{"title":"Mettl3-m<sup>6</sup>A-NPY axis governing neuron-microglia interaction regulates sleep amount of mice.","authors":"Qihang Sun, Jinpiao Zhu, Xingsen Zhao, Xiaoli Huang, Wenzheng Qu, Xia Tang, Daqing Ma, Qiang Shu, Xuekun Li","doi":"10.1038/s41421-024-00756-y","DOIUrl":"10.1038/s41421-024-00756-y","url":null,"abstract":"<p><p>Sleep behavior is regulated by diverse mechanisms including genetics, neuromodulation and environmental signals. However, it remains completely unknown regarding the roles of epitranscriptomics in regulating sleep behavior. In the present study, we showed that the deficiency of RNA m<sup>6</sup>A methyltransferase Mettl3 in excitatory neurons specifically induces microglia activation, neuroinflammation and neuronal loss in thalamus of mice. Mettl3 deficiency remarkably disrupts sleep rhythm and reduces the amount of non-rapid eye movement sleep. We also showed that Mettl3 regulates neuropeptide Y (NPY) via m<sup>6</sup>A modification and Mettl3 conditional knockout (cKO) mice displayed significantly decreased expression of NPY in thalamus. In addition, the dynamic distribution pattern of NPY is observed during wake-sleep cycle in cKO mice. Ectopic expression of Mettl3 and NPY significantly inhibits microglia activation and neuronal loss in thalamus, and restores the disrupted sleep behavior of cKO mice. Collectively, our study has revealed the critical function of Mettl3-m<sup>6</sup>A-NPY axis in regulating sleep behavior.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"10"},"PeriodicalIF":13.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188435","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}
{"title":"Stromal architecture and fibroblast subpopulations with opposing effects on outcomes in hepatocellular carcinoma.","authors":"Yifei Cheng, Xiaofang Chen, Li Feng, Zhicheng Yang, Liyun Xiao, Bin Xiang, Xiaodong Wang, Dongbin Liu, Penghui Lin, Jieyi Shi, Guohe Song, Wulei Qian, Boan Zhang, Yanan Xu, Zheng Gao, Lv Chen, Yingcheng Wu, Jiaqiang Ma, Youpei Lin, Haichao Zhao, Lihua Peng, Xuebin Mao, Yang Liu, Hao Hou, Mingyu Yang, Yuan Ji, Xiaoying Wang, Jian Zhou, Xun Xu, Xiyang Liu, Wu Wei, Xiaoming Zhang, Qiang Gao, Hu Zhou, Yidi Sun, Kui Wu, Jia Fan","doi":"10.1038/s41421-024-00747-z","DOIUrl":"10.1038/s41421-024-00747-z","url":null,"abstract":"<p><p>Dissecting the spatial heterogeneity of cancer-associated fibroblasts (CAFs) is vital for understanding tumor biology and therapeutic design. By combining pathological image analysis with spatial proteomics, we revealed two stromal archetypes in hepatocellular carcinoma (HCC) with different biological functions and extracellular matrix compositions. Using paired single-cell RNA and epigenomic sequencing with Stereo-seq, we revealed two fibroblast subsets CAF-FAP and CAF-C7, whose spatial enrichment strongly correlated with the two stromal archetypes and opposing patient prognosis. We discovered two functional units, one is the intratumor inflammatory hub featured by CAF-FAP plus CD8_PDCD1 proximity and the other is the marginal wound-healing hub with CAF-C7 plus Macrophage_SPP1 co-localization. Inhibiting CAF-FAP combined with anti-PD-1 in orthotopic HCC models led to improved tumor regression than either monotherapy. Collectively, our findings suggest stroma-targeted strategies for HCC based on defined stromal archetypes, raising the concept that CAFs change their transcriptional program and intercellular crosstalk according to the spatial context.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"1"},"PeriodicalIF":13.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051809","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}
Cell DiscoveryPub Date : 2025-01-28DOI: 10.1038/s41421-024-00760-2
Guixian Liang, Shicheng Liu, Chunyu Zhou, Mengyao Liu, Yifan Zhang, Dongyuan Ma, Lu Wang, Jing-Dong J Han, Feng Liu
{"title":"Conversion of placental hemogenic endothelial cells to hematopoietic stem and progenitor cells.","authors":"Guixian Liang, Shicheng Liu, Chunyu Zhou, Mengyao Liu, Yifan Zhang, Dongyuan Ma, Lu Wang, Jing-Dong J Han, Feng Liu","doi":"10.1038/s41421-024-00760-2","DOIUrl":"10.1038/s41421-024-00760-2","url":null,"abstract":"<p><p>Hematopoietic stem and progenitor cells (HSPCs) are critical for the treatment of blood diseases in clinic. However, the limited source of HSPCs severely hinders their clinical application. In the embryo, hematopoietic stem cells (HSCs) arise from hemogenic endothelial (HE) cells lining the major arteries in vivo. In this work, by engineering vascular niche endothelial cells (VN-ECs), we generated functional HSPCs in vitro from ECs at various sites, including the aorta-gonad-mesonephros (AGM) region and the placenta. Firstly, we converted mouse embryonic HE cells from the AGM region (aHE) into induced HSPCs (iHSPCs), which have the abilities for multilineage differentiation and self-renewal. Mechanistically, we found that VN-ECs can promote the generation of iHSPCs via secretion of CX3CL1 and IL1A. Next, through VN-EC co-culture, we showed that placental HE (pHE) cells, a type of extra-embryonic HE cells, were successfully converted into iHSPCs (pHE-iHSPCs), which have multilineage differentiation capacity, but exhibit limited self-renewal ability. Furthermore, comparative transcriptome analysis of aHE-iHSPCs and pHE-iHSPCs showed that aHE-iHSPCs highly expressed HSC-specific and self-renewal-related genes. Moreover, experimental validation showed that retinoic acid (RA) treatment promoted the transformation of pHE cells into iHSPCs that have self-renewal ability. Collectively, our results suggested that pHE cells possess the potential to transform into self-renewing iHSPCs through RA treatment, which will facilitate the clinical application of placental endothelial cells in hematopoietic cell generation.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"9"},"PeriodicalIF":13.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058317","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}
Cell DiscoveryPub Date : 2025-01-21DOI: 10.1038/s41421-024-00750-4
Jie Ruan, Xuxia Wei, Suizhi Li, Zijian Ye, Linyi Hu, Ru Zhuang, Yange Cao, Shaozhou Wang, Shengpeng Wu, Dezhi Peng, Shangwu Chen, Shaochun Yuan, Anlong Xu
{"title":"Apaf-1 is an evolutionarily conserved DNA sensor that switches the cell fate between apoptosis and inflammation.","authors":"Jie Ruan, Xuxia Wei, Suizhi Li, Zijian Ye, Linyi Hu, Ru Zhuang, Yange Cao, Shaozhou Wang, Shengpeng Wu, Dezhi Peng, Shangwu Chen, Shaochun Yuan, Anlong Xu","doi":"10.1038/s41421-024-00750-4","DOIUrl":"10.1038/s41421-024-00750-4","url":null,"abstract":"<p><p>Apoptotic protease activating factor 1 (Apaf-1) was traditionally defined as a scaffold protein in mammalian cells for assembling a caspase activation platform known as the 'apoptosome' after its binding to cytochrome c. Although Apaf-1 structurally resembles animal NOD-like receptor (NLR) and plant resistance (R) proteins, whether it is directly involved in innate immunity is still largely unknown. Here, we found that Apaf-1-like molecules from lancelets, fruit flies, mice, and humans have conserved DNA sensing functionality. Mechanistically, mammalian Apaf-1 recruits receptor-interacting protein 2 (RIP2, also known as RIPK2) via its WD40 repeat domain and promotes RIP2 oligomerization to initiate NF-κB-driven inflammation upon cytoplasmic DNA recognition. Furthermore, DNA binding of Apaf-1 determines cell fate by switching the cellular processes between intrinsic stimuli-activated apoptosis and inflammation. These findings suggest that Apaf-1 is an evolutionarily conserved DNA sensor and may serve as a cell fate checkpoint, which determines whether cells initiate inflammation or undergo apoptosis by distinct ligand binding.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"4"},"PeriodicalIF":13.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000773","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}
Cell DiscoveryPub Date : 2025-01-21DOI: 10.1038/s41421-025-00770-8
Honggui Wu, Maoxu Wang, Yinghui Zheng, X Sunney Xie
{"title":"Droplet-based high-throughput 3D genome structure mapping of single cells with simultaneous transcriptomics.","authors":"Honggui Wu, Maoxu Wang, Yinghui Zheng, X Sunney Xie","doi":"10.1038/s41421-025-00770-8","DOIUrl":"10.1038/s41421-025-00770-8","url":null,"abstract":"<p><p>Single-cell three-dimensional (3D) genome techniques have advanced our understanding of cell-type-specific chromatin structures in complex tissues, yet current methodologies are limited in cell throughput. Here we introduce a high-throughput single-cell Hi-C (dscHi-C) approach and its transcriptome co-assay (dscHi-C-multiome) using droplet microfluidics. Using dscHi-C, we investigate chromatin structural changes during mouse brain aging by profiling 32,777 single cells across three developmental stages (3 months, 12 months, and 23 months), yielding a median of 78,220 unique contacts. Our results show that genes with significant structural changes are enriched in pathways related to metabolic process and morphology change in neurons, and innate immune response in glial cells, highlighting the role of 3D genome organization in physiological brain aging. Furthermore, our multi-omics joint assay, dscHi-C-multiome, enables precise cell type identification in the adult mouse brain and uncovers the intricate relationship between genome architecture and gene expression. Collectively, we developed the sensitive, high-throughput dscHi-C and its multi-omics derivative, dscHi-C-multiome, demonstrating their potential for large-scale cell atlas studies in development and disease.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"8"},"PeriodicalIF":13.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11751028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000779","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}
{"title":"Generation of live mice from haploid ESCs with germline-DMR deletions or switch.","authors":"Yongjian Ma, Meng Yan, Zhenfei Xie, Hongling Zhang, Zhoujie Li, Yuanyuan Li, Suming Yang, Meiling Zhang, Wen Li, Jinsong Li","doi":"10.1038/s41421-024-00757-x","DOIUrl":"10.1038/s41421-024-00757-x","url":null,"abstract":"<p><p>Genomic imprinting is required for sexual reproduction and embryonic development of mammals, in which, differentially methylated regions (DMRs) regulate the parent-specific monoallelic expression of imprinted genes. Numerous studies on imprinted genes have highlighted their critical roles in development. However, what imprinting network is essential for development is still unclear. Here, we establish a stepwise system to reconstruct a development-related imprinting network, in which diploid embryonic stem cells (ESCs) are derived by fusing between parthenogenetic (PG)- and androgenetic (AG)-haploid embryonic stem cells (haESCs) with different DMR deletions (termed Ha-Ha-fusion system), followed by tetraploid complementation to produce all-haESC fetuses. Diploid ESCs fused between PG-haESCs carrying 8 maternally-derived DMR deletions and AG-haESCs with 2 paternally-derived DMR deletions give rise to live pups efficiently, among which, one lives to weaning. Strikingly, diploid ESCs derived from the fusion of PG-haESCs with 7 maternal DMR deletions and AG-haESCs with 2 paternal DMR deletions and maternal Snrpn-DMR deletion also support full-term embryonic development. Moreover, embryos reconstructed by injection of AG-haESCs with hypomethylated H19-DMR into oocytes with H19-DMR deletion develop into live mice sustaining inverted allelic gene expression. Together, our findings indicate that restoration of monoallelic expression of 10 imprinted regions is adequate for the full-term development of all-haESC pups, and it works irrespective of their parental origins. Meanwhile, Ha-Ha-fusion system provides a useful tool for deciphering imprinting regulation networks during embryonic development.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"5"},"PeriodicalIF":13.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747502/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000784","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}
Cell DiscoveryPub Date : 2025-01-10DOI: 10.1038/s41421-024-00738-0
Gema Mondéjar-Parreño, Ana I Moreno-Manuel, Juan Manuel Ruiz-Robles, José Jalife
{"title":"Ion channel traffic jams: the significance of trafficking deficiency in long QT syndrome.","authors":"Gema Mondéjar-Parreño, Ana I Moreno-Manuel, Juan Manuel Ruiz-Robles, José Jalife","doi":"10.1038/s41421-024-00738-0","DOIUrl":"10.1038/s41421-024-00738-0","url":null,"abstract":"<p><p>A well-balanced ion channel trafficking machinery is paramount for the normal electromechanical function of the heart. Ion channel variants and many drugs can alter the cardiac action potential and lead to arrhythmias by interfering with mechanisms like ion channel synthesis, trafficking, gating, permeation, and recycling. A case in point is the Long QT syndrome (LQTS), a highly arrhythmogenic disease characterized by an abnormally prolonged QT interval on ECG produced by variants and drugs that interfere with the action potential. Disruption of ion channel trafficking is one of the main sources of LQTS. We review some molecular pathways and mechanisms involved in cardiac ion channel trafficking. We highlight the importance of channelosomes and other macromolecular complexes in helping to maintain normal cardiac electrical function, and the defects that prolong the QT interval as a consequence of variants or the effect of drugs. We examine the concept of \"interactome mapping\" and illustrate by example the multiple protein-protein interactions an ion channel may undergo throughout its lifetime. We also comment on how mapping the interactomes of the different cardiac ion channels may help advance research into LQTS and other cardiac diseases. Finally, we discuss how using human induced pluripotent stem cell technology to model ion channel trafficking and its defects may help accelerate drug discovery toward preventing life-threatening arrhythmias. Advancements in understanding ion channel trafficking and channelosome complexities are needed to find novel therapeutic targets, predict drug interactions, and enhance the overall management and treatment of LQTS patients.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"3"},"PeriodicalIF":13.0,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11717978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945304","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}
{"title":"Integrated proteogenomic characterization of ampullary adenocarcinoma.","authors":"Qiao Zhang, Xiaomeng Xu, Dongxian Jiang, Yunzhi Wang, Haixing Wang, Jiajun Zhu, Shaoshuai Tang, Ronghua Wang, Shuang Zhao, Kai Li, Jinwen Feng, Hang Xiang, Zhenmei Yao, Ning Xu, Rundong Fang, Wenjia Guo, Yu Liu, Yingyong Hou, Chen Ding","doi":"10.1038/s41421-024-00742-4","DOIUrl":"https://doi.org/10.1038/s41421-024-00742-4","url":null,"abstract":"<p><p>Ampullary adenocarcinoma (AMPAC) is a rare and heterogeneous malignancy. Here we performed a comprehensive proteogenomic analysis of 198 samples from Chinese AMPAC patients and duodenum patients. Genomic data illustrate that 4q loss causes fatty acid accumulation and cell proliferation. Proteomic analysis has revealed three distinct clusters (C-FAM, C-AD, C-CC), among which the most aggressive cluster, C-AD, is associated with the poorest prognosis and is characterized by focal adhesion. Immune clustering identifies three immune clusters and reveals that immune cluster M1 (macrophage infiltration cluster) and M3 (DC cell infiltration cluster), which exhibit a higher immune score compared to cluster M2 (CD4<sup>+</sup> T-cell infiltration cluster), are associated with a poor prognosis due to the potential secretion of IL-6 by tumor cells and its consequential influence. This study provides a comprehensive proteogenomic analysis for seeking for better understanding and potential treatment of AMPAC.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"2"},"PeriodicalIF":13.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11704194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945302","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}