European journal of cell biology最新文献_第5页

Versatility of vimentin assemblies: From filaments to biomolecular condensates and back 静脉蛋白组装的多功能性：从细丝到生物分子凝聚体再回来

IF 4.5 3区生物学 Q2 CELL BIOLOGY

European journal of cell biology

Pub Date : 2025-04-02 DOI: 10.1016/j.ejcb.2025.151487

Dolores Pérez-Sala, Silvia Zorrilla

Cytoskeletal structures shape and confer resistance to cells. The intermediate filament protein vimentin forms versatile structures that play key roles in cytoskeletal crosstalk, in the integration of cellular responses to a variety of external and internal cues, and in the defense against stress. Such multifaceted roles can be fulfilled thanks to the vast variety of vimentin proteoforms, which in turn arise from the combinations of a myriad of tightly regulated posttranslational modifications. Diverse vimentin proteoforms will differentially shape its polymeric assemblies, underlying vimentin ability to organize in filaments, bundles, squiggles, droplets, cell surface-bound and/or various secreted forms. Interestingly, certain vimentin dots or droplets have been lately categorized as biomolecular condensates. Biomolecular condensates are phase-separated membraneless structures that are critical for the organization of cellular components and play important roles in pathophysiology. Recent findings have unveiled the importance of low complexity sequence domains in vimentin filament assembly. Moreover, several oxidants trigger the transition of vimentin filaments into phase-separated biomolecular condensates, a reversible process that may provide clues on the role of condensates as seeds for filament formation. Revisiting previous results in the light of recent knowledge prompts the hypothesis that vimentin condensates could play a role in traffic of filament precursors, cytoskeletal crosstalk and cellular responses to stress. Deciphering the “vimentin posttranslational modification code”, that is, the structure-function relationships of vimentin proteoforms, constitutes a major challenge to understand the regulation of vimentin behavior and its multiple personalities. This will contribute to unveil essential cellular mechanisms and foster novel opportunities for drug discovery.

细胞骨架结构形成并赋予细胞抵抗力。中间丝蛋白波形蛋白形成多种多样的结构，在细胞骨架串扰中发挥关键作用，在细胞对各种外部和内部信号的反应整合中发挥关键作用，并在抵抗压力方面发挥关键作用。这种多面性的作用可以通过多种多样的蛋白形态来实现，而这些蛋白形态又源于无数严格调控的翻译后修饰的组合。不同的波形蛋白会形成不同的聚合物组合，从而使波形蛋白能够以丝状、束状、卷曲状、液滴状、细胞表面结合和/或各种分泌形式组织。有趣的是，某些波形蛋白点或液滴最近被归类为生物分子凝聚物。生物分子凝聚体是一种相分离的无膜结构，对细胞成分的组织至关重要，在病理生理中起着重要作用。最近的研究结果揭示了低复杂性序列域在静脉蛋白细丝组装中的重要性。此外，几种氧化剂触发了vimentin细丝向相分离的生物分子凝析物的转变，这一可逆过程可能为凝析物作为细丝形成种子的作用提供线索。根据最近的知识，回顾以前的结果提示了一个假设，即波形蛋白凝聚物可能在丝前体的运输、细胞骨架串扰和细胞对应激的反应中发挥作用。破解“弧菌蛋白翻译后修饰密码”，即弧菌蛋白的结构-功能关系，是理解弧菌蛋白行为调控及其多重人格的重大挑战。这将有助于揭示基本的细胞机制，并为药物发现创造新的机会。

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引用次数: 0

Human pluripotent stem cell-derived intestinal organoids for pharmacokinetic studies 用于药代动力学研究的人多能干细胞衍生的肠道类器官

IF 4.5 3区生物学 Q2 CELL BIOLOGY

European journal of cell biology

Pub Date : 2025-04-01 DOI: 10.1016/j.ejcb.2025.151489

Takumi Saito , Junichiro Amako , Teruhiko Watanabe , Nobuaki Shiraki , Shoen Kume

The human small intestine is essential for orally administered drugs' absorption, metabolism, and excretion. Human induced pluripotent stem cell (hiPSC)-derived intestinal epithelial cells (IECs) offer a useful model for evaluating drug candidate compounds. We previously reported a protocol to generate matured enterocyte-like cells that exhibit P-gp-mediated efflux and cytochrome P450 3A (CYP3A)-mediated metabolism from human iPSCs. However, under the current protocols, generating iPSC-derived intestinal enterocyte-like cells requires a multi-step differentiation procedure and is time-consuming. Recent progress in intestinal organoid (IO) study provides an understanding of the growth factors that enable the maintenance of adult stem cells. Here, we established an easily accessible protocol using a direct 3D cluster culture to derive IOs from hiPSCs (iPSC-IOs) with high self-proliferative ability. The hiPSC-IOs can be propagated for a long-term and maintained capacity to differentiate and can be cryopreserved. Upon seeding on a two-dimensional monolayer, hiPSC-IOs gave rise to the intestinal epithelial cells (IECs) containing mature cell types of the intestine. The hiPSC-IOs-derived IECs contain enterocytes that show CYP metabolizing enzyme and transporter activities and can be used for pharmacokinetic studies.

人体小肠对于口服药物的吸收、代谢和排泄至关重要。人诱导多能干细胞（hiPSC）来源的肠上皮细胞（IECs）为评价候选药物化合物提供了一个有用的模型。我们之前报道了一种从人iPSCs中产生成熟的肠细胞样细胞的方案，这些细胞表现出p- gp介导的外流和细胞色素P450 3A （CYP3A）介导的代谢。然而，在目前的方案下，生成ipsc衍生的肠细胞样细胞需要一个多步骤的分化过程，并且很耗时。肠道类器官（IO）研究的最新进展提供了对维持成体干细胞的生长因子的理解。在这里，我们建立了一个易于访问的协议，使用直接3D集群培养从具有高自我增殖能力的hiPSCs （iPSC-IOs）中获得IOs。hiPSC-IOs可以长期繁殖并保持分化能力，可以冷冻保存。在二维单层上播种后，hiPSC-IOs产生含有肠成熟细胞类型的肠上皮细胞（IECs）。hipsc - ios衍生的IECs含有显示CYP代谢酶和转运蛋白活性的肠细胞，可用于药代动力学研究。

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引用次数: 0

Activity and function of auxiliary fluxes of glucose metabolism in response to physiological normoxia (5 % O2) during long-term Adipose-Derived Stem/Stromal cell culture 长期脂肪源性干细胞/基质细胞培养过程中生理常氧（5 % O2）下葡萄糖代谢辅助通量的活性和功能

IF 4.5 3区生物学 Q2 CELL BIOLOGY

European journal of cell biology

Pub Date : 2025-03-28 DOI: 10.1016/j.ejcb.2025.151486

Paulina Rybkowska , Maria Kawalec , Dorota Dymkowska , Klaudia Radoszkiewicz , Barbara Zabłocka , Krzysztof Zabłocki , Anna Sarnowska

Energy metabolism homeostasis emerges as a dominant element influencing mesenchymal stem/stromal cells’ trajectory of development. The predominant glycolysis activity is a primary driver of cell proliferation and maintenance of the high-energetic state. Here, we examined the functions of two crucial auxiliary pathways: the phosphate-pentose pathway (PPP) and fructose-2,6-biphosphate pathway (FBP) to evaluate their impact on the therapeutic potential of Adipose-Derived Stem/Stromal cells (ASCs) during prolonged culture in various oxygen conditions: 5 % O₂ - physiological normoxia or 21 % O₂ - atmospheric oxygen. Our findings demonstrate that ASCs cultured in 5 % O₂ increased the rate of proliferation, migration, and expression of stemness factors, which is prominent during the initial and middle passages. Additionally, ASCs cultured in a 5 % O₂ exhibited heightened protection mechanisms against free radicals, increased LDH gene expression, and elevated extracellular acidification rate (ECAR). By estimating the HIF-1α level, we concluded that 5 % oxygen conditions were insufficient to induce a profound hypoxic state in ASCs. However, at the protein level, both the PPP and FBP pathways appeared to be more active in young (2-passage) cells, regardless of oxygen conditions, and their activity diminished over time. Additionally, the chemical suppression of G6PDH by Polydatin and inhibition of PFKFB3 by PFK-158 in ASCs (passage-2) revealed dose- and time-dependent effect on decreasing migratory capabilities of cells. Nevertheless, our work underscores the adaptable nature of ASC metabolism to prevailing external conditions, with the aging of the culture contributing to the decline in glycolysis-associated auxiliary pathways.

能量代谢稳态是影响间充质干细胞/基质细胞发育轨迹的主要因素。主要的糖酵解活性是细胞增殖和维持高能量状态的主要驱动因素。在这里，我们研究了两个关键的辅助途径的功能：磷酸戊糖途径（PPP）和果糖-2,6-二磷酸途径（FBP），以评估它们对脂肪衍生干细胞/基质细胞（ASCs）在不同氧条件下的治疗潜力的影响：5 % O2 -生理常氧或21 % O2 -大气氧。我们的研究结果表明，在5 % O2中培养的ASCs增加了增殖、迁移和干性因子的表达率，这在初始和中期表现突出。此外，在5 % O2中培养的ASCs表现出增强的抗自由基保护机制，增加LDH基因表达，提高细胞外酸化率（ECAR）。通过估计HIF-1α水平，我们得出结论，5% %的氧气条件不足以诱导ASCs的深度缺氧状态。然而，在蛋白质水平上，无论氧条件如何，PPP和FBP通路在年轻（2代）细胞中似乎都更活跃，并且它们的活性随着时间的推移而减弱。此外，在ASCs中，Polydatin对G6PDH的化学抑制和PFK-158对PFKFB3的抑制（传代-2）显示了剂量和时间依赖性对降低细胞迁移能力的影响。然而，我们的工作强调了ASC代谢对普遍外部条件的适应性，培养物的老化导致糖酵解相关辅助途径的下降。

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引用次数: 0

Advances in modeling the Charcot-Marie-Tooth disease: Human induced pluripotent stem cell-derived Schwann cells harboring SH3TC2 variants Charcot-Marie-Tooth病建模的进展：人类诱导的多能干细胞衍生的雪旺细胞含有SH3TC2变体

IF 4.5 3区生物学 Q2 CELL BIOLOGY

European journal of cell biology

Pub Date : 2025-03-24 DOI: 10.1016/j.ejcb.2025.151485

Camille Loret , Camille Scherrer , Amandine Rovini , Ioanna Pyromali , Pierre-Antoine Faye , Angélique Nizou , Franck Sturtz , Frédéric Favreau , Anne-Sophie Lia

Human induced pluripotent stem cells (hiPSCs) represent a powerful tool for investigating neuropathological disorders, such as Charcot-Marie-Tooth disease (CMT), the most prevalent inherited peripheral neuropathy, where the cells of interest are hardly accessible. Advancing the development of appropriate cellular models is crucial for studying the disease’s pathophysiology. In this study, we present the first two isogenic hiPSC-derived Schwann cell models for studying CMT4C, also known as AR-CMTde-SH3TC2. This subtype of CMT is associated with alterations in SH3TC2 and is the most prevalent form of autosomal recessive demyelinating CMT. We aimed to study the impact of two nonsense mutations in SH3TC2. To achieve this, we used two CRISPR hiPSC clones, one carrying a homozygous nonsense mutation: c.211C>T, p.Gln71*, and the other one, carrying the most common AR-CMTde-SH3TC2 alteration, c.2860G>A, p.Arg954*. To study the endogenous expression of SH3TC2 in the cells mainly altered in AR-CMTde-SH3TC2, we initiated the differentiation of both our CMT clones and their isogenic control into Schwann cells (SCs). This study represents the first in vitro investigation of human endogenous SH3TC2 expression in AR-CMTde-SH3TC2 hiPSC-derived SC models, allowing for the examination of its expression and of its cellular impact. By comparing this AR-CMTde-SH3TC2 models to the control one, we observed disparities in RNA and protein expression of SH3TC2. Additionally, our RNA and coculture experiments with hiPSC-derived motor neurons (MNs) revealed delayed maturation of SCs and a reduced ability of SH3TC2-deficient SCs to sustain motor neuron culture. Our findings also demonstrated a disability in receptor recycling in SH3TC2-deficient cells, depending on the AR-CMTde-SH3TC2 alteration. These hiPSC-derived-SC models further provide a new modelling tool for studying Schwann cell contribution to CMT4C.

人类诱导多能干细胞（hipsc）是研究神经病理疾病的有力工具，例如最普遍的遗传性周围神经病变Charcot-Marie-Tooth病（CMT），其中感兴趣的细胞很难获得。推进适当的细胞模型的发展对研究该疾病的病理生理至关重要。在这项研究中，我们提出了头两个等基因hipsc衍生的雪旺细胞模型，用于研究CMT4C，也称为AR-CMTde-SH3TC2。这种CMT亚型与SH3TC2的改变有关，是常染色体隐性脱髓鞘性CMT最常见的形式。我们的目的是研究SH3TC2中两个无义突变的影响。为了实现这一点，我们使用了两个CRISPR hiPSC克隆，一个携带纯合无义突变：c.211C>；T, p.Gln71*，另一个携带最常见的AR-CMTde-SH3TC2突变，c.2860G> a, p.Arg954*。为了研究AR-CMTde-SH3TC2主要改变的细胞中SH3TC2的内源性表达，我们启动了将CMT克隆及其等基因对照分化为雪旺细胞（SCs）。本研究首次在体外研究AR-CMTde-SH3TC2 hipsc衍生的SC模型中人类内源性SH3TC2表达，从而检测其表达及其细胞影响。通过将AR-CMTde-SH3TC2模型与对照模型进行比较，我们观察到SH3TC2在RNA和蛋白表达上的差异。此外，我们的RNA和hipsc衍生的运动神经元（MNs）共培养实验显示，sc的成熟延迟，sh3tc2缺陷SCs维持运动神经元培养的能力降低。我们的研究结果还表明，在sh3tc2缺陷细胞中，受体循环障碍取决于AR-CMTde-SH3TC2的改变。这些hipsc衍生的sc模型进一步为研究雪旺细胞对CMT4C的贡献提供了新的建模工具。

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引用次数: 0

iPSC screening identifies CACNA2D2 as a potential therapeutic target for FTLD-Tau iPSC筛选发现CACNA2D2是FTLD-Tau的潜在治疗靶点

IF 4.5 3区生物学 Q2 CELL BIOLOGY

European journal of cell biology

Pub Date : 2025-03-21 DOI: 10.1016/j.ejcb.2025.151484

Keiko Imamura , Ayako Nagahashi , Aya Okusa , Tomoki Sakasai , Kayoko Tsukita , Yumiko Kutoku , Yutaka Ohsawa , Yoshihide Sunada , Naruhiko Sahara , Nicholas M. Kanaan , Makoto Higuchi , Kohji Mori , Manabu Ikeda , Haruhisa Inoue

Frontotemporal Lobar Degeneration (FTLD) is a neurodegenerative disorder that affects the frontal and temporal lobes, which are crucial for regulating personality, behavior, and language. Pathologically, FTLD is characterized by Tau protein accumulation and neuronal death. In our effort to identify disease-modifying treatments, we conducted drug screening using neurons derived from induced pluripotent stem cells (iPSCs) of FTLD-Tau patients. This screening identified gabapentin as an existing drug that suppresses neuronal cell death with suppressed accumulation of Tau oligomers. Treatment with gabapentinoids, including pregabalin and mirogabalin, demonstrated similar neuroprotective effects. These compounds bind to the α2δ subunit of voltage-dependent calcium channels and specifically target the two isoforms α2δ-1 and α2δ-2. To determine which isoform is involved in the neurodegeneration seen in FTLD-Tau, we employed a knockout approach using iPSCs, which revealed that α2δ-2, encoded by CACNA2D2, plays a key role in the degeneration of FTLD-Tau neurons. Moreover, Neural organoids of FTLD-Tau exhibited features indicative of neurodegeneration, and CACNA2D2 knockout reversed a part of the gene expression alterations associated with these neurodegenerative features. These findings suggest that α2δ-2 may be a promising target for disease-modifying therapies in FTLD-Tau.

额颞叶变性（FTLD）是一种影响额叶和颞叶的神经退行性疾病，额叶和颞叶对调节人格、行为和语言至关重要。病理上，FTLD以Tau蛋白积累和神经元死亡为特征。在我们努力确定疾病改善治疗的过程中，我们使用来自FTLD-Tau患者的诱导多能干细胞（iPSCs）的神经元进行了药物筛选。该筛选确定加巴喷丁是一种现有的药物，通过抑制Tau寡聚物的积累来抑制神经元细胞死亡。加巴喷丁类药物治疗，包括普瑞巴林和米罗巴林，显示出类似的神经保护作用。这些化合物结合到电压依赖性钙通道的α2δ亚基上，并特异性靶向α2δ-1和α2δ-2两种亚型。为了确定哪种亚型参与FTLD-Tau的神经变性，我们使用iPSCs进行敲除，结果表明CACNA2D2编码的α2δ-2在FTLD-Tau神经元的变性中起关键作用。此外，FTLD-Tau的神经类器官表现出神经退行性特征，CACNA2D2敲除逆转了与这些神经退行性特征相关的部分基因表达改变。这些发现表明α2δ-2可能是FTLD-Tau疾病修饰治疗的一个有希望的靶点。

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引用次数: 0

The role of prostanoids in regulatory T cells and their implications in inflammatory diseases and cancers 前列腺素在调节性T细胞中的作用及其在炎症性疾病和癌症中的意义

IF 4.5 3区生物学 Q2 CELL BIOLOGY

European journal of cell biology

Pub Date : 2025-03-14 DOI: 10.1016/j.ejcb.2025.151482

Somsak Prasongtanakij , Kitipong Soontrapa , Dean Thumkeo

Regulatory T cells (Tregs) play an important role in the immune system through the regulation of immunological self-tolerance and homeostasis. Furthermore, increasing evidence suggests the potential contribution of Tregs beyond immunity in the process of repairing various injured tissues. Tregs are generally characterised by the constitutive expression of forkhead box protein 3 (FOXP3) transcription factor in the nucleus and high expression levels of CD25 and CTLA-4 on the cell surface. To date, a large number of molecules have been identified as key regulators of Treg differentiation and function. Among these molecules are prostanoids, which are multifaceted lipid mediators. Prostanoids are produced from arachidonic acid through the catalytic activity of the enzyme cyclooxygenase and exert their functions through the 9 cognate receptors, DP1‐2, EP1-EP4, FP, IP and TP. We briefly review previous studies on the regulatory mechanism of Tregs and then discuss recent works on the modulatory role of prostanoids.

调节性T细胞（Regulatory T cells, Tregs）通过调节免疫自身耐受和体内平衡在免疫系统中发挥重要作用。此外，越来越多的证据表明，Tregs在修复各种损伤组织的过程中具有免疫之外的潜在贡献。treg的一般特征是叉头盒蛋白3 （FOXP3）转录因子在细胞核内组成性表达，CD25和CTLA-4在细胞表面高表达。迄今为止，大量分子已被确定为Treg分化和功能的关键调节因子。在这些分子中有前列腺素，它是多方面的脂质介质。类前列腺素由花生四烯酸通过环氧化酶的催化活性产生，并通过9个同源受体DP1‐2、EP1-EP4、FP、IP和TP发挥其功能。我们简要回顾了Tregs调控机制的研究进展，并对近年来前列腺素的调控作用进行了讨论。

引用次数: 0

The dual nature of KLHL proteins: From cellular regulators to disease drivers KLHL蛋白的双重性质：从细胞调节因子到疾病驱动因子

IF 4.5 3区生物学 Q2 CELL BIOLOGY

European journal of cell biology

Pub Date : 2025-03-14 DOI: 10.1016/j.ejcb.2025.151483

Verdiana Di Giulio , Angelo Canciello , Erminia Carletti , Antonella De Luca , Antonio Giordano , Andrea Morrione , Jacopo Berardinelli , Valentina Russo , Domenico Solari , Luigi Maria Cavallo , Barbara Barboni

The Kelch-like (KLHL) protein family, characterized by its conserved BTB, BACK, and Kelch domains, serves as substrate adaptors for Cullin 3-RING ligases (CRL3), facilitating the ubiquitination and degradation of specific target proteins. Through this mechanism, KLHL proteins regulate numerous physiological processes, including cytoskeletal organization, oxidative stress response, and cell cycle progression. Dysregulation of KLHL proteins—via mutations or abnormal expression—has been implicated in various pathological conditions, including neurodegenerative disorders, cancer, cardiovascular diseases, and hereditary syndromes. This review provides a comprehensive overview of the physiological and pathological roles of KLHL proteins, emphasizing their specific substrates and mechanisms of action. By integrating structural and mechanistic insights with translational research, this review underscores the potential of KLHL proteins as promising therapeutic targets, offering new opportunities to combat a wide spectrum of complex diseases.

Kelch样蛋白（KLHL）家族以其保守的BTB、BACK和Kelch结构域为特征，作为Cullin 3-RING连接酶（CRL3）的底物接头，促进特定靶蛋白的泛素化和降解。通过这一机制，KLHL蛋白调节了许多生理过程，包括细胞骨架组织、氧化应激反应和细胞周期进程。KLHL蛋白的失调——通过突变或异常表达——与各种病理状况有关，包括神经退行性疾病、癌症、心血管疾病和遗传性综合征。本文综述了KLHL蛋白的生理和病理作用，重点介绍了它们的具体底物和作用机制。通过将结构和机制见解与转化研究相结合，本综述强调了KLHL蛋白作为有希望的治疗靶点的潜力，为对抗广泛的复杂疾病提供了新的机会。

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引用次数: 0

Evolution of organoid genetics 类器官遗传学的进化

IF 4.5 3区生物学 Q2 CELL BIOLOGY

European journal of cell biology

Pub Date : 2025-02-28 DOI: 10.1016/j.ejcb.2025.151481

Thomas M. Klompstra , Ki-Jun Yoon , Bon-Kyoung Koo

Organoids have revolutionized in vitro research by offering three-dimensional, multicellular systems that recapitulate the structure, function, and genetics of human tissues. Initially developed from both pluripotent stem cells (PSCs) and adult stem cells (AdSCs), organoids have expanded to model nearly every major human organ, significantly advancing developmental biology, disease modeling, and therapeutic screening. This review highlights the progression of organoid technologies, emphasizing the integration of genetic tools, including CRISPR-Cas9, prime editing, and lineage tracing. These advancements have facilitated precise modeling of human-specific pathologies and drug responses, often surpassing traditional 2D cultures and animal models in accuracy. Emerging technologies, such as organoid fusion, xenografting, and optogenetics, are expected to further enhance our understanding of cellular interactions and microenvironmental dynamics. As organoid complexity and genetic engineering methods continue to evolve, they will become increasingly indispensable for personalized medicine and translational research, bridging gaps between in vitro and in vivo systems.

类器官通过提供三维、多细胞系统来概括人体组织的结构、功能和遗传学，从而彻底改变了体外研究。类器官最初由多能干细胞（PSCs）和成体干细胞（AdSCs）发展而来，现已扩展到几乎所有主要人体器官的建模，显著推进了发育生物学、疾病建模和治疗筛选。这篇综述强调了类器官技术的进展，强调了遗传工具的整合，包括CRISPR-Cas9、引体编辑和谱系追踪。这些进步促进了人类特异性病理和药物反应的精确建模，在准确性上往往超过传统的二维培养和动物模型。新兴技术，如类器官融合、异种移植和光遗传学，有望进一步增强我们对细胞相互作用和微环境动力学的理解。随着类器官复杂性和基因工程方法的不断发展，它们将在个性化医疗和转化研究中变得越来越不可或缺，弥合了体外和体内系统之间的差距。

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引用次数: 0

Transient pharmacological inhibition of SUMOylation during pregnancy induces craniofacial malformations in offspring mice 妊娠期间短暂的药物抑制SUMOylation诱导子代小鼠颅面畸形

IF 4.5 3区生物学 Q2 CELL BIOLOGY

European journal of cell biology

Pub Date : 2025-02-20 DOI: 10.1016/j.ejcb.2025.151480

Jorge Mata-Garrido , Isabella Zafferri , Alice Nordlinger , Yann Loe-Mie , Anne Dejean , Jack-Christophe Cossec

Cell identity plays a pivotal role in embryo development, guiding the process of cellular differentiation essential for tissue and organ formation. Post-translational modification by the ubiquitin-related SUMO protein acts as a chromatin barrier to cell fate conversions. While SUMOylation deficiency is incompatible with mammalian embryonic development, haploinsufficiency for the SUMOylation machinery's E1 enzyme, UBA2, leads to various phenotypic traits in humans, including craniofacial malformations and aplasia cutis congenita. To investigate SUMO's role in organogenesis, SUMOylation was transiently suppressed using a specific pharmacological inhibitor, TAK981, administered during the early post-implantation embryo stage. A high-concentration injection led to embryonic lethality associated with epigenetic scars and alterations in nuclear and nucleolar integrity observed in treated embryo-derived fibroblasts. Lower-concentration injections resulted in viable mice with craniofacial deformities often accompanied by hydrocephalus, syndactyly and an aplasia cutis-like phenotype. Transcriptomic analysis revealed the repression of genes involved in neural crest differentiation in the TAK981-treated embryos as well as the overexpression of the Fgfr gene family in the adult TAK981 progeny. These genes, expressed in neural crest derivatives, are known for their gain-of-function mutations linked to human craniosynostosis syndromes, suggesting that potential overactivation of the FGF signaling pathway may contribute to the malformations observed in TAK981 progeny. Altogether, disruption of the SUMOylation/deSUMOylation equilibrium during a short embryonic period is sufficient to induce persistent cellular defects and transcriptional alterations, resulting in severe offspring malformations. In conclusion, the SUMO inhibitor TAK981 has teratogenic effects, disrupting normal fetal development and causing congenital disabilities reminiscent of traits observed in UBA2-related syndrome.

细胞身份在胚胎发育中起着关键作用，指导组织和器官形成所必需的细胞分化过程。泛素相关SUMO蛋白的翻译后修饰作为细胞命运转换的染色质屏障。虽然SUMOylation缺陷与哺乳动物胚胎发育不相容，但SUMOylation机制的E1酶UBA2的单倍不足导致人类的各种表型特征，包括颅面畸形和先天性皮肤发育不全。为了研究SUMO在器官发生中的作用，在胚胎着床后的早期阶段，使用一种特定的药物抑制剂TAK981暂时抑制SUMO化。高浓度注射导致胚胎致死性，在处理的胚胎源性成纤维细胞中观察到与表观遗传疤痕和细胞核和核仁完整性改变相关的胚胎致死性。低浓度注射导致存活小鼠颅面畸形，通常伴有脑积水、并指畸形和皮肤发育不全样表型。转录组学分析显示，在TAK981处理的胚胎中，参与神经嵴分化的基因受到抑制，Fgfr基因家族在成年TAK981后代中过度表达。这些基因在神经嵴衍生物中表达，以其与人类颅缝闭锁综合征相关的功能获得突变而闻名，这表明FGF信号通路的潜在过度激活可能导致TAK981后代中观察到的畸形。总之，在胚胎期短时间内破坏SUMOylation/deSUMOylation平衡足以诱导持续的细胞缺陷和转录改变，导致严重的后代畸形。总之，SUMO抑制剂TAK981具有致畸作用，破坏胎儿正常发育，导致先天性残疾，与uba2相关综合征的特征相似。

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引用次数: 0

Mouse colorectal cancer organoids: Lessons from syngeneic and orthotopic transplantation systems 小鼠结直肠癌类器官：同基因和原位移植系统的经验教训

IF 4.5 3区生物学 Q2 CELL BIOLOGY

European journal of cell biology

Pub Date : 2025-02-06 DOI: 10.1016/j.ejcb.2025.151478

Yu Muta, Yuki Nakanishi

Colorectal cancer (CRC) organoids provide more accurate and tissue-relevant models compared to conventional two-dimensional cultured cell cultures. Mouse CRC organoids, in particular, offer unique advantages over their human counterparts, as they can be transplanted into immunocompetent mice. These syngeneic transplantation models create a robust system for studying cancer biology in the immunocompetent tumor microenvironment (TME). This article discusses the development and applications of these organoid systems, emphasizing their capacity to faithfully recapitulate in vivo tumor progression, metastasis, and the immune landscape.

与传统的二维细胞培养相比，结直肠癌（CRC）类器官提供了更准确和组织相关的模型。与人类相比，小鼠CRC类器官具有独特的优势，因为它们可以移植到免疫能力强的小鼠体内。这些同基因移植模型为在免疫活性肿瘤微环境（TME）中研究癌症生物学创造了一个强大的系统。本文讨论了这些类器官系统的发展和应用，强调了它们忠实地概括体内肿瘤进展、转移和免疫景观的能力。

引用次数: 0