Cell stem cell最新文献_第3页

Clinical base editing for β-hemoglobinopathies across different genetic backgrounds 不同遗传背景下β-血红蛋白病的临床碱基编辑

IF 23.9 1区医学

Cell stem cell Pub Date : 2026-09-07 DOI: 10.1016/j.stem.2026.08.009

Rongrong Liu,Yongrong Lai,Lijie Wang,Xiaowen Qian,Xu-Kai Ma,Yaliang Li,Gaohui Yang,Lingling Shi,Zifeng Li,Jia Wei,Zhenbin Wei,Hongsheng Wang,Xuemei Zhou,Ling Yu,Bei Yang,Xiaowen Zhai,Xiaodun Mou,Li Yang,Jia Chen

{"title":"Clinical base editing for β-hemoglobinopathies across different genetic backgrounds","authors":"Rongrong Liu,Yongrong Lai,Lijie Wang,Xiaowen Qian,Xu-Kai Ma,Yaliang Li,Gaohui Yang,Lingling Shi,Zifeng Li,Jia Wei,Zhenbin Wei,Hongsheng Wang,Xuemei Zhou,Ling Yu,Bei Yang,Xiaowen Zhai,Xiaodun Mou,Li Yang,Jia Chen","doi":"10.1016/j.stem.2026.08.009","DOIUrl":"https://doi.org/10.1016/j.stem.2026.08.009","url":null,"abstract":"β-Hemoglobinopathies are monogenic disorders. We previously applied a transformer base editor (tBE) to reactivate fetal hemoglobin (HbF) expression, and five Chinese transfusion-dependent β-thalassemia (TDT) patients achieved transfusion independence. However, the applicability of tBE to sickle cell disease (SCD) and genetically different TDT populations remained unknown. Here, we show a four-patient descriptive report from three trials, including one African SCD patient and three TDT patients carrying mutations common in South and Southeast Asia. All patients achieve hematopoietic recovery, and red blood cell transfusions are discontinued in all cases. After more than 12 months of follow-up, all patients show durable editing, sustained high-level pan-cellular HbF expression, and transfusion independence. No vaso-occlusive episodes occur in the SCD patient. No off-target mutations, malignancies, or deaths are observed. These initial results support the feasibility of applying tBE to treat SCD and the reported TDT genotypes, warranting broader evaluation across diverse populations. ClinicalTrials.gov identifiers are as follows: NCT06328764, NCT06065189, and NCT06565026.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"28 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899078","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

Epi-Allele elicits compensatory expression of the non-targeted allele and prevents haploinsufficiency in dominant genetic diseases 外显子等位基因引起非靶向等位基因的代偿性表达，防止显性遗传病的单倍性不足

IF 23.9 1区医学

Cell stem cell Pub Date : 2026-09-03 DOI: 10.1016/j.stem.2026.08.004

Zhengmin Wang,Chengzhi Han,Yiming Huang,Yuyuan Fu,Kaijie Hu,Zheyong Huang,Weiying Meng,Qiyao Chen,Leilei Wu,Qiaozi Wang,Jinyan Zhang,Hao Luo,Yifan Wang,Lulu Zuo,Yingqi Li,Yiwen Tan,Qin Zhou,Shaoshuai Mao,Wenbo Peng,Juan Meng,Maoxiang Chen,Zhiyang Tian,Shuwei Chen,Zihan Hu,Lu Zhao,Yihan Shen,Shanshan Chen,Zhixin Shen,Lijuan Mo,Jinfeng Gao,Qiyu Li,Shiteng Cai,Jianhuang Xue,Yanan Song,Yidi Sun,Junbo Ge,Changyang Zhou

{"title":"Epi-Allele elicits compensatory expression of the non-targeted allele and prevents haploinsufficiency in dominant genetic diseases","authors":"Zhengmin Wang,Chengzhi Han,Yiming Huang,Yuyuan Fu,Kaijie Hu,Zheyong Huang,Weiying Meng,Qiyao Chen,Leilei Wu,Qiaozi Wang,Jinyan Zhang,Hao Luo,Yifan Wang,Lulu Zuo,Yingqi Li,Yiwen Tan,Qin Zhou,Shaoshuai Mao,Wenbo Peng,Juan Meng,Maoxiang Chen,Zhiyang Tian,Shuwei Chen,Zihan Hu,Lu Zhao,Yihan Shen,Shanshan Chen,Zhixin Shen,Lijuan Mo,Jinfeng Gao,Qiyu Li,Shiteng Cai,Jianhuang Xue,Yanan Song,Yidi Sun,Junbo Ge,Changyang Zhou","doi":"10.1016/j.stem.2026.08.004","DOIUrl":"https://doi.org/10.1016/j.stem.2026.08.004","url":null,"abstract":"Epigenetic regulation may underlie asymmetric allelic expression of many genes during development and disease pathogenesis. Allele-specific epigenetic modification could provide an efficient therapy for dominant genetic diseases due to heterozygous mutations. We developed an allele-specific epigenetic editing method (“Epi-Allele”) for silencing pathogenic alleles and found surprisingly elevated expression of the non-targeted alleles, leaving total gene expression unchanged. Genome-wide screening revealed that such compensated allelic expression represents a common phenomenon, suggesting that the Epi-Allele approach could avoid the haploinsufficiency induced by current allele-specific silencing therapies. This notion was validated by allele-specific epigenetic remodeling of Myh6 and MYH7 genes in ameliorating cardiac phenotypes in a hypertrophic cardiomyopathy (HCM) mouse model and HCM patient iPSC-derived cardiomyocytes, respectively. Thus, Epi-Allele offers an allele-specific haploinsufficiency-free therapeutic approach for treating dominant genetic diseases.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"84 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148877391","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

APOE4 astrocytes call the shots on neuronal α-synuclein pathology APOE4星形胶质细胞在神经元α-突触核蛋白病理中起主导作用

IF 23.9 1区医学

Cell stem cell Pub Date : 2026-09-03 DOI: 10.1016/j.stem.2026.08.007

Nicole R. West,Julia TCW

引用次数: 0

Feeling the tension: Engineered stem cells convert tumor stiffness into a drug target 感受紧张：工程干细胞将肿瘤僵硬转化为药物靶标

IF 23.9 1区医学

Cell stem cell Pub Date : 2026-09-03 DOI: 10.1016/j.stem.2026.08.010

Peihang Jiang,Ke Cheng

引用次数: 0

Endothelialized callus organoids drive rapid regeneration of critical-size segmental long bone defects 内皮化的骨痂类器官驱动临界大小的节段性长骨缺损的快速再生

IF 23.9 1区医学

Cell stem cell Pub Date : 2026-09-03 DOI: 10.1016/j.stem.2026.08.005

Hanna Svitina,Jiarun Bai,Tobie Martens,Pieter Vanden Berghe,Ioannis Papantoniou

{"title":"Endothelialized callus organoids drive rapid regeneration of critical-size segmental long bone defects","authors":"Hanna Svitina,Jiarun Bai,Tobie Martens,Pieter Vanden Berghe,Ioannis Papantoniou","doi":"10.1016/j.stem.2026.08.005","DOIUrl":"https://doi.org/10.1016/j.stem.2026.08.005","url":null,"abstract":"Large bone defects remain a major clinical challenge, as current treatments cannot effectively regenerate them and fail to restore functionality. To recapitulate the cellular complexity of the early fracture callus, we engineered human endothelialized callus organoids (hECOs) by co-culturing periosteum-derived skeletal progenitors with endothelial cells. This co-culture resulted in cellular self-assembly, leading to spatially organized, callus-like structures. Endothelial cells promoted skeletal progenitor cell expansion, extracellular matrix maturation, and progression toward hypertrophic cartilage, hallmarks of endochondral ossification. Multi-omics analyses identified endothelial cell-mediated activation of regenerative programs associated with skeletal maturation, matrix remodeling, and angiogenesis. Following brief in vitro differentiation, macroscale aggregates of hECOs supported rapid host vascularization and regeneration of critical-size tibial defects in immunocompromised mice. Donor-derived cells actively contributed to early regeneration but were progressively replaced during remodeling, consistent with hECOs functioning as transient biological templates that guide host-mediated bone regeneration.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"31 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148877385","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

Heart valves enter their organoid era 心脏瓣膜进入了类器官时代

IF 23.9 1区医学

Cell stem cell Pub Date : 2026-09-03 DOI: 10.1016/j.stem.2026.08.003

Ana M. Porras,Kristyn S. Masters

引用次数: 0

Beyond compensation: Organized pathological hematopoiesis in the myelofibrotic spleen 超越补偿：骨髓纤维化脾脏组织病理造血

IF 23.9 1区医学

Cell stem cell Pub Date : 2026-09-03 DOI: 10.1016/j.stem.2026.08.008

Guohuan Sun,Tao Cheng

引用次数: 0

Cholesterol dysregulation in APOE4 astrocytes promotes α-synuclein pathology in miBrains APOE4星形胶质细胞胆固醇失调可促进大鼠脑α-突触核蛋白病理

IF 23.9 1区医学

Cell stem cell Pub Date : 2026-08-24 DOI: 10.1016/j.stem.2026.08.001

Louise A. Mesentier-Louro,Camille Goldman,Sebastian Gaese,Alice Buonfiglioli,Dimitrios Kyriakis,Ashley Harlock,Alain Ndayisaba,Emily R. Sartori,Abigail Uchitelev,John F. Fullard,Evelyn Hennigan,Donghoon Lee,Braxton R. Schuldt,Rikki B. Rooklin,Jonathan Barra,Jose Javier Bravo-Cordero,Panos Roussos,Vikram Khurana,Joel W. Blanchard

{"title":"Cholesterol dysregulation in APOE4 astrocytes promotes α-synuclein pathology in miBrains","authors":"Louise A. Mesentier-Louro,Camille Goldman,Sebastian Gaese,Alice Buonfiglioli,Dimitrios Kyriakis,Ashley Harlock,Alain Ndayisaba,Emily R. Sartori,Abigail Uchitelev,John F. Fullard,Evelyn Hennigan,Donghoon Lee,Braxton R. Schuldt,Rikki B. Rooklin,Jonathan Barra,Jose Javier Bravo-Cordero,Panos Roussos,Vikram Khurana,Joel W. Blanchard","doi":"10.1016/j.stem.2026.08.001","DOIUrl":"https://doi.org/10.1016/j.stem.2026.08.001","url":null,"abstract":"The pathological hallmarks of neurodegeneration are the aberrant post-translational modification and aggregation of proteins. Genetic factors, like APOE4, increase the prevalence and severity of tau, amyloid, and α-synuclein pathologies. However, the human brain is largely inaccessible during this process, limiting mechanistic understanding. Here, we developed an iPSC-based 3D model that integrates neurons, glia, myelin, and cerebrovascular cells into a human brain-like tissue (“miBrain”). Single-nucleus RNA sequencing of miBrains confirmed the presence of diverse cell populations and revealed transcriptional responses to α-synuclein pathology. Like the human brain, pathogenic α-synuclein is increased in APOE4/4 miBrains. Combinatorial experiments revealed that endolysosomal dysfunction caused by cholesterol accumulation in APOE4/4 astrocytes impairs the degradation of soluble α-synuclein leading to a pathogenic transformation that seeds α-synuclein inclusions in neurons. Collectively, this study establishes a robust model for investigating protein inclusions in human iPSC-derived brain tissue and highlights the role of astrocytes and cholesterol in APOE4-mediated pathologies.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"131 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148805908","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

Engineered mechanosensitive MSCs enable synthetic radiotheranostic targeting across tumor types 工程化的机械敏感间充质干细胞能够实现跨肿瘤类型的合成放射治疗靶向

IF 23.9 1区医学

Cell stem cell Pub Date : 2026-08-20 DOI: 10.1016/j.stem.2026.07.015

Xiujie Yang,Qi Yin,Kui Li,Jianze Wang,Rui Song,Haoyi Zhou,Shu Han,Linyu Zhang,Yuwen Zeng,Da Xu,Feng Wang,Shixin Zhou,Yang Yang,Hua Zhu,Chunhong Zheng,Yang Li,Zhi Yang,Xing Yang,Zhaofei Liu

{"title":"Engineered mechanosensitive MSCs enable synthetic radiotheranostic targeting across tumor types","authors":"Xiujie Yang,Qi Yin,Kui Li,Jianze Wang,Rui Song,Haoyi Zhou,Shu Han,Linyu Zhang,Yuwen Zeng,Da Xu,Feng Wang,Shixin Zhou,Yang Yang,Hua Zhu,Chunhong Zheng,Yang Li,Zhi Yang,Xing Yang,Zhaofei Liu","doi":"10.1016/j.stem.2026.07.015","DOIUrl":"https://doi.org/10.1016/j.stem.2026.07.015","url":null,"abstract":"Radiopharmaceutical-based imaging and targeted radionuclide therapy are often limited by heterogeneous or absent molecular targets in tumors. Here, we present a stiffness-responsive mesenchymal stem cell (MSC)-assisted relayed tumor-targeting (SMART) platform that converts matrix stiffness into a programmable molecular entry point for radiotheranostics. Engineered MSCs sense elevated mechanical stiffness within the tumor microenvironment and induce localized expression of synthetic biomarkers, thereby enabling radiopharmaceutical targeting independent of endogenous target availability. As a proof of concept, SMART-driven expression of prostate-specific membrane antigen (PSMA) enables sensitive tumor detection by 68Ga-PSMA-617 positron emission tomography (PET) and effective treatment with 177Lu-AB-PSMA-617 across multiple tumor models, with improved sensitivity and reduced off-target uptake compared with conventional 18F-fluorodeoxyglucose PET. This platform is readily adaptable to alternative synthetic targets and induced pluripotent stem cell (iPSC)-derived MSCs. By translating a universal physical feature of tumors into an actionable molecular signature, SMART expands the scope of precision radiotheranostics beyond native biomarkers.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"66 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148768899","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

Morphogen-guided neocortical organoids with anteroposterior areal identity 形态因子引导的具有前后面同一性的新皮质类器官

IF 23.9 1区医学

Cell stem cell Pub Date : 2026-08-20 DOI: 10.1016/j.stem.2026.07.014

Yuan-Chen Tsai,Hajime Ozaki,Axel A. Almet,Isabel Fleming,Caihao Nie,Songhao Luo,Xinyi Wang,Kaori Shiraiwa,Matthew Jung Min Noh,Sunnyana Trejo,Bret Kiyoshi Sugita,Jiya Dalal,Ruben Alberto Gonzalez,Briana De Jesus,Nate Branco,Gregory Li-Min Chen,Michael J. Gandal,Qing Nie,Momoko Watanabe

{"title":"Morphogen-guided neocortical organoids with anteroposterior areal identity","authors":"Yuan-Chen Tsai,Hajime Ozaki,Axel A. Almet,Isabel Fleming,Caihao Nie,Songhao Luo,Xinyi Wang,Kaori Shiraiwa,Matthew Jung Min Noh,Sunnyana Trejo,Bret Kiyoshi Sugita,Jiya Dalal,Ruben Alberto Gonzalez,Briana De Jesus,Nate Branco,Gregory Li-Min Chen,Michael J. Gandal,Qing Nie,Momoko Watanabe","doi":"10.1016/j.stem.2026.07.014","DOIUrl":"https://doi.org/10.1016/j.stem.2026.07.014","url":null,"abstract":"The human neocortex exhibits characteristic regional patterning (arealization) critical for higher-order cognitive function. Disrupted arealization is implicated in neurodevelopmental disorders (NDDs), but current neocortical organoid models largely fail to recapitulate this patterning, limiting mechanistic understanding. We establish a straightforward method for generating arealized organoids through short-term early exposure to anterior or posterior morphogens. These treatments created distinct anteroposterior (AP) signaling centers, supporting long-lasting polarization validated by spatial and single-cell RNA sequencing, which revealed area-specific molecular signatures matching the prenatal human cortex. To demonstrate utility, we modeled fragile X syndrome (FXS) in organoids with distinct AP identities. FXS organoids showed disrupted expression gradients along the AP axis, consistent with alterations in autism spectrum disorder, demonstrating how regional patterning defects may contribute to NDD pathology. Together, our study provides a robust platform for generating neocortical organoids with AP molecular signatures and highlights the importance of modeling NDDs using experimental platforms with neuroanatomic specificity.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"114 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148768900","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