Cell stem cell最新文献

Generation of iPSC-derived human venous endothelial cells for the modeling of vascular malformations and drug discovery 生成 iPSC 衍生的人静脉内皮细胞，用于血管畸形建模和药物研发

IF 23.9 1区医学

Cell stem cell Pub Date : 2024-11-22 DOI: 10.1016/j.stem.2024.10.015

Zihang Pan, Qiyang Yao, Weijing Kong, Xiaojing Ma, Liangliang Tian, Yun Zhao, Shuntian Zhu, Sheng Chen, Mengze Sun, Jiao Liu, Simin Jiang, Jianxun Ma, Qijia Liu, Xiaohong Peng, Xiaoxia Li, Zixuan Hong, Yi Hong, Xue Wang, Jiarui Liu, Jingjing Zhang, Kai Wang

{"title":"Generation of iPSC-derived human venous endothelial cells for the modeling of vascular malformations and drug discovery","authors":"Zihang Pan, Qiyang Yao, Weijing Kong, Xiaojing Ma, Liangliang Tian, Yun Zhao, Shuntian Zhu, Sheng Chen, Mengze Sun, Jiao Liu, Simin Jiang, Jianxun Ma, Qijia Liu, Xiaohong Peng, Xiaoxia Li, Zixuan Hong, Yi Hong, Xue Wang, Jiarui Liu, Jingjing Zhang, Kai Wang","doi":"10.1016/j.stem.2024.10.015","DOIUrl":"https://doi.org/10.1016/j.stem.2024.10.015","url":null,"abstract":"Venous malformations (VMs) represent prevalent vascular anomalies typically attributed to non-inherited somatic mutations within venous endothelial cells (VECs). The lack of robust disease models for VMs impedes drug discovery. Here, we devise a robust protocol for the generation of human induced VECs (iVECs) through manipulation of cell-cycle dynamics via the retinoic signaling pathway. We introduce an L914F mutation into the TIE2 gene locus of induced pluripotent stem cells (iPSCs) and show that the mutated iVECs form dilated blood vessels after transplantation into mice, thereby recapitulating the phenotypic characteristics observed in VMs. Moreover, utilizing a deep neural network and a high-throughput digital RNA with perturbation of genes sequencing (DRUG-seq) approach, we perform drug screening and demonstrate that bosutinib effectively rescues the disease phenotype in vitro and in vivo. In summary, by leveraging genome editing and stem cell technology, we generate VM models that enable the development of additional therapeutics.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"19 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142690671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Post-transplant G-CSF impedes engraftment of gene-edited human hematopoietic stem cells by exacerbating p53-mediated DNA damage response 移植后的 G-CSF 通过加剧 p53 介导的 DNA 损伤反应，阻碍基因编辑的人类造血干细胞的移植

IF 23.9 1区医学

Cell stem cell Pub Date : 2024-11-12 DOI: 10.1016/j.stem.2024.10.013

Daisuke Araki, Vicky Chen, Neelam Redekar, Christi Salisbury-Ruf, Yan Luo, Poching Liu, Yuesheng Li, Richard H. Smith, Pradeep Dagur, Christian Combs, Andre Larochelle

{"title":"Post-transplant G-CSF impedes engraftment of gene-edited human hematopoietic stem cells by exacerbating p53-mediated DNA damage response","authors":"Daisuke Araki, Vicky Chen, Neelam Redekar, Christi Salisbury-Ruf, Yan Luo, Poching Liu, Yuesheng Li, Richard H. Smith, Pradeep Dagur, Christian Combs, Andre Larochelle","doi":"10.1016/j.stem.2024.10.013","DOIUrl":"https://doi.org/10.1016/j.stem.2024.10.013","url":null,"abstract":"Granulocyte-colony-stimulating factor (G-CSF) is commonly used to accelerate recovery from neutropenia following chemotherapy and autologous transplantation of hematopoietic stem and progenitor cells (HSPCs) for malignant disorders. However, its utility after ex vivo gene therapy in human HSPCs remains unexplored. We show that administering G-CSF from day 1 to 14 post-transplant impedes engraftment of CRISPR-Cas9 gene-edited human HSPCs in murine xenograft models. G-CSF affects gene-edited HSPCs through a cell-intrinsic mechanism, causing proliferative stress and amplifying the early p53-mediated DNA damage response triggered by Cas9-mediated DNA double-strand breaks. This underscores a threshold mechanism where p53 activation must reach a critical level to impair cellular function. Transiently inhibiting p53 or delaying the initiation of G-CSF treatment to day 5 post-transplant attenuates its negative impact on gene-edited HSPCs. The potential for increased HSPC toxicity associated with post-transplant G-CSF administration in CRISPR-Cas9 autologous HSPC gene therapy warrants consideration in clinical trials.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"107 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Regulated GATA1 expression as a universal gene therapy for Diamond-Blackfan anemia 将调控 GATA1 表达作为钻石-黑方贫血症的通用基因疗法

IF 23.9 1区医学

Cell stem cell Pub Date : 2024-11-11 DOI: 10.1016/j.stem.2024.10.012

Richard A. Voit, Xiaotian Liao, Alexis Caulier, Mateusz Antoszewski, Blake Cohen, Myriam Armant, Henry Y. Lu, Travis J. Fleming, Elena Kamal, Lara Wahlster, Aoife M. Roche, John K. Everett, Angelina Petrichenko, Mei-Mei Huang, William Clarke, Kasiani C. Myers, Craig Forester, Antonio Perez-Atayde, Frederic D. Bushman, Danilo Pellin, Vijay G. Sankaran

{"title":"Regulated GATA1 expression as a universal gene therapy for Diamond-Blackfan anemia","authors":"Richard A. Voit, Xiaotian Liao, Alexis Caulier, Mateusz Antoszewski, Blake Cohen, Myriam Armant, Henry Y. Lu, Travis J. Fleming, Elena Kamal, Lara Wahlster, Aoife M. Roche, John K. Everett, Angelina Petrichenko, Mei-Mei Huang, William Clarke, Kasiani C. Myers, Craig Forester, Antonio Perez-Atayde, Frederic D. Bushman, Danilo Pellin, Vijay G. Sankaran","doi":"10.1016/j.stem.2024.10.012","DOIUrl":"https://doi.org/10.1016/j.stem.2024.10.012","url":null,"abstract":"Gene therapy using hematopoietic stem and progenitor cells is altering the therapeutic landscape for patients with hematologic, immunologic, and metabolic disorders but has not yet been successfully developed for individuals with the bone marrow failure syndrome Diamond-Blackfan anemia (DBA). More than 30 mutations cause DBA through impaired ribosome function and lead to inefficient translation of the erythroid master regulator GATA1, providing a potential avenue for therapeutic intervention applicable to all patients with DBA, irrespective of the underlying genotype. Here, we report the development of a clinical-grade lentiviral gene therapy that achieves erythroid lineage-restricted expression of GATA1. We show that this vector is capable of augmenting erythropoiesis in DBA models and diverse patient samples without impacting hematopoietic stem cell function or demonstrating any signs of premalignant clonal expansion. These preclinical safety and efficacy data provide strong support for the first-in-human universal gene therapy trial for DBA through regulated GATA1 expression.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"10 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

All roads lead to cholesterol: Modulating lipid biosynthesis in multiple sclerosis patient-derived models 条条大路通罗马调节多发性硬化症患者衍生模型中的脂质生物合成

IF 23.9 1区医学

Cell stem cell Pub Date : 2024-11-07 DOI: 10.1016/j.stem.2024.10.011

Sophie Eichhorner, Larissa Traxler, Oliver Borgogno, Jerome Mertens

引用次数: 0

Nurturing protectors: Macrophages in the human pancreatic islet 培育保护者人类胰岛中的巨噬细胞

IF 23.9 1区医学

Cell stem cell Pub Date : 2024-11-07 DOI: 10.1016/j.stem.2024.10.006

Christopher Z.W. Lee, Francesca M. Spagnoli

引用次数: 0

CRISPRi/a screens in human iPSC-cardiomyocytes identify glycolytic activation as a druggable target for doxorubicin-induced cardiotoxicity 在人类 iPSC-心肌细胞中进行 CRISPRi/a 筛选，确定糖酵解激活是多柔比星诱导的心脏毒性的药物靶点

IF 23.9 1区医学

Cell stem cell Pub Date : 2024-11-07 DOI: 10.1016/j.stem.2024.10.007

Chun Liu, Mengcheng Shen, Yanxia Liu, Amit Manhas, Shane Rui Zhao, Mao Zhang, Nadjet Belbachir, Lu Ren, Joe Z. Zhang, Arianne Caudal, Masataka Nishiga, Dilip Thomas, Angela Zhang, Huaxiao Yang, Yang Zhou, Mohamed Ameen, Nazish Sayed, June-Wha Rhee, Lei S. Qi, Joseph C. Wu

{"title":"CRISPRi/a screens in human iPSC-cardiomyocytes identify glycolytic activation as a druggable target for doxorubicin-induced cardiotoxicity","authors":"Chun Liu, Mengcheng Shen, Yanxia Liu, Amit Manhas, Shane Rui Zhao, Mao Zhang, Nadjet Belbachir, Lu Ren, Joe Z. Zhang, Arianne Caudal, Masataka Nishiga, Dilip Thomas, Angela Zhang, Huaxiao Yang, Yang Zhou, Mohamed Ameen, Nazish Sayed, June-Wha Rhee, Lei S. Qi, Joseph C. Wu","doi":"10.1016/j.stem.2024.10.007","DOIUrl":"https://doi.org/10.1016/j.stem.2024.10.007","url":null,"abstract":"Doxorubicin is limited in its therapeutic utility due to its life-threatening cardiovascular side effects. Here, we present an integrated drug discovery pipeline combining human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs), CRISPR interference and activation (CRISPRi/a) bidirectional pooled screens, and a small-molecule screening to identify therapeutic targets mitigating doxorubicin-induced cardiotoxicity (DIC) without compromising its oncological effects. The screens revealed several previously unreported candidate genes contributing to DIC, including carbonic anhydrase 12 (CA12). Genetic inhibition of CA12 protected iCMs against DIC by improving cell survival, sarcomere structural integrity, contractile function, and calcium handling. Indisulam, a CA12 antagonist, can effectively attenuate DIC in iCMs, engineered heart tissue, and animal models. Mechanistically, doxorubicin-induced CA12 potentiated a glycolytic activation in cardiomyocytes, contributing to DIC by interfering with cellular metabolism and functions. Collectively, our study provides a roadmap for future drug discovery efforts, potentially leading to more targeted therapies with minimal off-target toxicity.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"149 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

To BE or to PE: Prime editors provide more choices for epitope-editing-based immunotherapy 要BE还是要PE：主编辑器为基于表位编辑的免疫疗法提供了更多选择

IF 23.9 1区医学

Cell stem cell Pub Date : 2024-11-07 DOI: 10.1016/j.stem.2024.10.009

S.M. Yin, D.L. Li

引用次数: 0

Trained immunity in the bone marrow: Hub of autoimmunity 骨髓中训练有素的免疫力自身免疫的枢纽

IF 23.9 1区医学

Cell stem cell Pub Date : 2024-11-07 DOI: 10.1016/j.stem.2024.10.008

Mihai G. Netea, Leo A.B. Joosten

引用次数: 0

Reconsidering the 14-day rule in human embryo research: Advice from the Dutch Health Council 重新考虑人类胚胎研究中的 14 天规则：荷兰卫生委员会的建议

IF 23.9 1区医学

Cell stem cell Pub Date : 2024-11-07 DOI: 10.1016/j.stem.2024.09.019

Hafez Ismaili M’hamdi, Guido de Wert

引用次数: 0

Maturation and persistence of CAR T cells derived from human pluripotent stem cells via chemical inhibition of G9a/GLP 通过化学抑制 G9a/GLP 实现人类多能干细胞 CAR T 细胞的成熟和持久性

IF 23.9 1区医学

Cell stem cell Pub Date : 2024-11-05 DOI: 10.1016/j.stem.2024.10.004

Ran Jing, Marcelo Falchetti, Tianxiao Han, Mohamad Najia, Luca T. Hensch, Eleanor Meader, Edroaldo Lummertz da Rocha, Martin Kononov, Stephanie Wang, Trevor Bingham, Zhiheng Li, Yunliang Zhao, Katie Frenis, Caroline Kubaczka, Song Yang, Deepak Jha, Gabriela F. Rodrigues-Luiz, R. Grant Rowe, Thorsten M. Schlaeger, Marcela V. Maus, George Q. Daley

{"title":"Maturation and persistence of CAR T cells derived from human pluripotent stem cells via chemical inhibition of G9a/GLP","authors":"Ran Jing, Marcelo Falchetti, Tianxiao Han, Mohamad Najia, Luca T. Hensch, Eleanor Meader, Edroaldo Lummertz da Rocha, Martin Kononov, Stephanie Wang, Trevor Bingham, Zhiheng Li, Yunliang Zhao, Katie Frenis, Caroline Kubaczka, Song Yang, Deepak Jha, Gabriela F. Rodrigues-Luiz, R. Grant Rowe, Thorsten M. Schlaeger, Marcela V. Maus, George Q. Daley","doi":"10.1016/j.stem.2024.10.004","DOIUrl":"https://doi.org/10.1016/j.stem.2024.10.004","url":null,"abstract":"Elucidating mechanisms of T cell development can guide in vitro T cell differentiation from induced pluripotent stem cells (iPSCs) and facilitate off-the-shelf T cell-based immunotherapies. Using a stroma-free human iPSC-T cell differentiation platform, we screened for epigenetic modulators that influence T cell specification and identified the H3K9-directed histone methyltransferases G9a/GLP as repressors of T cell fate. We show that G9a/GLP inhibition during specific time windows of differentiation of hematopoietic stem and progenitor cells (HSPCs) skews cell fates toward lymphoid lineages. Inhibition of G9a/GLP promotes the production of lymphoid cells during zebrafish embryonic hematopoiesis, demonstrating the evolutionary conservation of G9a/GLP function. Importantly, chemical inhibition of G9a/GLP facilitates the generation of mature iPSC-T cells that bear transcriptional similarity to peripheral blood αβ T cells. When engineered to express chimeric antigen receptors, the epigenetically engineered iPSC-T cells exhibit enhanced effector functions in vitro and durable, persistent antitumor activity in a xenograft tumor-rechallenge model.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"84 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0