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Single-cell spatiotemporal analysis reveals alveolar dendritic cell-T cell immunity hubs defending against pulmonary infection. 单细胞时空分析揭示了肺泡树突状细胞-T 细胞免疫中枢抵御肺部感染的能力。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-16 DOI: 10.1038/s41421-024-00733-5
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

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+Ido1+ dendritic cells, Cd160+Cd8+ T cells, and Tnfrsf4+Cd4+ T cells physiologically co-localize, rapidly expand during SARS-CoV-2 infection, eliminate SARS-CoV-2 with the aid of Slamf9+ 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.

免疫细胞如何在肺部进行时空协调,以有效监测、应对和解决感染和炎症,这需要充分说明。在这里,我们将免疫图谱(一种通过解卷积和共定位分析整合空间和单细胞 RNA 测序(scRNA-seq)的高分辨率技术)应用于感染 SARS-CoV-2 的叙利亚仓鼠模型。我们在器官尺度和单细胞分辨率上生成了肺部感染全过程的综合转录组图谱,从生理状态、感染开始、重症肺炎到自然恢复,共涉及 25 只仓鼠在 5 个时间点的 142,965 个细胞和 45 个肺叶。综合分析发现,肺泡树突状细胞-T细胞免疫中枢(Ccr7+Ido1+树突状细胞、Cd160+Cd8+ T细胞和Tnfrsf4+Cd4+ T细胞在生理上共定位)在SARS-CoV-2感染期间迅速扩张,在Slamf9+巨噬细胞的帮助下清除SARS-CoV-2,然后在病毒清除后恢复到生理水平。我们在正常小鼠模型和感染 SARS-CoV-2 的 hACE2 小鼠模型以及公开的人类 scRNA-seq 数据集中验证了这些细胞亚群在免疫中枢的存在,证明了我们的发现在肺部免疫中的潜在广泛相关性。
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引用次数: 0
Single-cell spatiotemporal analysis of the lungs reveals Slamf9+ macrophages involved in viral clearance and inflammation resolution. 肺部单细胞时空分析显示,Slamf9+巨噬细胞参与病毒清除和炎症消退。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-16 DOI: 10.1038/s41421-024-00734-4
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

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+ macrophages, which are induced after SARS-CoV-2 infection and resistant to impairment caused by SARS-CoV-2. Slamf9+ macrophages contain SARS-CoV-2, recruit and interact with Isg12+Cst7+ neutrophils to clear the viruses. After viral clearance, Slamf9+ macrophages differentiate into Trem2+ and Fbp1+ 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+ macrophages and their coordination with neutrophils in post-injury tissue repair and inflammation resolution.

肺部感染后如何实现免疫平衡尚未完全清楚。在这里,我们分析了叙利亚仓鼠 SARS-CoV-2 感染模型在重症肺炎自然恢复 2 周内肺部的时空变化。我们发现,SARS-CoV-2 会感染多种类型的细胞,并在早期导致包括肺泡巨噬细胞在内的大量细胞死亡。我们发现了一组来源于单核细胞的 Slamf9+ 巨噬细胞,它们在感染 SARS-CoV-2 后被诱导,并能抵抗 SARS-CoV-2 造成的损伤。Slamf9+ 巨噬细胞含有 SARS-CoV-2,招募并与 Isg12+Cst7+ 中性粒细胞相互作用,清除病毒。病毒清除后,Slamf9+ 巨噬细胞分化为 Trem2+ 和 Fbp1+ 巨噬细胞,促进炎症晚期的消退,并最终补充肺泡巨噬细胞。这些发现在SARS-CoV-2感染的hACE2小鼠模型中得到了验证,并通过公开的人类尸检单细胞RNA-seq数据得到了证实,证明了Slamf9+巨噬细胞及其与中性粒细胞的协调在损伤后组织修复和炎症消退中的潜在作用。
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引用次数: 0
Mediator MED23 controls oligodendrogenesis and myelination by modulating Sp1/P300-directed gene programs. 介导因子 MED23 通过调节 Sp1/P300 引导的基因程序控制少突形成和髓鞘化。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-15 DOI: 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

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 Med23Q649R mutation that has been identified in a patient with hypomyelination features. The MED23Q649R 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.

了解髓鞘发育和再生的分子机制一直是神经学研究的长期目标。转录辅助因子 Mediator Med23 亚基的突变通常与智力障碍和白质缺陷有关,但 Mediator 在髓鞘形成中的确切功能和机制仍不清楚。在这项研究中,我们生成了一个携带 Med23Q649R 突变的小鼠模型,该突变已在一名具有髓鞘功能减退特征的患者身上发现。MED23Q649R 小鼠模型会出现白质变薄和认知能力下降,模仿了常见的临床表型。此外,少突胶质细胞系特异性 Med23 基因敲除小鼠验证了 MED23 在调节中枢神经系统髓鞘化和损伤后再髓鞘化方面的重要功能。利用体外细胞分化试验,我们发现无论是携带 Q649R 突变还是缺乏 Med23 的少突胶质细胞祖细胞,其分化为成熟少突胶质细胞的能力都存在显著缺陷。基因图谱分析与报告实验相结合证明,调解因子 Med23 控制着与少突胶质细胞分化和胆固醇代谢有关的 Sp1 主导基因程序。综合分析表明,Med23 可调节 P300 与 Sp1 靶向基因的结合,从而协调 H3K27 乙酰化和增强子激活,促进少突胶质细胞系的发展。总之,我们的研究结果确定了 Mediator Med23 在少突胶质细胞命运决定中的关键作用,并为 MED23 基因突变相关的髓鞘化发病机制提供了机理上的见解。
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引用次数: 0
Intercellular genetic tracing by alternative synthetic Notch signaling. 通过替代合成 Notch 信号进行细胞间基因追踪。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-15 DOI: 10.1038/s41421-024-00721-9
Kuo Liu, Shaohua Zhang, Xinfeng Meng, Hongxin Li, Jingting Zhu, Enci Wang, Muxue Tang, Mingjun Zhang, Bin Zhou, Lixin Wang
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引用次数: 0
Pathogenic BALB/c mice infection model for evaluation of mpox countermeasures. 用于评估 mpox 对策的致病性 BALB/c 小鼠感染模型。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-13 DOI: 10.1038/s41421-024-00739-z
Lin Cheng, Wenqi Huang, Meimei Duan, Zhuohuan Li, Qi Chen, Mingxia Zhang, Zheng Zhang
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引用次数: 0
Programmable broad-spectrum resistance to bacterial blight using targeted insertion in rice. 利用水稻中的靶向插入技术对细菌性枯萎病产生可编程的广谱抗性。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-08 DOI: 10.1038/s41421-024-00714-8
Xuening Zhang, Minglei Song, Yingying Wang, Qi Yao, Rundong Shen, Yifu Tian, Yuming Lu, Jian-Kang Zhu
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引用次数: 0
Developing an erythrocyte‒MHC-I conjugate for cancer treatment. 开发用于癌症治疗的红细胞-MHC-I 结合物。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-01 DOI: 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

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+ T cells in peripheral blood mononuclear cells (PBMCs) from HPV16+ cervical cancer patients. Additionally, MHC-I‒Ery monotherapy was shown to inhibit antigen-positive tumor growth in mice. This treatment immediately activated CD8+ 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.

众所周知,成熟的红细胞缺乏主要组织相容性复合体(MHC)蛋白。不过,偶尔也有报道称红细胞上存在 MHC 分子,但没有明确的功能。在这项研究中,我们设计了仅与一种融合蛋白结合的红细胞,这种融合蛋白由与 MHC I 类蛋白质(MHC-I)相连的抗原肽组成,被称为 MHC-I-Ery。经修饰的红细胞上装饰有来自人类乳头瘤病毒(HPV)16 肿瘤蛋白 E6/E7 的多肽,能有效激活 HPV16+ 宫颈癌患者外周血单核细胞(PBMC)中的抗原特异性 CD8+ T 细胞。此外,MHC-I-Ery 单药疗法还能抑制抗原阳性肿瘤在小鼠体内的生长。这种疗法能立即激活 CD8+ T 细胞,减少脾脏中的抑制性髓细胞,从而产生全身抗肿瘤活性。MHC-I-Ery在非人灵长类动物中的安全性和耐受性评估进一步证实了它的临床潜力。我们的研究结果首次证明了红细胞仅配备抗原肽-MHC-I 复合物就能强有力地刺激免疫系统,为推进癌症免疫疗法提供了一种新颖而有前景的方法。
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引用次数: 0
Human embryos harbor complex mosaicism with broad presence of aneuploid cells during early development. 人类胚胎在早期发育过程中存在复杂的嵌合现象,非整倍体细胞广泛存在。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-09-24 DOI: 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

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.

约有一半的体外受精周期使用植入前非整倍体基因检测(PGT-A)。由于对人类胚胎遗传学的了解有限,目前 PGT-A 的使用是基于生物学上不确定的假设和未经验证的指导原则,从而可能导致具有妊娠潜能的胚胎被弃置。我们对体外培养的 20 个人类囊胚的所有单细胞(1133 个)进行了分离和测序。我们发现,所有囊胚都表现出与有丝分裂诱导的非整倍体细胞嵌合,每个胚胎的非整倍体率约为 25%。此外,70%(14/20)的囊胚含有 "染色体互补 "细胞,这表明在常规 PGT-A 中基因嵌合被低估了。此外,对来自第 8-14 天胚胎(体外培养)和胚胎/胎儿器官的 20,945 个单细胞进行的分析表明,97% 的受分析胚胎/器官是镶嵌的。96%以上的非整倍体细胞含有≤2条染色体错误。我们的研究结果表明,人类胚胎中镶嵌现象非常普遍。
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引用次数: 0
Epigenetic editing alleviates Angelman syndrome phenotype in mice by unsilencing paternal Ube3a 表观遗传编辑通过解除父系 Ube3a 的沉默减轻小鼠的安杰曼综合征表型
IF 33.5 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-09-17 DOI: 10.1038/s41421-024-00727-3
Yajing Liu, Sensen Lou, Jinhui Li, Yuanhua Liu, Shisheng Huang, Yu Wei, Jikai Liu, Ruimin Lv, Junjie Tang, Zhixin Shen, Yidi Sun, Xingxu Huang, Zhiqi Xiong, Hui Yang, Changyang Zhou
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引用次数: 0
Targeting SNRNP200-induced splicing dysregulation offers an immunotherapy opportunity for glycolytic triple-negative breast cancer 以 SNRNP200 诱导的剪接失调为靶点,为糖代谢三阴性乳腺癌提供免疫疗法机会
IF 33.5 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-09-17 DOI: 10.1038/s41421-024-00715-7
Wenxiao Yang, Luo Hong, Linwei Guo, Yunjin Wang, Xiangchen Han, Boyue Han, Zheng Xing, Guoliang Zhang, Hongxia Zhou, Chao Chen, Hong Ling, Zhimin Shao, Xin Hu

Metabolic dysregulation is prominent in triple-negative breast cancer (TNBC), yet therapeutic strategies targeting cancer metabolism are limited. Here, utilizing multiomics data from our TNBC cohort (n = 465), we demonstrated widespread splicing deregulation and increased spliceosome abundance in the glycolytic TNBC subtype. We identified SNRNP200 as a crucial mediator of glucose-driven metabolic reprogramming. Mechanistically, glucose induces acetylation at SNRNP200 K1610, preventing its proteasomal degradation. Augmented SNRNP200 then facilitates splicing key metabolic enzyme-encoding genes (GAPDH, ALDOA, and GSS), leading to increased lactic acid and glutathione production. Targeting SNRNP200 with antisense oligonucleotide therapy impedes tumor metabolism and enhances the efficacy of anti-PD-1 therapy by activating intratumoral CD8+ T cells while suppressing regulatory T cells. Clinically, higher SNRNP200 levels indicate an inferior response to immunotherapy in glycolytic TNBCs. Overall, our study revealed the intricate interplay between RNA splicing and metabolic dysregulation, suggesting an innovative combination strategy for immunotherapy in glycolytic TNBCs.

代谢失调在三阴性乳腺癌(TNBC)中非常突出,但针对癌症代谢的治疗策略却很有限。在这里,我们利用 TNBC 队列(n = 465)的多组学数据,证明了在糖酵解 TNBC 亚型中广泛存在剪接失调和剪接体丰度增加的现象。我们发现 SNRNP200 是葡萄糖驱动的代谢重编程的关键介质。从机理上讲,葡萄糖会诱导 SNRNP200 K1610 处的乙酰化,阻止其蛋白酶体降解。增强的 SNRNP200 会促进关键代谢酶编码基因(GAPDH、ALDOA 和 GSS)的剪接,从而增加乳酸和谷胱甘肽的产生。以 SNRNP200 为靶点的反义寡核苷酸疗法会阻碍肿瘤的新陈代谢,并通过激活瘤内 CD8+ T 细胞同时抑制调节性 T 细胞来提高抗 PD-1 疗法的疗效。在临床上,SNRNP200水平越高,表明糖代谢性TNBC对免疫疗法的反应越差。总之,我们的研究揭示了RNA剪接与代谢失调之间错综复杂的相互作用,为糖代谢性TNBCs的免疫疗法提出了一种创新的组合策略。
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引用次数: 0
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Cell Discovery
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