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Immune rebalancing at the maternal-fetal interface of maternal SARS-CoV-2 infection during early pregnancy

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Protein & Cell 2024年第6期15卷 460-473页

作者： Chenxiang Xi Zihui Yan Dandan Bai Yalin Zhang Beiying Wang Xiaoxiao Han Li Wu Xiaohui Shi Zhiyi Hu Ming Tang Zhongqu Su Yingdong Liu Binya Liu Jiqing Yin Hong Wang Xiaocui Li Yanping Zhang Shaorong Gao Wenqiang Liu shanghai Key Laboratory of Maternal Fetal Medicine Clinical and Translational Research Center of Shanghai First Maternity and Infant HospitalShanghai Institute of Maternal-Fetal Medicine and Gynecologic OncologyFrontier Science Center for Stem Cell ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China Jiaxing maternity and Child Health Care hospital Jiaxing 314050China

The current coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2)remains a threat to pregnant ***,the impact of early pregnancy SARS-CoV-2 infection on the maternal-fetal interface remains poorly ***,we present a comprehensive analysis of single-cell transcriptomics and metabolomics in placental samples infected with SARS-CoV-2 during early *** to control placentas,SARS-CoV-2 infection elicited immune responses at the maternal-fetal interface and induced metabolic alterations in amino acid and phospholipid profiles during the initial weeks ***,subsequent immune cell activation and heightened immune tolerance in trophoblast cells established a novel dynamic equilibrium that mitigated the impact on the maternal-fetal ***,the immune response and metabolic alterations at the maternal-fetal interface exhibited a gradual decline during the second *** study underscores the adaptive immune tolerance mechanisms and establishment of immunological balance during the first two trimesters following maternal SARS-CoV-2 infection.

关键词： fetal alterations pregnancy

Genome transfer for the prevention of female infertility caused by maternal gene mutation

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Journal of Genetics and Genomics 2020年第6期47卷 311-319页

作者： Dandan Bai Jin Sun Yanping Jia Jiqing Yin Yalin Zhang Yanhe Li Rui Gao Xiling Du Kunming Li Jiaming Lin Zhifen Tu Yu Wang Jiaping Pan Shanshan Liang Yi Guo Jingling Ruan Xiaochen Kou Yanhong Zhao Hong Wang Cizhong Jiang Fengchao Wang Xiaoming Teng Wenqiang Liu Shaorong Gao clinical and translational research center of shanghai first maternity and infant hospital.shanghai Key Laboratory of Signaling and Disease research Frontier Science Center for Stem Cell ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai200092China National Institute of Biological Sciences.NIBS.Beijing 102206China

Poor oocyte quality is associated with early embryo developmental arrest and *** gene plays crucial roles in the regulation of oocyte maturation,and its mutation is a common cause of female ***,how to improve oocyte quality and develop effective therapy for maternal gene mutation remains ***,we use Zar1 as an example to assess the feasibility of genome transfer to cure maternal gene mutationecaused female *** first discover that cytoplasmic deficiency primarily leads to Zar1-null embryo developmental arrest by disturbing maternal transcript degradation and minor zygotic genome activation(ZGA)during the maternal-zygotic *** next perform genome transfer at the oocyte(spindle transfer or polar body transfer)and zygote(early pronuclear transfer or late pronuclear transfer)stages to validate the feasibility of preventing Zar1 mutationecaused *** finally demonstrate that genome transfer either at the oocyte or at the early pronuclear stage can support normal preimplantation embryo development and produce live ***,those pups grow to adulthood and show normal ***,our findings provide an effective basis of therapies for the treatment of female infertility caused by maternal gene mutation.

关键词： Infertility Oocytes Zar1 Maternal-zygotic transition ZGA Spindle transfer Genome transfer

Phosphatidylinositol 4-kinase β is required for the ciliogenesis of zebrafish otic vesicle

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Journal of Genetics and Genomics 2020年第10期47卷 627-636页

作者： Yufei Feng Ping Yu Jingyu Li Ying Cao Jingjing Zhang Affiliated hospital of Guangdong Medical University&Key Laboratory of Zebrafish Model for Development and Disease of Guangdong Medical University Zhanjiang 524001China clinical and translational research center Shanghai First Maternity and Infant HospitalSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China

The primary cilium,an important microtubule-based organelle,protrudes from nearly all the vertebrate *** motility of cilia is necessary for various developmental and physiological ***(PIs)and its metabolite,Ptd Ins(4,5)P2,have been revealed to contribute to cilia assembly and *** an important kinase of the PI pathway and signaling,phosphatidylinositol 4-kinaseβ(PI4 KB)is the one of the most extensively studied phosphatidylinositol 4-kinase ***,its potential roles in organ development remain to be *** investigate the developmental role of Pi4 kb,especially its function on zebrafish ciliogenesis,we generated pi4 kb deletion mutants using clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9 *** homozygous pi4 kb mutants exhibit an absence of primary cilia in the inner ear,neuromasts,and pronephric ducts accompanied by severe edema in the eyes and other ***,smaller otic vesicle,malformed semicircular canals,and the insensitivity on sound stimulation were characteristics of pi4 kb *** the protein level,both in vivo and in vitro analyses revealed that synthesis of Pi4 p was greatly reduced owing to the loss of Pi4 *** addition,the expression of the Pi4 kb-binding partner of neuronal calcium sensor-1,as well as the phosphorylation of phosphatidylinositol-4-phosphate downstream effecter of Akt,was significantly inhibited in pi4 kb *** together,our work uncovers a novel role of Pi4 kb in zebrafish inner ear development and the functional formation of hearing ability by determining hair cell ciliogenesis.

关键词： Ciliogenesis Pi4kb Hair cell Hearing loss Zebrafish

Single senescent cell sequencing reveals heterogeneity in senescent cells induced by telomere erosion

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Protein & Cell 2019年第5期10卷 370-375页

作者： Huanyin Tang Anke Geng Tengjiao Zhang Chen Wang Ying Jiang Zhiyong Mao clinical and translational research center of shanghai first maternity infant hospital Shanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Scien ces and Tech no logyTongji UniversityShanghai 200092China School of Life Sciences and Technology Tongji UniversityShanghai 200092China

Dear Editor,Over a half-century ago,*** Hayflick described the phenotype of a finite lifespan for human fibroblasts being passaged in in vitro cell culture(Hayflick et al.,1961),a phenomenon today known as replicative cellular *** senescence has been defined as a state in which cells lose their potential to divide and are permanently arrested in either the G1,or arguably the G2 stage of the cell cycle(Mao et al.,2012).In addition to replicative cellular senescenee—which is induced by large amounts of DNA damage at telomeres due to loss of the specialized T-loop structure—xogenous sublethal stresses such as ionizing radiati on,genotoxic chemicals or hyper-activated on cogenes may also trigger a similar form of senescence,stress induced premature cellular senescenee(SIPS).

关键词： Single senescent cell telomere erosion

Esrrb plays important roles in maintaining self-renewal of trophoblast stem cells (TSCs) and reprogramming somatic cells to induced TSCs

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Journal of Molecular Cell Biology 2019年第6期11卷 463-473页

作者： Haibo Gao Rui Gao Linfeng Zhang Wenchao Xiu Ruge Zang Hong Wang Yong Zhang Jiayu Chen Yawei Gao Shaorong Gao clinical and translational research center of shanghai first maternity and infant hospital Shanghai Key Laboratory of Signaling and Disease Research School of Life Sciences and Technology Tongji University Shanghai 200092 China Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program School of Life Sciences Tsinghua University Beijing 100084 China

Trophoblast stem cells (TSCs), which can be derived from the trophoectoderm of a blastocyst, have the ability to sustain self-renewal and differentiate into various placental trophoblast cell types. Meanwhile, essential insights into the molecular mechanisms controlling the placental development can be gained by using TSCs as the cell model. Esrrb is a transcription factor that has been shown to play pivotal roles in both embryonic stem cell (ESC) and TSC, but the precise mechanism whereby Esrrb regulates TSC-specific transcriptome during differentiation and reprogramming is still largely unknown. In the present study, we elucidate the function of Esrrb in self-renewal and differentiation of TSCs, as well as during the induced TSC (iTSC) reprogramming. We demonstrate that the precise level of Esrrb is critical for stem state maintenance and further trophoblast differentiation of TSCs, as ectopically expressed Esrrb can partially block the rapid differentiation of TSCs in the absence of fibroblast growth factor 4. However, Esrrb depletion results in downregulation of certain key TSC-specific transcription factors, consequently causing a rapid differentiation of TSCs and these Esrrb-deficient TSCs lose the ability of hemorrhagic lesion formation in vivo. This function of Esrrb is exerted by directly binding and activating a core set of TSC-specific target genes including Cdx2, Eomes, Sox2, Fgfr4, and Bmp4. Furthermore, we show that Esrrb overexpression can facilitate the MEF-to-iTSC conversion. Moreover, Esrrb can substitute for Eomes to generate GEsTM-iTSCs. Thus, our findings provide a better understanding of the molecular mechanism of Esrrb in maintaining TSC self-renewal and during iTSC reprogramming.

关键词： Esrrb trophoblast stem cell self-renwwal differentiation iTSC reprogramming

Bilineage embryo-like structure from EPS cells can produce live mice with tetraploid trophectoderm

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Protein & Cell 2023年第4期14卷 262-278页

作者： Kuisheng Liu Xiaocui Xu Dandan Bai Yanhe Li Yalin Zhang Yanping Jia Mingyue Guo Xiaoxiao Han Yingdong Liu Yifan Sheng Xiaochen Kou Yanhong Zhao jiqing Yin Sheng Liu jiayu Chen Hong Wang Yixuan Wang Wenqiang Liu Shaorong Gao shanghai Key Laboratory of Matemal Fetal Medicine Clinical and Translational Research Center of Shanghai First Matemity and Infant HospitalFrontier Science Center for Stem Cell ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China translational Medical center for Stem Cell Therapy and Institute for Regenerative Medicine Shanghai East HospitalSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China shanghai Institute of Matermal-Fetal Medicine and Gynecologic Oncology Shanghai First Matermity and Infant HospitalTongji UniversityShanghai 200092China

Self-organized blastoids from extended pluripotent stem(EPs)cells possess enormous potential for investigating postimplantation embryo development and related ***,the limited ability of postimplantation development of Eps-blastoids hinders its further *** this study,single-cell transcriptomic analysis indicated that the“trophectoderm(TE)-like structure”of EPSblastoids was primarily composed of primitive endoderm(PrE)-related cells instead of TE-related *** further identified PrE-like cells in EPS cell culture that contribute to the blastoid formation with TE-like *** of PrE cell differentiation by inhibiting MEK signaling or knockout of Gata6 in EPS cells markedly suppressed EPS-blastoid ***,we demonstrated that blastocyst-like structures reconstituted by combining the EPs-derived bilineage embryo-like structure(BLEs)with either tetraploid embryos or tetraploid TE cells could implant normally and develop into live *** summary,our study reveals that TE improvement is critical for constructing a functional embryo using stem cells in vitro.

关键词： EPS cells blastoid primitive endoderm(PrE) trophectoderm(TE) Gata6

Insights into epigenetic patterns in mammalian early embryos

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Protein & Cell 2021年第1期12卷 7-28页

作者： Ruimin Xu Chong Li Xiaoyu Liu Shaorong Gao clinical and translational research center of shanghai first maternity and infant hospital Shanghai Key Laboratory of Signaling and Disease ResearchFrontier Science Center for Stem Cell ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China Institute for Regenerative Medicine Shanghai East HospitalShanghai Key Laboratory of Signaling and Disease ResearchFrontier Science Center for Stem Cell ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China Tsingtao Advanced research Institute Tongji UniversityQingdao 266071China

Mammalian fertilization begins with the fusion of two specialized gametes,followed by major epigenetic remodeling leading to the formation of a totipotent *** the development of the pre-implantation embryo,precise reprogramming progress is a prerequisite for avoiding developmental defects or embryonic lethality,but the underlying molecular mechanisms remain *** the past few years,unprecedented breakthroughs have been made in mapping the regulatory network of dynamic epigenomes during mammalian early embryo development,taking advantage of multiple advances and innovations in low-input genome-wide chromatin analysis *** aim of this review is to highlight the most recent progress in understanding the mechanisms of epigenetic remodeling during early embryogenesis in mammals,including DNA methylation,histone modifications,chromatin accessibility and 3D chromatin organization.

关键词： epigenetic reprogramming DNA methylation histone modifications early embryo development

IDDoR:a novel reporter mouse system for simultaneous and quantitative in vivo analysis of both DNA double-strand break repair pathways

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Protein & Cell 2023年第5期14卷 369-375页

作者： Yu Chen Zhen Cui Zhixi Chen Ying Jiang Zhiyong Mao shanghai Key Laboratory of Maternal Fetal Medicine Clinical and Translational Research Center of Shanghai First Maternity and Infant HospitalFrontier Science Center for Stem Cell ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China Tsingtao Advanced research Institute Tongji UniversityQingdao 266071China State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China

Dear Editor,Two distinct pathways,non-homologous end joining(NHEJ)and homologous recombination(HR)repair,have evolved to repair DNA double-strand breaks(DSBs),the most deleterious type of DNA *** NHEJ and HR are often associated with a high incidence of tumorigenesis and the early onset of aging.A number of methods and tools have been developed to help elucidate the regulatory mechanisms of the two repair pathways in the *** vitro biochemical assays employ 32P-labeled broken DNA fragments and cell extracts to evaluate DSB repair *** DSB sites,several DSB repair factors form foci,which can be visualized through immunofluorescence and *** them,phosphorylated H2AX at the Ser139 residue is often considered a DSB marker,and its formation and removal at different time points post the induction of DSBs can be used to reflect the repair capacity and genomic *** addition,by quantifying the kinetics of the recruitment of specific NHEJ and HR factors such as 53BP1,DNA-PKcs,MRE11,RPA2,and RAD51,one would be able to make judgments on whether NHEJ,HR,or both pathways is/are affected and sometimes at which steps DSB repair pathways are *** alternative approach for kinetic analysis is to quantify the microirradiation-induced recruitment of repair ***,comet assays are also utilized to measure DNA damage-induced genomic stability at the single-cell ***,with these assays,it is still difficult to measure NHEJ and HR efficiency in a relatively less time-consuming and more quantitative manner.

关键词： double repair simultaneous

LincRNA-1614 coordinates Sox2/PRC2-mediated repression of developmental genes in pluripotency maintenance

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Journal of Molecular Cell Biology 2018年第2期10卷 118-129页

作者： Xudong Guo Zikang Wang Chenqi Lu Wujun Hong Guiying Wang Yanxin Xu Zhongmin Liu Jiuhong Kang clinical and translational research center of shanghai first maternity & infant Health hospital Shanghai Key Laboratory of Signaling and Disease Research Collaborative Innovation Center for Brain Science School of Life Science and Technology Tongji University Shanghai 200092 China Institute of Regenerative Medicine East Hospital Tongji University School of Medicine Shanghai 200120 China Laboratory of Population and Quantitative Genetics institute of Biostatistics School of Life Sciences Fudan University Shanghai 200433 China

Large-intergenic noncoding RNAs （lincRNAs） cooperate with core transcription factors to coordinate the pluripotency network of embryonic stem cells. The mechanisms by which lincRNAs affect chromatin structure and gene transcription remain mostly unknown. Here, we identified that a UncRNA （linc1614）, occupied by pluripotency factors at its promoter, was indispensable for both maintenance and acquisition of pluripotency. Linc1614 sewed as a specific partner of core factor Sox2 in maintaining pluripotency, primarily by mediating the function of Sox2 in the repression of developmental genes. Moreover, Ezh2, an essential subunit of polycomb repressive complex 2 （PRC2）, physically interacted with linc1614 and contributed to lincRNA-mediated transcriptional silencing. Thus, we propose that the interplay of linc1614 with Sox2 implicates this lincRNA as a recruitment platform that mediates transcriptional silencing by guiding the PRC2 complex to the loci of developmental genes.

关键词： lincRNA Sox2 pluripotency maintenance PRC2 reprogramming