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Gene-knockout by iSTOP enables rapid reproductive disease modeling and phenotyping in germ cells of the founder generation

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Science China(Life Sciences) 2024年第5期67卷 1035-1050页

作者： Yaling Wang Jingwen Chen Xueying Huang Bangguo Wu Peng Dai Feng Zhang Jinsong Li Lingbo Wang State Key laboratory of Genetic Engineering Shanghai Key Laboratory of Metabolic Remodeling and HealthInstitute of Metabolism and Integrative BiologyFudan UniversityShanghai 200438China Institute of Reproduction and Development Obstetrics and Gynecology HospitalFudan UniversityShanghai 200011China NHC Key Lab of Reproduction Regulation(Shanghai Institute for Biomedical and Pharmaceutical Technologies) School of PharmacyFudan UniversityShanghai 200433China Shanghai Key laboratoryof Maternal and Fetal Medicine Clinical and Translational Research Center of Shanghai First Maternity and Infant HospitalFrontier Science Center for Stem Cell ResearchSchoolof Life Sciences and TechnologyTongji UniversityShanghai 200092China State Key laboratory of cell Biology CAS Center for Excellence in Molecular Cell ScienceShanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai 200031China

Cytosine base editing achieves C·G-to-T·A substitutions and can convert four codons(CAA/CAG/CGA/TGG)into STOP-codons(induction of STOP-codons,iSTOP)to knock out genes with reduced *** enables direct phenotyping in founders’somatic cells,but it remains unknown whether this works in founders’germ cells so as to rapidly reveal novel genes for ***,we initially establish that iSTOP in mouse zygotes enables functional characterization of known genes in founders’germ cells:Cfap43-iSTOP male founders manifest expected sperm features resembling human“multiple morphological abnormalities of the flagella”syndrome(i.e.,MMAF-like features),while oocytes of Zp3-iSTOP female founders have no zona *** further illustrate iSTOP’s utility for dissecting the functions of unknown genes with Ccdc183,observing MMAF-like features and male infertility in Ccdc183-iSTOP founders,phenotypes concordant with those of Ccdc183-KO *** ultimately establish that CCDC183 is essential for sperm morphogenesis through regulating the assembly of outer dynein arms and participating in the intra-flagellar *** study demonstrates iSTOP as an efficient tool for direct reproductive disease modeling and phenotyping in germ cells of the founder generation,and rapidly reveals the essentiality of Ccdc183 in fertility,thus providing a time-saving approach for validating genetic defects(like nonsense mutations)for human infertility.

关键词： disease modeling infertility multiple morphological abnormalities of the flagella(MMAF) induction of STOP-codons(iSTOP CRISPR-STOP) sperm motility

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Charting epimutation dynamics in human hematopoietic differentiation Xiaohuan Qina

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Blood Science 2024年第3期6卷 1-10页

作者： Jiayi Lu Peng Wu Chunyong Zhang Lei Shi Ping Zhu State Key laboratory of Experimental Hematology National Clinical Research Center for Blood DiseasesHaihe Laboratory of Cell EcosystemDepartment of Stem Cell and Regenerative MedicineInstitute of Hematology and Blood Diseases HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjinChina The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics Key Laboratory of Immune Microenvironment and Disease(Ministry of Education)Department of Biochemistry and Molecular BiologySchool of Basic Medical SciencesTianjin Medical UniversityTianjinChina

DNA methylation plays a critical role in hematopoietic *** is a stochastic variation in DNA methylation that induces epigenetic ***,the effects of epimutations on normal hematopoiesis and hematopoietic diseases remain *** this study,we developed a Julia package called EpiMut that enabled rapid and accurate quantification of *** was used to evaluate and provide an epimutation landscape in steady-state hematopoietic differentiation involving 13 types of blood cells ranging from hematopoietic stem/progenitor cells to mature *** showed that substantial genomic regions exhibited epigenetic variations rather than significant differences in DNA methylation levels between the myeloid and lymphoid *** dynamics of epimutations were observed during the differentiation of each ***,we found that epimutation significantly enriched signals associated with lineage ***,epimutations in hematopoietic stem cells(HSCs)derived from various sources and acute myeloid leukemia were related to the function of HSCs and malignant cell *** together,our study comprehensively documented an epimutation map and uncovered its important roles in human hematopoiesis,thereby offering insights into hematopoietic regulation.

关键词： DNA methylation Epimutation Hematopoietic differentiation Hematopoietic stem cell

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乳酸化修饰参与调控DNA损伤修复和癌细胞化疗敏感性

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Science Bulletin 2024年第9期69卷 1185-1187页

作者：刘子超黄奕乐刘兴国 CAS Key laboratory of Regenerative Biology Joint School of Life SciencesGuangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhou Medical UniversityGuangzhou 510530China Centre for Regenerative Medicine and Health Hong Kong Institute of Science&InnovationChinese Academy of SciencesHong Kong 999077China Guangdong Provincial Key laboratory of stem cell and Regenerative Medicine Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative MedicineChina-New Zealand Joint Laboratory on Biomedicine and HealthCUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative MedicineGIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research CentreInstitute for Stem Cell and RegenerationGuangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhou 510530China University of Chinese Academy of Sciences Beijing 100049China

The phenomenon in which cells prefer glycolysis to oxidative phosphorylation with increased lactate production is known as the Warburg effect and is found prevalent in cancer cells and pluripotent stem cells [1]. In addition to being an intermediate metabolite of glycolysis, lactate has been reported as a signal involved in multiple important biological processes, such as innate immunity [2], the cell cycle [3], hippocampal neurogenesis [4].

关键词：化疗敏感性 immunity DNA损伤修复

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Single-nucleus transcriptomics uncovers a geroprotective role of YAP in primate gingival aging

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Protein & cell 2024年第8期15卷 612-632页

作者： Qinchao Hu Bin Zhang Yaobin Jing Shuai Ma Lei Hu jingyi Li Yandong Zheng Zijuan Xin Jianmin Peng Si Wang Bin Cheng Jing Qu Weiqi zhang Guang-Hui Liu Songlin Wang State Key laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Hospital of Stomatology Guanghua School of StomatologyGuangdong Provincial Key Laboratory of StomatologySun Yat-sen UniversityGuangzhou 510060China Salivary Gland Disease Center and Beijing Key laboratory of Tooth Regeneration and Function Reconstruction Beijing Laboratory of Oral Health and Beijing Stomatological HospitalCapital Medical UniversityBeijing 100050China Department of Biochemistry and Molecular Biology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China CAS Key laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China State Key laboratory of stem cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Key laboratory of Organ Regeneration and Reconstruction Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Institute for stem cell and Regeneration Chinese Academy of SciencesBeijing 100101China Beijing Institute for stem cell and Regenerative Medicine Beijing 100101China Advanced Innovation Center for Human Brain Protection and national Clinical Research Center for Geriatric Disorders Xuanwu Hospital Capital Medical UniversityBeijing 100053China Aging Translational Medicine Center Intermational Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuan Wu HospitalCapital Medical UniversityBeijing 100053China Intemational Center for Aging and Cancer Hainan Medical UniversityHaikou 571199China Aging Biomarker Consortium Beijing 100101China

Aging has a profound impact on the gingiva and significantly increases its susceptibility to periodontitis,a worldwide prevalent inflammatory ***,a systematic characterization and comprehensive understanding of the regulatory mechanism underlying gingival aging is still ***,we systematically dissected the phenotypic characteristics of gingiva during aging in primates and constructed the first single-nucleus transcriptomic landscape of gingival aging,by which a panel of cell type-specific signatures were *** cells were identified as the most affected cell types by aging in the *** analyses pinpointed the crucial role of YAP in epithelial self-renew and homeostasis,which declined during aging in epithelial cells,especially in basal *** decline of YAP activity during aging was confrmed in the human gingival tissues,and downregulation of YAP in human primary gingival keratinocytes recapitulated the major phenotypic defects observed in the aged primate gingiva while overexpression of YAP showed rejuvenation *** work provides an in-depth understanding of gingival aging and serves as a rich resource for developing novel strategies to combat aging-associated gingival diseases,with the ultimate goal of advancing periodontal health and promoting healthy aging.

关键词： single-nucleus RNA-sequencing primate gingiva aging YAP

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Multimodal Omics Approaches to Aging and Age‑Related Diseases

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Phenomics 2024年第1期4卷 56-71页

作者： Qianzhao Ji Xiaoyu Jiang Minxian Wang Zijuan Xin Weiqi Zhang Jing Qu Guang‑Hui Liu State Key laboratory of Membrane Biology Instituteof ZoologyChinese Academy of SciencesBeijing 100101China State Key laboratory of stem cell and ReproductiveBiology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Key laboratory of Organ Regeneration and Reconstruction Institute of ZoologyChinese Academy of SciencesBeijing 100101China CAS Key laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academyof Sciences and China National Center for BioinformationBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Institute for stem cell and Regeneration Chinese Academyof SciencesBeijing 100101China Beijing Institute for stem cell and Regenerative Medicine Beijing 100101China School of Future Technology University of ChineseAcademy of SciencesBeijing 100190China Advanced Innovation Center for Human Brain Protection National Clinical Research Center for GeriatricDisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China Aging Translational Medicine Center International Centerfor Aging and CancerXuanwu HospitalCapital MedicalUniversityBeijing 100053China

Aging is associated with a progressive decline in physiological capacities and an increased risk of aging-associated *** increasing body of experimental evidence shows that aging is a complex biological process coordinately regulated by multiple factors at diferent molecular ***,it is difcult to delineate the overall systematic aging changes based on single-layer ***,multimodal omics approaches,in which data are acquired and analyzed using complementary omics technologies,such as genomics,transcriptomics,and epigenomics,are needed for gaining insights into the precise molecular regulatory mechanisms that trigger *** recent years,multimodal omics sequencing technologies that can reveal complex regulatory networks and specifc phenotypic changes have been developed and widely applied to decode aging and age-related *** review summarizes the classifcation and progress of multimodal omics approaches,as well as the rapidly growing number of articles reporting on their application in the feld of aging research,and outlines new developments in the clinical treatment of age-related diseases based on omics technologies.

关键词： Multimodal omics approaches Aging Genome Epigenome

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Unresolved Excess Accumulation of Myelin-Derived Cholesterol Contributes to Scar Formation after Spinal Cord Injury

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Research 2024年第1期2023卷 17-32页

作者： Bolin Zheng Yijing He Shuai Yin Xu Zhu Qing Zhao Huiyi Yang Zhaojie wang Rongrong Zhu Liming Cheng Key laboratory of Spine and Spinal Cord Injury Repair and Regeneration Ministry of EducationDepartment of OrthopedicsTongji HospitalSchool of MedicineTongji UniversityShanghai 200092China Frontier Science Center for stem cell Research School of Life Science and TechnologyTongji UniversityShanghai 200092China Clinical Center for Brain and Spinal Cord Research Tongji UniversityShanghai 200092China

Spinal cord injury triggers complex pathological cascades,resulting in destructive tissue damage and incomplete tissue *** formation is generally considered a barrier for regeneration in the central nervous ***,the intrinsic mechanism of scar formation after spinal cord injury has not been fully ***,we report that excess cholesterol accumulates in phagocytes and is inefficiently removed from spinal cord lesions in young adult ***,we observed that excessive cholesterol also accumulates in injured peripheral nerves but is subsequently removed by reverse ***,preventing reverse cholesterol transport leads to macrophage accumulation and fibrosis in injured peripheral ***,the neonatal mouse spinal cord lesions are devoid of myelin-derived lipids and can heal without excess cholesterol *** found that transplantation of myelin into neonatal lesions disrupts healing with excessive cholesterol accumulation,persistent macrophage activation,and *** internalization suppresses macrophage apoptosis mediated by CD5L expression,indicating that myelin-derived cholesterol plays a critical role in impaired wound *** together,our data suggest that the central nervous system lacks an efficient approach for cholesterol clearance,resulting in excessive accumulation of myelin-derived cholesterol,thereby inducing scar formation after injury.

关键词： healing Spinal impaired

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Human iP SC-derived mesenchymal stem cells relieve high blood pressure in spontaneously hypertensive rats via splenic nerve activated choline acetyltransferase-positive cells

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Science China Life Sciences 2024年

作者： Zhen Zhang Weijun Huang Xiaoran Zhang Zhecun Wang Manting Xie Bingbing Xie Yiling Wang Xiaoyong Chen Andy Peng Xiang Qiuling Xiang Center for stem cell Biology and Tissue Engineering Key Laboratory for Stem Cells and Tissue Engineering Ministry of Education Sun Yat-sen University Department of Physiology Zhongshan School of Medicine Sun Yat-sen University Department of Vascular Surgery the First Affiliated Hospital Sun Yat-sen University

Despite substantial advancements in modern medicine, the management of hypertension remains a major challenge. stem cell-based therapies have recently demonstrated remarkable efficacy in treating cardiovascular diseases, including hypertension. However, the antihypertensive mechanism of mesenchymal stem cells（MSCs） has not been extensively explored. This study aimed to investigate the role of injected MSCs in regulating blood pressure homeostasis. Our previous study demonstrated that human induced pluripotent stem cellderived mesenchymal stem cells（hiPSC-MSCs） are functional and homogeneous sources for MSC-based therapy. After the injection of hiPSCMSCs, a significant reduction in blood pressure and end target organ inflammation were observed in spontaneously hypertensive rats（SHRs）. cell tracking assays demonstrated that the injected hiPSC-MSCs accumulated in the spleens of the SHRs. The injected hiPSC-MSCs accumulated adjacent to the splenic nerve, potentially contributing to the antihypertensive effects. Furthermore, the hiPSC-MSCs released abundant glutamate, which acts as a neuromodulator to activate the splenic sympathetic nerve. After inhibition of glutamate synthesis by siRNA, the ability of hiPSC-MSCs to activate sympathetic nerves was significantly diminished. In addition, the antihypertensive effects of hiPSC-MSCs were eliminated after splenic nerve denervation（SND）, underscoring the critical role of the splenic nerve. Moreover, activation of the splenic nerve resulted in increased release of norepinephrine（NE）, which increased the number of choline acetyltransferase-positive（ChAT+） cells in the spleen and peripheral blood. Consequently, the acetylcholine（ACh） produced by elevated ChAT+cells could act as a vasodilator, lowering blood pressure and mitigating inflammation in end target organs. In summary, our findings indicate that hiPSC-MSCs effectively lower blood pressure in hypertension by influencing the splenic nerves and regulating ChAT+cells. The co

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High dimensional proteomic mapping of bone marrow immune characteristics in immune thrombocytopenia

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Science China(Life Sciences) 2024年第8期67卷 1635-1647页

作者： Feng-Qi Liu Qing-Yuan Qu Ying Lei Qi Chen Yu-Xiu Chen Meng-Lin Li Xue-Yan Sun Ye-Jun Wu Qiu-Sha Huang Hai-Xia Fu Yuan Kong Yue-Ying Li Qian-Fei Wang Xiao-Jun Huang Xiao-Hui Zhang Peking University People’s Hospital Peking University Institute of HematologyBeijing 100044China Beijing Key laboratory of Hematopoietic stem cell Transplantation Beijing 100044China national Clinical Research Center for Hematologic Disease Beijing 100044China Collaborative Innovation Centre of Hematology Peking UniversityBeijing 100044China CAS Key laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijing 100074China State Key laboratory of Natural and Biomimetic Drugs Peking UniversityBeijing 100191China

To investigate the role of co-stimulatory and co-inhibitory molecules on immune tolerance in immune thrombocytopenia(ITP),this study mapped the immune cell heterogeneity in the bone marrow of ITP at the single-cell level using Cytometry by Time of Flight(CyTOF).Thirtysix patients with ITP and nine healthy volunteers were enrolled in the *** soluble immunomodulatory molecules,more sCD25 and sGalectin-9 were detected in ITP *** the cell surface,co-stimulatory molecules like ICOS and HVEM were observed to be upregulated in mainly central memory and effector T *** contrast,co-inhibitory molecules such as CTLA-4 were significantly reduced in Th1 and Th17 cell *** a platelet count of 30×10^(9)L^(−1)as the cutoff value,ITP patients with high and low platelet counts showed different T cell immune ***-presenting cells such as monocytes and B cells may regulate the activation of T cells through CTLA-4/CD86 and HVEM/BTLA interactions,respectively,and participate in the pathogenesis of *** conclusion,the proteomic and soluble molecular profiles brought insight into the interaction and modulation of immune cells in the bone marrow of *** may offer novel targets to develop personalized immunotherapies.

关键词： immune thrombocytopenia autoimmune diseases co-stimulatory co-inhibitory immune checkpoint CTLA4 Cytometry by Time of Flight bone marrow

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Comparison of clinical features of nephrotic syndrome after haploidentical and matched donor hematopoietic stem cell transplantation

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Chinese Medical Journal 2024年第4期137卷 478-480页

作者： Wei Sun Yuanyuan Zhang Yuhong Chen Yuqian Sun Yifei Cheng Fengrong Wang Huan Chen Yao Chen Chenhua Yan Xiaodong Mo Wei Han Lanping Xu Yu Wang Xiaohui Zhang Kaiyan Liu Xiaojun Huang Peking University People’s Hospital Peking University Institute of HematologyNational Clinical Research Center for Hematologic DiseaseBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationPeking UniversityBeijing 10004China

To the Editor:Allogeneic hematopoietic stem cell transplantation(allo-HSCT)is one of the most effective options for hematological ***,allo-HSCT treatment can cause serious ***-transplant kidney damage is an important *** this study,we retrospectively analyzed the frequency of nephrotic syndrome(NS)after allo-HSCT and compared the frequency and clinical characteristics of NS between haploidentical donor(HID)and matched donor(MD)HSCT(including matched sibling donors[MSD]and unrelated donors[URD]).

关键词： hematopoietic clinical matched

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Mesenchymal stem cell-derived exosomes: Versatile nanomaterials for skin wound treatment

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Nano Research 2024年第4期17卷 2836-2856页

作者： Yuzhen Xiao Hexi Li Junhui Zhang Songyun Yang Chunsen Zhang Yizhou Huang Xin Tang Huiqi Xie Department of Orthopedic Surgery and Orthopedic Research Institute Laboratory of Stem Cell and Tissue EngineeringState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China West China School of Basic Medical Sciences and Forensic Medicine Sichuan UniversityChengdu 610041China West China School of Public Health and West China Fourth Hospital Sichuan UniversityChengdu 610041China Sports Medicine Center West China HospitalSichuan UniversityChengdu 610041China

Accumulating studies reveal that mesenchymal stem cells(MSCs)promote skin wound healing mainly through the paracrine ***,one of the crucial paracrine mediators in wound healing,are cell-derived nanosized membranous vesicles containing diverse bioactive *** the potent ability of modulating skin cell behaviors,MSC-derived exosomes(MSC-Exos)are regarded as a promising nanomaterial for regenerative wound *** hostile conditions,MSC-Exos are efficient in protecting skin cells from severe damage and restoring their *** to recent studies,MSC-Exos possess remarkable pro-healing effects in a variety of skin wounds,typically resulting in increased wound closure,inhibited scar tissue formation,and better restoration of skin *** further enhance the therapeutic potential of MSC-Exos,the development of applicable pretreatment strategies and the optimization of exosome delivery are under intensive ***,we summarize current research progress of MSC-Exos for skin wound treatment,with an emphasis on the biological effects of these nanovesicles,the repair mechanisms,and future challenges in clinical translation.

关键词： exosomes mesenchymal stem cells diabetic wounds burn wounds scar wound healing

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