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Dietary fat quantity and composition influence hepatic lipid metabolism and metabolic disease risk in humans.
IF 4 3区 医学 Q2 CELL BIOLOGY Pub Date : 2025-01-01 Epub Date: 2025-01-29 DOI: 10.1242/dmm.050878
Nikola Srnic, Felix Westcott, Eleanor Caney, Leanne Hodson

The excessive accumulation of intrahepatic triglyceride (IHTG) in the liver is a risk factor for metabolic diseases, including type 2 diabetes and cardiovascular disease. IHTG can excessively accumulate owing to imbalances in the delivery, synthesis, storage and disposal of fat to, in and from the liver. Although obesity is strongly associated with IHTG accumulation, emerging evidence suggests that the composition of dietary fat, in addition to its quantity, plays a role in mediating IHTG accumulation. Evidence from human cross-sectional and interventional studies indicates that diets enriched with saturated fat compared to other fat types and carbohydrates produce divergent effects on IHTG content. However, the mechanistic reasons for these observations remain unknown. Given the challenges of investigating such mechanisms in humans, cellular models are needed that can recapitulate human hepatocyte fatty acid metabolism. Here, we review what is known from human studies about how dietary fat, its quantity and composition contribute to IHTG accumulation. We also explore the effects of fatty acid composition on hepatocellular fat metabolism from data generated in cellular models to help explain the divergences observed in in vivo studies.

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引用次数: 0
Multi-omics analysis reveals distinct gene regulatory mechanisms between primary and organoid-derived human hepatocytes.
IF 4 3区 医学 Q2 CELL BIOLOGY Pub Date : 2025-01-01 Epub Date: 2025-01-29 DOI: 10.1242/dmm.050883
Haoyu Wu, Annie S P Yang, Suzan Stelloo, Floris J M Roos, René H M Te Morsche, Anne H Verkerk, Maria V Luna-Velez, Laura Wingens, Johannes H W de Wilt, Robert W Sauerwein, Klaas W Mulder, Simon J van Heeringen, Monique M A Verstegen, Luc J W van der Laan, Hendrik Marks, Richárd Bártfai

Hepatic organoid cultures are a powerful model to study liver development and diseases in vitro. However, hepatocyte-like cells differentiated from these organoids remain immature compared to primary human hepatocytes (PHHs), which are the benchmark in the field. Here, we applied integrative single-cell transcriptome and chromatin accessibility analysis to reveal gene regulatory mechanisms underlying these differences. We found that, in mature human hepatocytes, activator protein 1 (AP-1) factors co-occupy regulatory regions with hepatocyte-specific transcription factors, including HNF4A, suggesting their potential cooperation in governing hepatic gene expression. Comparative analysis identified distinct transcription factor sets that are specifically active in either PHHs or intrahepatic cholangiocyte organoid (ICO)-derived human hepatocytes. ELF3 was one of the factors uniquely expressed in ICO-derived hepatocytes, and its expression negatively correlated with hepatic marker gene expression. Functional analysis further revealed that ELF3 depletion increased the expression of key hepatic markers in ICO-derived hepatocytes. Our integrative analysis provides insights into the transcriptional regulatory networks of PHHs and hepatic organoids, thereby informing future strategies for developing improved hepatic models.

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引用次数: 0
Development of a genetically tailored implantation hepatocellular carcinoma model in Oncopigs by somatic cell CRISPR editing. 体细胞CRISPR编辑技术在肿瘤细胞中建立基因定制的原位植入肝癌模型。
IF 4 3区 医学 Q2 CELL BIOLOGY Pub Date : 2025-01-01 Epub Date: 2025-01-29 DOI: 10.1242/dmm.052079
Lobna Elkhadragy, Maximillian J Carlino, Luke R Jordan, Thomas Pennix, Nahed Ismail, Grace Guzman, Jonathan P Samuelson, Lawrence B Schook, Kyle M Schachtschneider, Ron C Gaba

Hepatocellular carcinoma (HCC) is an aggressive disease with poor prognosis, necessitating preclinical models for evaluating novel therapies. Large-animal models are particularly valuable for assessing locoregional therapies, which are widely employed across HCC stages. This study aimed to develop a large-animal HCC model with tailored tumor mutations. The Oncopig, a genetically engineered pig with inducible TP53R167H and KRASG12D, was used in the study. Hepatocytes were isolated from Oncopigs and exposed to Cre recombinase in vitro to create HCC cells, and additional mutations were introduced by CRISPR/Cas9 knockout of PTEN and CDKN2A. These edits increased Oncopig HCC cell proliferation and migration. Autologous HCC cells with these CRISPR edits were implanted into Oncopigs using two approaches: ultrasound-guided percutaneous liver injections, which resulted in the development of localized intrahepatic masses, and portal vein injections, which led to multifocal tumors that regressed over time. Tumors developed by both approaches harbored PTEN and CDKN2A knockout mutations. This study demonstrates the feasibility of developing genetically tailored HCC tumors in Oncopigs using somatic cell CRISPR editing and autologous implantation, providing a valuable large-animal model for in vivo therapeutic assessment.

肝细胞癌(HCC)是一种预后不良的侵袭性疾病,需要临床前模型来评估新的治疗方法。大型动物模型对于评估局部治疗特别有价值,局部治疗在HCC分期中广泛应用。本研究旨在建立具有定制肿瘤突变的大型动物HCC模型。Oncopig是一种具有可诱导TP53R167H和KRASG12D基因工程猪,用于研究。从Oncopigs中分离肝细胞并暴露于Cre重组酶体外形成HCC细胞,并通过CRISPR/Cas9敲除(KO) PTEN和CDKN2A基因引入额外的突变。这些编辑增加了肝癌细胞的增殖和迁移。使用两种方法将具有这些CRISPR编辑的自体HCC细胞植入Oncopigs。超声引导下经皮肝脏注射导致局部肝内肿块的发展,而门静脉注射导致多灶性肿瘤随着时间的推移而消退。两种方法产生的肿瘤都含有PTEN和CDKN2A KO突变。本研究证明了利用体细胞CRISPR编辑和自体植入在Oncopigs中开发基因定制HCC肿瘤的可行性,为体内治疗评估提供了有价值的大型动物模型。
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引用次数: 0
Abca4, mutated in Stargardt disease, is required for structural integrity of cone outer segments. 在Stargardt病中突变的Abca4是圆锥体外节结构完整性所必需的。
IF 4 3区 医学 Q2 CELL BIOLOGY Pub Date : 2025-01-01 Epub Date: 2025-01-10 DOI: 10.1242/dmm.052052
John J Willoughby, Abbie M Jensen

Stargardt disease (STGD), the leading cause of inherited childhood blindness, is primarily caused by mutations in the ABCA4 gene; yet, the underlying mechanisms of photoreceptor degeneration remain elusive, partly due to limitations in existing animal disease models. To expand our understanding, we mutated the human ABCA4 paralogues abca4a and abca4b in zebrafish, which has a cone-rich retina. Our study unveiled striking dysmorphology and elongation of cone outer segments (COS) in abca4a;abca4b double mutants, alongside reduced phagocytosis by the retinal pigmented epithelium (RPE). We report that zebrafish Abca4 protein forms a distinctive stripe along the length of COS, suggesting a potential structural role. We further show that, in wild-type zebrafish, outer segments of cone cells constitutively present externalized phosphatidylserine, an apoptotic 'eat-me' signal, and that this pattern is disrupted in abca4a;abca4b double mutants, potentially contributing to reduced RPE phagocytic activity. More broadly, constitutive presentation of the 'eat-me' signal by COS - if conserved in humans - might have important implications for other retinal degenerative diseases, including age-related macular degeneration. Our zebrafish model provides novel insights into cone dysfunction and presents a promising platform for unraveling the mechanisms of STGD pathogenesis and advancing therapeutic interventions.

Stargardt病(STGD)是遗传性儿童失明的主要原因,主要由ABCA4基因突变引起,但光感受器变性的潜在机制仍然难以捉摸,部分原因是现有动物疾病模型的局限性。为了扩大我们的理解,我们在斑马鱼中突变了ABCA4的类似物,abca4a和abca4b,斑马鱼的视网膜有丰富的锥体。我们的研究揭示了abca4a和abca4b双突变体的显著畸变和锥体外段的伸长,同时视网膜色素上皮的吞噬作用减少。我们报道Abca4蛋白沿着圆锥体外段的长度形成独特的条纹,表明潜在的结构作用。我们进一步表明,野生型锥体外段组成性地呈现外化磷脂酰丝氨酸,这是一种“吃我”信号,这种模式在abca4a和abca4b双突变体中被破坏,可能导致RPE吞噬活性降低。更广泛地说,“吃我”信号在锥体外节的构成表现,如果在人类中保守,对其他视网膜退行性疾病,包括年龄相关性黄斑变性,具有重要意义。该斑马鱼模型提供了对视锥细胞功能障碍的新见解,并为揭示STGD发病机制和推进治疗干预提供了一个有希望的平台。
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引用次数: 0
Slc26a2-mediated sulfate metabolism is important in tooth development. Slc26a2- 介导的硫酸盐代谢对牙齿的发育至关重要。
IF 4 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-12-10 DOI: 10.1242/dmm.052107
Yuka Yoshida, Toshihiro Inubushi, Mika Yokoyama, Priyanka Nag, Jun-Ichi Sasaki, Ayaka Oka, Tomoya Murotani, Renshiro Kani, Yuki Shiraishi, Hiroshi Kurosaka, Yoshifumi Takahata, Riko Nishimura, Satoshi Imazato, Petros Papagerakis, Takashi Yamashiro

The sulfate transporter gene SLC26A2 is crucial for skeletal formation, as evidenced by its role in diastrophic dysplasia, a type of skeletal dysplasia in humans. Although SLC26A2-related chondrodysplasia also affects craniofacial and tooth development, its specific role in these processes remains unclear. In this study, we explored the pivotal roles of SLC26A2-mediated sulfate metabolism during tooth development. We found that Slc26a2 was predominantly expressed in dental tissues, including odontoblasts and ameloblasts. Slc26a2 knockout (Slc26a2-KO-Δexon2) mice exhibited distinct craniofacial abnormalities, such as a retrognathic upper jaw, small upper incisors and upper molar hypoplasia. These mice also showed flattened odontoblasts and loss of nuclear polarity in upper incisors and molars, with significant reductions in odontoblast differentiation markers Dspp and Dmp1. Ex vivo and in vitro studies further revealed dentin matrix hypoplasia, tooth root shortening and downregulation of Wnt signaling in Slc26a2-deficient cells. These findings highlight the crucial role of SLC26A2-mediated sulfate metabolism in tooth development and offer insights into the mechanisms underlying dental abnormalities in patients with SLC26A2-related chondrodysplasias.

硫酸盐转运体基因 SLC26A2 对骨骼的形成至关重要,它在人类骨骼发育不良中的作用就证明了这一点。虽然与 SLC26A2 相关的软骨发育不良也会影响颅面和牙齿的发育,但它在这些过程中的具体作用仍不清楚。在本研究中,我们探讨了 SLC26A2 介导的硫酸盐代谢在牙齿发育过程中的关键作用。我们发现,Slc26a2 主要表达于牙齿组织,包括牙本质细胞和成骨细胞。Slc26a2 基因敲除小鼠(Slc26a2-KO-Δexon2)表现出明显的颅面畸形,如上颌骨后突、上切牙变小和上臼齿发育不良。这些小鼠还表现出扁平的牙本质,上切牙和臼齿的核极性丧失,牙本质分化标记物 Dspp 和 Dmp1 显著减少。体内外研究进一步揭示了在 Slc26a2 缺失的细胞中牙本质基质发育不良、牙根缩短和 Wnt 信号下调。这些发现凸显了 SLC26A2 介导的硫酸盐代谢在牙齿发育中的重要作用,并为了解 SLC26A2 相关软骨发育异常患者牙齿异常的机制提供了启示。
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引用次数: 0
Making sense of missense: challenges and opportunities in variant pathogenicity prediction. 解读错义:变异致病性预测的挑战与机遇。
IF 4 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-12-16 DOI: 10.1242/dmm.052218
Ivan Molotkov, Elaine R Mardis, Mykyta Artomov

Computational tools for predicting variant pathogenicity are widely used to support clinical variant interpretation. Recently, several models, which do not rely on known variant classifications during training, have been developed. These approaches can potentially overcome biases of current clinical databases, such as misclassifications, and can potentially better generalize to novel, unclassified variants. AlphaMissense is one such model, built on the highly successful protein structure prediction model, AlphaFold. AlphaMissense has shown great performance in benchmarks of functional and clinical data, outperforming many supervised models that were trained on similar data. However, like other in silico predictors, AlphaMissense has notable limitations. As a large deep learning model, it lacks interpretability, does not assess the functional impact of variants, and provides pathogenicity scores that are not disease specific. Improving interpretability and precision in computational tools for variant interpretation remains a promising area for advancing clinical genetics.

预测变异致病性的计算工具被广泛用于支持临床变异解释。最近,一些在训练过程中不依赖已知变异分类的模型被开发出来。这些方法有可能克服当前临床数据库的偏差(如分类错误),并有可能更好地概括未分类的新型变异体。AlphaMissense 就是这样一个模型,它建立在非常成功的蛋白质结构预测模型 AlphaFold 上。AlphaMissense 在功能和临床数据的基准测试中表现出色,超过了许多在类似数据上训练的监督模型。然而,与其他硅学预测模型一样,AlphaMissense 也有明显的局限性。作为一个大型深度学习模型,它缺乏可解释性,不能评估变异的功能影响,提供的致病性评分也不具有疾病特异性。提高用于变异解释的计算工具的可解释性和精确性仍是推动临床遗传学发展的一个前景广阔的领域。
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引用次数: 0
The role of mesenchymal cells in cholangiocarcinoma. 间质细胞在胆管癌中的作用。
IF 4 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-12-13 DOI: 10.1242/dmm.050716
Mireia Sueca-Comes, Elena Cristina Rusu, Jennifer C Ashworth, Pamela Collier, Catherine Probert, Alison Ritchie, Marian Meakin, Nigel P Mongan, Isioma U Egbuniwe, Jesper Bøje Andersen, David O Bates, Anna M Grabowska

The tumour microenvironment (TME) significantly influences tumour formation and progression through dynamic interactions. Cholangiocarcinoma (CCA), a highly desmoplastic tumour, lacks early diagnostic biomarkers and has limited effective treatments owing to incomplete understanding of its molecular pathogenesis. Investigating the role of the TME in CCA progression could lead to better therapies. RNA sequencing was performed on seven CCA patient-derived xenografts (PDXs) and their corresponding patient samples. Differential expression analysis was conducted, and Qiagen Ingenuity Pathway Analysis was used to predict dysregulated pathways and upstream regulators. PDX- and cell line-derived spheroids, with and without immortalised mesenchymal stem cells, were grown and analysed for morphology, growth and viability. Histological analysis confirmed biliary phenotypes. RNA sequencing indicated upregulation of extracellular matrix-receptor interaction and PI3K-AKT pathways in the presence of mesenchymal cells, with several genes linked to poor survival. Mesenchymal cells restored the activity of inhibited cancer-associated kinases. Thus, adding mesenchymal cells to CCA spheroid models restored key paracrine signalling pathways lost in PDXs, enhancing tumour growth and viability. These findings highlight the importance of including stromal components in cancer models to improve pre-clinical studies.

肿瘤微环境(TME)通过动态的相互作用对肿瘤的形成和发展产生重要影响。胆管癌(CCA)是一种高度脱鳞的肿瘤,由于对其分子发病机制了解不全面,因此缺乏早期诊断生物标志物,有效的治疗方法也很有限。研究TME在CCA进展过程中的作用可以找到更好的治疗方法。研究人员对 7 个 CCA PDX 及其相应的患者样本进行了 RNA 测序。进行了差异表达分析,并使用Qiagen Ingenuity Pathway Analysis(IPA)预测了失调通路和上游调控因子。对含有或不含有永生化间充质干细胞的PDX和细胞系衍生球形体进行了培养,并对其形态、生长和存活率进行了分析。组织学分析证实了胆汁表型。RNA测序表明,间充质干细胞存在时,ECM-受体相互作用和PI3K-Akt通路上调,其中几个基因与存活率低有关。间充质干细胞恢复了被抑制的癌症相关激酶(ICAKs)的活性。这项研究表明,在CCA球状模型中加入间充质干细胞可恢复PDXs中丧失的关键旁分泌信号通路,从而增强肿瘤的生长和存活能力。这些发现强调了在癌症模型中加入基质成分以改善临床前研究的重要性。
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引用次数: 0
Stat3 mediates Fyn kinase-driven dopaminergic neurodegeneration and microglia activation. Stat3介导Fyn激酶驱动的多巴胺能神经变性和小胶质细胞活化。
IF 4 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-12-06 DOI: 10.1242/dmm.052011
Sahiba Siddiqui, Fang Liu, Anumantha G Kanthasamy, Maura McGrail

The Alzheimer's disease and Parkinson's disease risk locus FYN kinase is implicated in neurodegeneration and inflammatory signaling. To investigate in vivo mechanisms of Fyn-driven neurodegeneration, we built a zebrafish neural-specific Gal4:UAS model of constitutively active FynY531F signaling. Using in vivo live imaging, we demonstrated that neural FynY531F expression leads to dopaminergic neuron loss and mitochondrial aggregation in 5 day larval brain. Dopaminergic loss coincided with microglia activation and induction of tnfa, il1b and il12a inflammatory cytokine expression. Transcriptome analysis revealed Stat3 signaling as a potential Fyn target. Chemical inhibition experiments confirmed Fyn-driven dopaminergic neuron loss, and the inflammatory response was dependent upon activation of Stat3 and NF-κB pathways. Dual chemical inhibition demonstrated that Stat3 acts synergistically with NF-κB in dopaminergic neuron degeneration. These results identify Stat3 as a novel downstream effector of Fyn signaling in neurodegeneration and inflammation.

阿尔茨海默病和帕金森病的风险位点FYN激酶与神经变性和炎症信号有关。为了研究FynY531F信号的体内机制,我们建立了斑马鱼神经特异性Gal4:UAS模型,该模型具有组成活性FynY531F信号。通过活体成像,我们证明了FynY531F的神经表达在5天的幼虫大脑中导致多巴胺能神经元丢失和线粒体聚集。多巴胺能损失与小胶质细胞激活和诱导tnf, il1b和il12a炎症细胞因子表达一致。转录组分析显示Stat3信号是Fyn的潜在靶标。化学抑制实验证实fynn驱动的多巴胺能神经元丢失,炎症反应依赖于Stat3和NF-κB通路的激活。双重化学抑制表明Stat3在多巴胺能神经元变性中与NF-κB协同作用。这些结果表明Stat3是Fyn信号在神经变性和炎症中的一种新的下游效应物。
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引用次数: 0
Scaling up the impact of melanoma advocacy: an interview with Bettina Ryll. 扩大黑色素瘤倡导的影响:采访贝蒂娜·赖尔。
IF 4 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-12-24 DOI: 10.1242/dmm.052202
Bettina Ryll
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引用次数: 0
Loss of function of VCP/TER94 causes neurodegeneration. VCP/TER94的功能丧失导致果蝇中枢神经系统的神经变性。
IF 4 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-12-23 DOI: 10.1242/dmm.050359
Kohei Tsumaki, Christian J F Bertens, Minoru Nakayama, Saya Kato, Yuki Jonao, Ayu Kuribayashi, Konosuke Sato, Shota Ishiyama, Momoko Asakawa, Riko Aihara, Yuki Yoshioka, Hidenori Homma, Hikari Tanaka, Kyota Fujita, Hitoshi Okazawa, Masaki Sone

Variants in several genes are linked to human frontotemporal lobar degeneration (FTLD) associated with TDP43- and/or ubiquitin-positive inclusions. However, it is not yet clear whether the underlying mechanism is a gain-of-function or a loss-of-function one. To answer this question, we used Drosophila expressing double-stranded RNA against the FTLD-associated gene TER94 (an ortholog of VCP/p97) and found that the knockdown (KD) of this gene caused premature lethality, reduction in brain volume and alterations in the morphology of mushroom bodies. The changes caused by TER94 KD were rescued by wild-type TER94 but not by the human disease-linked A229E mutant, indicating that this mutant causes loss of function. Alterations were also observed in pupal brains and were partially rescued by co-expression of Mcm2, which is involved in control of the cell cycle, suggesting that dysregulation of neuronal proliferation caused the phenotypes. TER94 KD also caused the disappearance of TBPH (an ortholog of TDP43/TARDBP) from nuclei. These data from Drosophila genetics suggest that VCP-linked FTLD is caused by loss-of-function of VCP.

几种基因突变与与TDP43和/或泛素阳性包涵体相关的人类额颞叶变性(FTLD)有关。然而,尚不清楚潜在的机制是功能的获得还是功能的丧失。为了回答这个问题,我们使用表达RNAi的果蝇来对抗ftld相关基因TER94 (VCP/p97的同源物),发现该基因的敲低(KD)会导致蘑菇体的过早死亡、脑容量减少和形态改变。由TER94 KD引起的变化被野生型TER94拯救,而不是被人类疾病相关的A229E突变体拯救,这表明该突变体导致功能丧失。在蛹大脑中也观察到改变,并通过MCM2的共表达部分恢复,MCM2参与细胞周期的控制。这表明神经元增殖失调导致了表型。我们还发现ter94kd导致TBPH (TDP43/TARDBP的同源物)从细胞核中消失。这些来自果蝇遗传学的数据表明,VCP相关的FTLD是由VCP功能丧失引起的。
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引用次数: 0
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