{"title":"A spatiotemporal transcriptomic atlas of mouse placentation.","authors":"Yanting Wu, Kaizhen Su, Ying Zhang, Langchao Liang, Fei Wang, Siyue Chen, Ling Gao, Qiutong Zheng, Cheng Li, Yunfei Su, Yiting Mao, Simeng Zhu, Chaochao Chai, Qing Lan, Man Zhai, Xin Jin, Jinglan Zhang, Xun Xu, Yu Zhang, Ya Gao, Hefeng Huang","doi":"10.1038/s41421-024-00740-6","DOIUrl":"https://doi.org/10.1038/s41421-024-00740-6","url":null,"abstract":"<p><p>The placenta, a temporary but essential organ for gestational support, undergoes intricate morphological and functional transformations throughout gestation. However, the spatiotemporal patterns of gene expression underlying placentation remain poorly understood. Utilizing Stereo-seq, we constructed a Mouse Placentation Spatiotemporal Transcriptomic Atlas (MPSTA) spanning from embryonic day (E) 7.5 to E14.5, which includes the transcriptomes of large trophoblast cells that were not captured in previous single-cell atlases. We defined four distinct strata of the ectoplacental cone, an early heterogeneous trophectoderm structure, and elucidated the spatial trajectory of trophoblast differentiation during early postimplantation stages before E9.5. Focusing on the labyrinth region, the interface of nutrient exchange in the mouse placenta, our spatiotemporal ligand-receptor interaction analysis unveiled pivotal modulators essential for trophoblast development and placental angiogenesis. We also found that paternally expressed genes are exclusively enriched in the placenta rather than in the decidual regions, including a cluster of genes enriched in endothelial cells that may function in placental angiogenesis. At the invasion front, we identified interface-specific transcription factor regulons, such as Atf3, Jun, Junb, Stat6, Mxd1, Maff, Fos, and Irf7, involved in gestational maintenance. Additionally, we revealed that maternal high-fat diet exposure preferentially affects this interface, exacerbating inflammatory responses and disrupting angiogenic homeostasis. Collectively, our findings furnish a comprehensive, spatially resolved atlas that offers valuable insights and benchmarks for future explorations into placental morphogenesis and pathology.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"110"},"PeriodicalIF":13.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11496649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495673","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":"Single-cell spatiotemporal analysis reveals alveolar dendritic cell-T cell immunity hubs defending against pulmonary infection.","authors":"Boyi Cong, Xuan Dong, Zongheng Yang, Pin Yu, Yangyang Chai, Jiaqi Liu, Meihan Zhang, Yupeng Zang, Jingmin Kang, Yu Feng, Yi Liu, Weimin Feng, Dehe Wang, Wei Deng, Fengdi Li, Zhiqi Song, Ziqiao Wang, Xiaosu Chen, Hua Qin, Qinyi Yu, Zhiqing Li, Shuxun Liu, Xun Xu, Nanshan Zhong, Xianwen Ren, Chuan Qin, Longqi Liu, Jian Wang, Xuetao Cao","doi":"10.1038/s41421-024-00733-5","DOIUrl":"10.1038/s41421-024-00733-5","url":null,"abstract":"<p><p>How immune cells are spatiotemporally coordinated in the lung to effectively monitor, respond to, and resolve infection and inflammation in primed form needs to be fully illustrated. Here we apply immunocartography, a high-resolution technique that integrates spatial and single-cell RNA sequencing (scRNA-seq) through deconvolution and co-localization analyses, to the SARS-CoV-2-infected Syrian hamster model. We generate a comprehensive transcriptome map of the whole process of pulmonary infection from physiological condition, infection initiation, severe pneumonia to natural recovery at organ scale and single-cell resolution, with 142,965 cells and 45 lung lobes from 25 hamsters at 5 time points. Integrative analysis identifies that alveolar dendritic cell-T cell immunity hubs, where Ccr7<sup>+</sup>Ido1<sup>+</sup> dendritic cells, Cd160<sup>+</sup>Cd8<sup>+</sup> T cells, and Tnfrsf4<sup>+</sup>Cd4<sup>+</sup> T cells physiologically co-localize, rapidly expand during SARS-CoV-2 infection, eliminate SARS-CoV-2 with the aid of Slamf9<sup>+</sup> macrophages, and then restore to physiological levels after viral clearance. We verify the presence of these cell subpopulations in the immunity hubs in normal and SARS-CoV-2-infected hACE2 mouse models, as well as in publicly available human scRNA-seq datasets, demonstrating the potential broad relevance of our findings in lung immunity.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"103"},"PeriodicalIF":13.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11484931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458790","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":"Single-cell spatiotemporal analysis of the lungs reveals Slamf9<sup>+</sup> macrophages involved in viral clearance and inflammation resolution.","authors":"Boyi Cong, Xuan Dong, Zongheng Yang, Pin Yu, Yangyang Chai, Jiaqi Liu, Meihan Zhang, Yupeng Zang, Jingmin Kang, Yu Feng, Yi Liu, Weimin Feng, Dehe Wang, Wei Deng, Fengdi Li, Zhiqi Song, Ziqiao Wang, Xiaosu Chen, Hua Qin, Qinyi Yu, Zhiqing Li, Shuxun Liu, Xun Xu, Nanshan Zhong, Xianwen Ren, Chuan Qin, Longqi Liu, Jian Wang, Xuetao Cao","doi":"10.1038/s41421-024-00734-4","DOIUrl":"10.1038/s41421-024-00734-4","url":null,"abstract":"<p><p>How the lung achieves immune homeostasis after a pulmonary infection is not fully understood. Here, we analyzed the spatiotemporal changes in the lungs over a 2-week natural recovery from severe pneumonia in a Syrian hamster model of SARS-CoV-2 infection. We find that SARS-CoV-2 infects multiple cell types and causes massive cell death at the early stage, including alveolar macrophages. We identify a group of monocyte-derived Slamf9<sup>+</sup> macrophages, which are induced after SARS-CoV-2 infection and resistant to impairment caused by SARS-CoV-2. Slamf9<sup>+</sup> macrophages contain SARS-CoV-2, recruit and interact with Isg12<sup>+</sup>Cst7<sup>+</sup> neutrophils to clear the viruses. After viral clearance, Slamf9<sup>+</sup> macrophages differentiate into Trem2<sup>+</sup> and Fbp1<sup>+</sup> macrophages, contributing to inflammation resolution at the late stage, and finally replenish alveolar macrophages. These findings are validated in a SARS-CoV-2-infected hACE2 mouse model and confirmed with publicly available human autopsy single-cell RNA-seq data, demonstrating the potential role of Slamf9<sup>+</sup> macrophages and their coordination with neutrophils in post-injury tissue repair and inflammation resolution.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"104"},"PeriodicalIF":13.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11484945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458789","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 : 2024-10-15DOI: 10.1038/s41421-024-00730-8
Shuai Zhang, Xue Feng, Chong-Hui Li, Yuan-Ming Zheng, Meng-Ya Wang, Jun-Jie Li, Yun-Peng Dai, Naihe Jing, Jia-Wei Zhou, Gang Wang
{"title":"Mediator MED23 controls oligodendrogenesis and myelination by modulating Sp1/P300-directed gene programs.","authors":"Shuai Zhang, Xue Feng, Chong-Hui Li, Yuan-Ming Zheng, Meng-Ya Wang, Jun-Jie Li, Yun-Peng Dai, Naihe Jing, Jia-Wei Zhou, Gang Wang","doi":"10.1038/s41421-024-00730-8","DOIUrl":"https://doi.org/10.1038/s41421-024-00730-8","url":null,"abstract":"<p><p>Gaining the molecular understanding for myelination development and regeneration has been a long-standing goal in neurological research. Mutations in the transcription cofactor Mediator Med23 subunit are often associated with intellectual disability and white matter defects, although the precise functions and mechanisms of Mediator in myelination remain unclear. In this study, we generated a mouse model carrying an Med23<sup>Q649R</sup> mutation that has been identified in a patient with hypomyelination features. The MED23<sup>Q649R</sup> mouse model develops white matter thinning and cognitive decline, mimicking common clinical phenotypes. Further, oligodendrocyte-lineage specific Med23 knockout mice verified the important function of MED23 in regulating central nervous system myelination and postinjury remyelination. Utilizing the in vitro cellular differentiation assay, we found that the oligodendrocyte progenitor cells, either carrying the Q649R mutation or lacking Med23, exhibit significant deficits in their capacity to differentiate into mature oligodendrocytes. Gene profiling combined with reporter assays demonstrated that Mediator Med23 controls Sp1-directed gene programs related to oligodendrocyte differentiation and cholesterol metabolism. Integrative analysis demonstrated that Med23 modulates the P300 binding to Sp1-targeted genes, thus orchestrating the H3K27 acetylation and enhancer activation for the oligodendrocyte lineage progression. Collectively, our findings identified the critical role for the Mediator Med23 in oligodendrocyte fate determination and provide mechanistic insights into the myelination pathogenesis associated with MED23 mutations.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"102"},"PeriodicalIF":13.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458786","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 : 2024-10-01DOI: 10.1038/s41421-024-00713-9
Yuehua Liu, Xiaoqian Nie, Xingyun Yao, Huafeng Shou, Yang Yuan, Yun Ge, Xiangmin Tong, Hsiang-Ying Lee, Xiaofei Gao
{"title":"Developing an erythrocyte‒MHC-I conjugate for cancer treatment.","authors":"Yuehua Liu, Xiaoqian Nie, Xingyun Yao, Huafeng Shou, Yang Yuan, Yun Ge, Xiangmin Tong, Hsiang-Ying Lee, Xiaofei Gao","doi":"10.1038/s41421-024-00713-9","DOIUrl":"10.1038/s41421-024-00713-9","url":null,"abstract":"<p><p>Mature erythrocytes are known to lack major histocompatibility complex (MHC) proteins. However, the presence of MHC molecules on erythrocytes has been occasionally reported, though without a defined function. In this study, we designed erythrocyte conjugated solely with a fusion protein consisting of an antigenic peptide linked to MHC class I (MHC-I) protein, termed MHC-I‒Ery. The modified erythrocyte, decorated with the peptide derived from human papillomavirus (HPV) 16 oncoprotein E6/E7, effectively activated antigen-specific CD8<sup>+</sup> T cells in peripheral blood mononuclear cells (PBMCs) from HPV16<sup>+</sup> cervical cancer patients. Additionally, MHC-I‒Ery monotherapy was shown to inhibit antigen-positive tumor growth in mice. This treatment immediately activated CD8<sup>+</sup> T cells and reduced suppressive myeloid cells in the spleen, leading to systemic anti-tumor activity. Safety and tolerability evaluations of MHC-I‒Ery in non-human primates further supported its clinical potential. Our results first demonstrated that erythrocytes equipped solely with antigen peptide‒MHC-I complexes can robustly stimulate the immune system, suggesting a novel and promising approach for advancing cancer immunotherapy.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"99"},"PeriodicalIF":13.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11443136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342290","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 : 2024-09-24DOI: 10.1038/s41421-024-00719-3
Fan Zhai, Siming Kong, Shi Song, Qianying Guo, Ling Ding, Jiaqi Zhang, Nan Wang, Ying Kuo, Shuo Guan, Peng Yuan, Liying Yan, Zhiqiang Yan, Jie Qiao
{"title":"Human embryos harbor complex mosaicism with broad presence of aneuploid cells during early development.","authors":"Fan Zhai, Siming Kong, Shi Song, Qianying Guo, Ling Ding, Jiaqi Zhang, Nan Wang, Ying Kuo, Shuo Guan, Peng Yuan, Liying Yan, Zhiqiang Yan, Jie Qiao","doi":"10.1038/s41421-024-00719-3","DOIUrl":"10.1038/s41421-024-00719-3","url":null,"abstract":"<p><p>Pre-implantation genetic testing for aneuploidy (PGT-A) is used in approximately half of in vitro fertilization cycles. Given the limited understanding of the genetics of human embryos, the current use of PGT-A is based on biologically uncertain assumptions and unvalidated guidelines, leading to the possibility of disposing of embryos with pregnancy potential. We isolated and sequenced all single cells (1133) from in vitro cultured 20 human blastocysts. We found that all blastocysts exhibited mosaicism with mitotic-induced aneuploid cells and showed an ~25% aneuploidy rate per embryo. Moreover, 70% (14/20) of blastocysts contained 'chromosome-complementary' cells, suggesting genetic mosaicism is underestimated in routine PGT-A. Additionally, the analysis of 20,945 single cells from day 8-14 embryos (in vitro cultured) and embryonic/fetal organs showed that 97% of the analyzed embryos/organs were mosaic. Over 96% of their aneuploid cells harbored ≤ 2 chromosome errors. Our findings have revealed a high prevalence of mosaicism in human embryos.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"98"},"PeriodicalIF":13.0,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307180","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}
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