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HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury HBO1是肝损伤过程中肝细胞可塑性和重编程的表观遗传屏障
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-05-21 DOI: 10.1016/j.stem.2025.04.010
Wei-Chien Yuan, Andrew S. Earl, Sai Ma, Karel Alcedo, Jacquelyn O. Russell, Fabiana M. Duarte, Yen-Ting Chu, Pei-Chi Chang, Hsin-Yi Chen, Hsin-Hui Chi, Qian Zhu, Alejo E. Rodriguez-Fraticelli, Sachin H. Patel, Yu-Ru Lee, Jason D. Buenrostro, Fernando D. Camargo
Hepatocytes can reprogram into biliary epithelial cells (BECs) during liver injury, but the underlying epigenetic mechanisms remain poorly understood. Here, we define the chromatin dynamics of this process using single-cell ATAC-seq and identify YAP/TEAD activation as a key driver of chromatin remodeling. An in vivo CRISPR screen highlights the histone acetyltransferase HBO1 as a critical barrier to reprogramming. HBO1 is recruited by YAP to target loci, where it promotes histone H3 lysine 14 acetylation (H3K14ac) and engages the chromatin reader zinc-finger MYND-type containing 8 (ZMYND8) to suppress YAP/TEAD-driven transcription. Loss of HBO1 accelerates chromatin remodeling, enhances YAP binding, and enables a more complete hepatocyte-to-BEC transition. Our findings position HBO1 as an epigenetic brake that restrains YAP-mediated reprogramming, suggesting that targeting HBO1 may enhance hepatocyte plasticity for liver regeneration.
肝损伤过程中肝细胞可重编程为胆道上皮细胞(BECs),但其潜在的表观遗传机制尚不清楚。在这里,我们使用单细胞ATAC-seq定义了这一过程的染色质动力学,并确定YAP/TEAD激活是染色质重塑的关键驱动因素。一项体内CRISPR筛选显示,组蛋白乙酰转移酶HBO1是重编程的关键障碍。HBO1被YAP招募到目标位点,在那里它促进组蛋白H3赖氨酸14乙酰化(H3K14ac),并参与染色质读取器锌指MYND-type containing 8 (ZMYND8)抑制YAP/ tead驱动的转录。HBO1的缺失加速了染色质重塑,增强了YAP的结合,并使肝细胞更完整地转变为bec。我们的研究结果表明HBO1是一种抑制yap介导的重编程的表观遗传制动,这表明靶向HBO1可能会增强肝细胞的可塑性,从而促进肝脏再生。
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引用次数: 0
Establishing dorsal-ventral patterning in human neural tube organoids with synthetic organizers 用合成组织者建立人神经管类器官的背-腹模式
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-05-14 DOI: 10.1016/j.stem.2025.04.011
Tao Luo, Cong Liu, Tao Cheng, Guo-Qin Zhao, Ying Huang, Jing-Yun Luan, Junyu Guo, Xiang Liu, Yi-Fan Wang, Yang Dong, Yu Xiao, Enhui He, Rui-Zhen Sun, Xiuyu Chen, Jiekai Chen, Jun Ma, Sean Megason, Junfeng Ji, Peng-Fei Xu
Precise dorsal-ventral (D-V) patterning of the neural tube (NT) is essential for the development and function of the central nervous system. However, existing models for studying NT D-V patterning and related human diseases remain inadequate. Here, we present organizers derived from pluripotent stem cell aggregate fusion (“ORDER”), a method that establishes opposing BMP and SHH gradients within neural ectodermal cell aggregates. Using this approach, we generated NT organoids with ordered D-V patterning from both zebrafish and human pluripotent stem cells (hPSCs). Single-cell transcriptomic analysis revealed that the synthetic human NT organoids (hNTOs) closely resemble the human embryonic spinal cord at Carnegie stage 12 (CS12) and exhibit greater similarity to human NT than to mouse models. Furthermore, using the hNTO model, we demonstrated the critical role of WNT signaling in regulating intermediate progenitors, modeled TCTN2-related D-V patterning defects, and identified a rescue strategy.
神经管(NT)的精确背腹(D-V)模式对中枢神经系统的发育和功能至关重要。然而,研究NT - D-V模式和相关人类疾病的现有模型仍然不足。在这里,我们介绍了来自多能干细胞聚集体融合(“ORDER”)的组织者,这是一种在神经外胚层细胞聚集体中建立相反的BMP和SHH梯度的方法。利用这种方法,我们从斑马鱼和人类多能干细胞(hPSCs)中生成了具有有序D-V模式的NT类器官。单细胞转录组学分析显示,合成的人类NT类器官(hNTOs)与卡内基12期(CS12)的人类胚胎脊髓非常相似,与人类NT的相似性高于小鼠模型。此外,利用hNTO模型,我们证明了WNT信号在调节中间祖细胞中的关键作用,模拟了tctn2相关的D-V模式缺陷,并确定了一种拯救策略。
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引用次数: 0
Vaccination-based immunotherapy to target profibrotic cells in liver and lung 针对肝和肺纤维化细胞的基于疫苗的免疫治疗
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-05-10 DOI: 10.1016/j.stem.2025.05.002
Michal Sobecki, Jing Chen, Ewelina Krzywinska, Shunmugam Nagarajan, Zheng Fan, Eric Nelius, Josep M. Monné Rodriguez, Frauke Seehusen, Amro Hussein, Greta Moschini, Edries Y. Hajam, Ravi Kiran, Dagmar Gotthardt, Julien Debbache, Cécile Badoual, Tatsuyuki Sato, Takayuki Isagawa, Norihiko Takeda, Corinne Tanchot, Eric Tartour, Christian Stockmann
(Cell Stem Cell 29, 1459–1474.e1–e9; October 6, 2022)
(细胞干细胞29,1459-1474.e1-e9;2022年10月6日)
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引用次数: 0
Integrating collecting systems in human kidney organoids through fusion of distal nephron to ureteric bud 通过远端肾元与输尿管芽融合整合人肾类器官收集系统
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-05-08 DOI: 10.1016/j.stem.2025.04.008
Min Shi, Brittney Crouse, Nambirajan Sundaram, Naomi Pode Shakked, Konrad Thorner, Nathaniel M. King, Parna Dutta, Lioba Ester, Weitao Zhang, Vinothini Govindarajah, Raphael Kopan, Cristina Cebrian, Christopher N. Mayhew, Michael A. Helmrath, Joseph V. Bonventre, Kyle W. McCracken
Kidneys maintain homeostasis through an array of parallel nephrons, which fuse during development to a system of collecting ducts (CDs), establishing the essential luminal pathway for excretion of metabolic waste. Human kidney organoids derived from pluripotent stem cells (human pluripotent stem cells [hPSCs]) generate nephrons that lack CDs and terminate as blind-ended tubules, limiting their functional potential. Here, we describe a developmentally inspired hPSC differentiation system that addresses this deficiency through assembly of induced nephrogenic mesenchyme with ureteric bud (UB) progenitors, leading to a CD network functionally integrated in kidney organoids through fusion with the distal tubule. The nephron fusion occurs stereotypically and is regulated by proximal-distal nephron patterning, which can be modulated through temporal manipulation of developmental pathways. This work provides a platform for interrogating the principles and mechanisms underlying nephron-UB fusion and a framework for engineering unobstructed nephrons with collecting systems, an important step toward de novo generation of functional kidney tissue.
肾脏通过一系列平行的肾单位来维持体内平衡,这些肾单位在发育过程中融合成一个收集管系统,建立了排泄代谢废物的基本管道。来源于多能干细胞的人肾类器官(Human pluripotent stem cells [hPSCs])产生缺乏cd的肾单位,并以盲端小管终止,限制了它们的功能潜力。在这里,我们描述了一个发育启发的hPSC分化系统,该系统通过与输尿管芽(UB)祖细胞的诱导肾原间质组装来解决这一缺陷,导致CD网络通过与远端小管融合在肾类器官中功能整合。肾元融合的发生是典型的,并受近端-远端肾元模式的调节,这可以通过发育途径的时间操纵来调节。这项工作为探究肾元- ub融合的原理和机制提供了一个平台,并为具有收集系统的无障碍肾元工程提供了一个框架,这是功能肾组织新生的重要一步。
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引用次数: 0
3D reconstruction of a human Carnegie stage 9 embryo provides a snapshot of early body plan formation 人类卡内基9期胚胎的三维重建提供了早期身体计划形成的快照
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-05-08 DOI: 10.1016/j.stem.2025.04.007
Yang Yuan, Xiaoyan Wang, Xiaodi Yan, Nannan He, Xiaojian Lu, Jingyu Yang, Xinwei Xie, Huiyao Yuan, Naixin Chen, Yinbo Liu, Hongan Ren, Runzhao Zhang, Lina Cui, Pengcheng Ren, Sirui Lin, Shuhan Cheng, Xiaolong Yang, Yifei Guo, Rong Li, Tianyi Yan, Leqian Yu
The Carnegie stage 9 (CS9) embryo is a pivotal phase signifying the conclusion of gastrulation and the onset of early organogenesis, crucial for initiating major organ system development. Utilizing spatial transcriptomics, we analyzed an intact CS9 human embryo in a spatially detailed manner. Through the examination of 75 transverse cryosections, we digitally reconstructed a 3D model, allowing us to identify diverse cell types, including those from brain and spine regions, the primitive gut tube, distinct somite formation stages, somatic mesoderm, splanchnic mesoderm, etc. Notably, we observed two distinct trajectories of hindbrain development, pinpointed the isthmic organizer at the midbrain-hindbrain boundary, delineated the bi-layered structure of neuromesodermal progenitor (NMP) cells, and described the early aorta formation and primordial germ cells (PGCs) presence in the aorta-gonad-mesonephros (AGM) region. This study provides key insights into the transcriptomic and spatial intricacies shaping the human body plan.
卡内基9期(CS9)胚胎是一个关键阶段,标志着原肠胚形成的结束和早期器官发生的开始,对主要器官系统的发育至关重要。利用空间转录组学,我们对一个完整的CS9人胚胎进行了详细的空间分析。通过检查75个横向冷冻切片,我们数字化重建了一个3D模型,使我们能够识别不同的细胞类型,包括来自大脑和脊柱区域的细胞,原始肠管,不同的体体形成阶段,体细胞中胚层,内脏中胚层等。值得注意的是,我们观察到后脑发育的两条不同轨迹,确定了中脑-后脑边界的缺血组织者,描绘了神经中胚层祖细胞(NMP)的双层结构,并描述了主动脉-性腺-中肾(AGM)区域的早期主动脉形成和原始生殖细胞(PGCs)的存在。这项研究为形成人体计划的转录组学和空间复杂性提供了关键见解。
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引用次数: 0
Specification of human brain regions with orthogonal gradients of WNT and SHH in organoids reveals patterning variations across cell lines 用类器官中WNT和SHH的正交梯度对人类大脑区域的描述揭示了不同细胞系间的模式变化
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-05-01 DOI: 10.1016/j.stem.2025.04.006
Soraya Scuderi, Tae-Yun Kang, Alexandre Jourdon, Alex Nelson, Liang Yang, Feinan Wu, George M. Anderson, Jessica Mariani, Livia Tomasini, Vivekananda Sarangi, Alexej Abyzov, Andre Levchenko, Flora M. Vaccarino
The repertoire of neurons and their progenitors depends on their location along the antero-posterior and dorso-ventral axes of the neural tube. To model these axes, we designed the Dual Orthogonal-Morphogen Assisted Patterning System (Duo-MAPS) diffusion device to expose spheres of induced pluripotent stem cells (iPSCs) to concomitant orthogonal gradients of a posteriorizing and a ventralizing morphogen, activating WNT and SHH signaling, respectively. Comparison with single-cell transcriptomes from the fetal human brain revealed that Duo-MAPS-patterned organoids generated an extensive diversity of neuronal lineages from the forebrain, midbrain, and hindbrain. WNT and SHH crosstalk translated into early patterns of gene expression programs associated with the generation of specific brain lineages with distinct functional networks. Human iPSC lines showed substantial interindividual and line-to-line variations in their response to morphogens, highlighting that genetic and epigenetic variations may influence regional specification. Morphogen gradients promise to be a key approach to model the brain in its entirety.
神经元及其祖细胞的种类取决于它们沿神经管的前后轴和背腹轴的位置。为了模拟这些轴,我们设计了双正交形态因子辅助模式系统(Dual orthogonal - morphogen Assisted Patterning System, Duo-MAPS)扩散装置,将诱导多能干细胞(iPSCs)球体暴露于后置和前置形态因子的正交梯度中,分别激活WNT和SHH信号。与胎儿大脑单细胞转录组的比较显示,双map模式类器官从前脑、中脑和后脑产生了广泛的神经谱系多样性。WNT和SHH的串扰被翻译成与具有不同功能网络的特定脑谱系的产生相关的早期基因表达程序模式。人类iPSC系在对形态因子的反应中显示出大量的个体间和系间差异,突出表明遗传和表观遗传变异可能影响区域规格。形态发生梯度有望成为全面模拟大脑的关键方法。
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引用次数: 0
Shaping intestinal organoids: Engineering crypt curvature to guide stem cell niches 塑造肠道类器官:工程隐窝曲率引导干细胞壁龛
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-05-01 DOI: 10.1016/j.stem.2025.03.015
Riccardo Barrile, Magdalena Kasendra
Yavitt et al.1 introduce a photodegradable hydrogel platform to control crypt curvature in intestinal organoids, revealing how epithelial morphology directs Paneth cell localization. This innovative approach advances organoid engineering, providing a reproducible method to study stem cell niche interactions and model intestinal development and disease.
Yavitt等人1介绍了一种可光降解的水凝胶平台来控制肠道类器官的隐窝弯曲,揭示了上皮形态如何指导Paneth细胞定位。这种创新的方法推进了类器官工程,为研究干细胞生态位相互作用和模拟肠道发育和疾病提供了一种可重复的方法。
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引用次数: 0
Dopaminergic neurons entering the brain under the immunological cover of darkness 多巴胺能神经元在黑暗的免疫掩护下进入大脑
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-05-01 DOI: 10.1016/j.stem.2025.04.004
Timothy Chai, Julie Y. Chen, Kyle M. Loh
The ability to transplant immunologically foreign cells into an animal without immune suppression would be transformative. Pavan et al. show that human pluripotent stem cell-derived dopaminergic neuron progenitors engineered to express eight immune-evasive proteins can engraft in humanized mice and a rat model of Parkinson’s disease without recourse to immune suppression.1
在没有免疫抑制的情况下,将免疫外来细胞移植到动物体内的能力将是革命性的。Pavan等人的研究表明,人类多能干细胞衍生的多巴胺能神经元祖细胞可以表达8种免疫逃避蛋白,无需免疫抑制就可以移植到人源化小鼠和帕金森病大鼠模型中
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引用次数: 0
Bioengineering innovations for neural organoids with enhanced fidelity and function 增强保真度和功能的类神经器官生物工程创新
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-05-01 DOI: 10.1016/j.stem.2025.03.014
Yubing Sun, Yoshiho Ikeuchi, Feng Guo, Insoo Hyun, Guo-li Ming, Jianping Fu
Neural organoids have been utilized to recapitulate different aspects of the developing nervous system. While hailed as promising experimental tools for studying human neural development and neuropathology, current neural organoids do not fully recapitulate the anatomy or microcircuitry-level functionality of the developing brain, spinal cord, or peripheral nervous system. In this review, we discuss emerging bioengineering approaches that control morphogen signals and biophysical microenvironments, which have improved the efficiency, fidelity, and utility of neural organoids. Furthermore, advancements in bioengineered tools have facilitated more sophisticated analyses of neural organoid functions and applications, including improved neural-bioelectronic interfaces and organoid-based information processing. Emerging bioethical issues associated with advanced neural organoids are also discussed. Future opportunities of neural organoid research lie in enhancing their fidelity, maturity, and complexity and expanding their applications in a scalable manner.
神经类器官已被用来概括发育中的神经系统的不同方面。虽然被誉为研究人类神经发育和神经病理学的有前途的实验工具,但目前的神经类器官并不能完全概括发育中的大脑、脊髓或周围神经系统的解剖结构或微电路水平的功能。在这篇综述中,我们讨论了控制形态信号和生物物理微环境的新兴生物工程方法,这些方法提高了神经类器官的效率、保真度和实用性。此外,生物工程工具的进步促进了对神经类器官功能和应用的更复杂的分析,包括改进的神经-生物电子接口和基于类器官的信息处理。新兴的生物伦理问题与先进的神经类器官也进行了讨论。神经类器官研究的未来机遇在于提高它们的保真度、成熟度和复杂性,并以可扩展的方式扩展它们的应用。
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引用次数: 0
Signaling switches: Metabolism regulates gastruloid self-organization 信号开关:代谢调节胃原质自组织
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-05-01 DOI: 10.1016/j.stem.2025.04.005
María J. Rodríguez Colman, Katharina F. Sonnen
Metabolic regulation of embryonic development is increasingly recognized. Villaronga-Luque et al.1 and Stopornwongkul et al.2 show that metabolic activity influences gastruloid formation from mouse embryonic stem cells, revealing that the balance between glycolysis and oxidative phosphorylation regulates cell fate decisions during gastruloid self-organization.
胚胎发育的代谢调节越来越被认识到。Villaronga-Luque等人1和Stopornwongkul等人2表明,代谢活动影响小鼠胚胎干细胞的胃原体形成,揭示糖酵解和氧化磷酸化之间的平衡调节了胃原体自组织过程中细胞命运的决定。
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引用次数: 0
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Cell stem cell
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