiaolu Li, Ling Xiao, Jiang Hu, Matthew J. Gaffrey, Garrett Fogarty, Sevim Kahraman, Jiangbo Wei, Giorgio Basile, Tariq M. Rana, Clayton Mathews, Alvin C. Powers, Audrey V. Parent, Mark A. Atkinson, Sirano Dhe-Paganon, Decio L. Eizirik, Wei-Jun Qian, Chuan He, Rohit N. Kulkarni
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