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A simple active fluid model unites cytokinesis, cell crawling, and axonal outgrowth. 一个简单的活性流体模型将细胞分裂、细胞爬行和轴突生长结合在一起。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-17 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1491429
Erin M Craig, Francesca Oprea, Sajid Alam, Ania Grodsky, Kyle E Miller

While the structural organization and molecular biology of neurons are well characterized, the physical process of axonal elongation remains elusive. The classic view posited elongation occurs through the deposition of cytoskeletal elements in the growth cone at the tip of a stationary array of microtubules. Yet, recent studies reveal axonal microtubules and docked organelles flow forward in bulk in the elongating axons of Aplysia, chick sensory, rat hippocampal, and Drosophila neurons. Noting that the morphology, molecular components, and subcellular flow patterns of growth cones strongly resemble the leading edge of migrating cells and the polar regions of dividing cells, our working hypothesis is that axonal elongation utilizes the same physical mechanisms that drive cell crawling and cell division. As a test of that hypothesis, here we take experimental data sets of sub-cellular flow patterns in cells undergoing cytokinesis, mesenchymal migration, amoeboid migration, neuronal migration, and axonal elongation. We then apply active fluid theory to develop a biophysical model that describes the different sub-cellular flow profiles across these forms of motility and how this generates cell motility under low Reynolds numbers. The modeling suggests that mechanisms for generating motion are shared across these processes, and differences arise through modifications of sub-cellular adhesion patterns and the profiles of internal force generation. Collectively, this work suggests that ameboid and mesenchymal cell crawling may have arisen from processes that first developed to support cell division, that growth cone motility and cell crawling are closely related, and that neuronal migration and axonal elongation are fundamentally similar, differing primarily in the motion and strength of adhesion under the cell body.

虽然神经元的结构组织和分子生物学特征已十分明确,但轴突伸长的物理过程仍然难以捉摸。传统观点认为,伸长是通过细胞骨架元素在微管静止阵列顶端的生长锥中沉积而发生的。然而,最近的研究发现,在水蚤、小鸡感觉器官、大鼠海马和果蝇神经元的伸长轴突中,轴突微管和对接的细胞器大量向前流动。注意到生长锥的形态、分子成分和亚细胞流动模式与迁移细胞的前缘和分裂细胞的极区非常相似,我们的工作假设是,轴突的伸长利用了驱动细胞爬行和细胞分裂的相同物理机制。作为对这一假设的验证,我们在这里使用了细胞分裂、间充质迁移、变形虫迁移、神经元迁移和轴突伸长过程中细胞亚细胞流动模式的实验数据集。然后,我们运用主动流体理论建立了一个生物物理模型,该模型描述了这些运动形式中不同的亚细胞流动剖面,以及在低雷诺数条件下如何产生细胞运动。该模型表明,这些过程中产生运动的机制是相同的,而差异则是通过改变亚细胞粘附模式和内力产生曲线而产生的。总之,这项研究表明,浮游动物细胞和间充质细胞的爬行可能源于最初为支持细胞分裂而发展起来的过程;生长锥运动和细胞爬行密切相关;神经元迁移和轴突伸长基本相似,主要区别在于细胞体下粘附的运动和强度。
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引用次数: 0
Telomere maintenance and the DNA damage response: a paradoxical alliance. 端粒维护和 DNA 损伤反应:矛盾的联盟。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-17 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1472906
Ashley Harman, Tracy M Bryan

Telomeres are the protective caps at the ends of linear chromosomes of eukaryotic organisms. Telomere binding proteins, including the six components of the complex known as shelterin, mediate the protective function of telomeres. They do this by suppressing many arms of the canonical DNA damage response, thereby preventing inappropriate fusion, resection and recombination of telomeres. One way this is achieved is by facilitation of DNA replication through telomeres, thus protecting against a "replication stress" response and activation of the master kinase ATR. On the other hand, DNA damage responses, including replication stress and ATR, serve a positive role at telomeres, acting as a trigger for recruitment of the telomere-elongating enzyme telomerase to counteract telomere loss. We postulate that repression of telomeric replication stress is a shared mechanism of control of telomerase recruitment and telomere length, common to several core telomere binding proteins including TRF1, POT1 and CTC1. The mechanisms by which replication stress and ATR cause recruitment of telomerase are not fully elucidated, but involve formation of nuclear actin filaments that serve as anchors for stressed telomeres. Perturbed control of telomeric replication stress by mutations in core telomere binding proteins can therefore cause the deregulation of telomere length control characteristic of diseases such as cancer and telomere biology disorders.

端粒是真核生物线性染色体末端的保护帽。端粒结合蛋白,包括称为 "庇护蛋白 "的复合体的六个组成部分,介导端粒的保护功能。它们通过抑制典型 DNA 损伤反应的许多环节来实现这一功能,从而防止端粒的不适当融合、切除和重组。其中一种方法是通过端粒促进DNA复制,从而防止 "复制压力 "反应和主激酶ATR的激活。另一方面,DNA损伤反应(包括复制应激和ATR)在端粒上发挥着积极作用,可触发端粒延长酶端粒酶的招募,从而抵消端粒的丢失。我们推测,端粒复制应激的抑制是端粒酶招募和端粒长度控制的共同机制,是包括TRF1、POT1和CTC1在内的几种核心端粒结合蛋白的共同机制。复制胁迫和 ATR 导致端粒酶招募的机制尚未完全阐明,但涉及作为受胁迫端粒锚的核肌动蛋白丝的形成。因此,核心端粒结合蛋白的突变导致端粒复制压力控制失调,可引起端粒长度控制失调,这是癌症和端粒生物学紊乱等疾病的特征。
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引用次数: 0
Mesenchymal stem cell-derived extracellular vesicles in systemic sclerosis: role and therapeutic directions. 间充质干细胞衍生的细胞外囊泡在系统性硬化症中的作用和治疗方向。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-17 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1492821
Xuan Wang, Jiaying Guo, Qiangfu Dai

Systemic sclerosis (SSc) is a complex autoimmune disease with clinical symptoms of vascular damage, immune disorders, and fibrosis, presenting significant treatment challenges and limited therapeutic options. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been demonstrated in numerous studies as more effective than MSCs in treating autoimmune diseases. Recent studies demonstrate that MSC-EVs can significantly ameliorate the symptoms of SSc and mitigate pathological changes such as vascular injury, immune dysregulation, and fibrosis. These findings underscore the promising therapeutic potential of MSC-EVs in the treatment of SSc. MSC-EVs promote angiogenesis, modulate immune dysfunction, and combat fibrosis. This article summarizes the therapeutic applications and possible mechanisms of MSC-EVs for SSc, thereby offering a novel therapeutic direction for the treatment of SSc.

系统性硬化症(SSc)是一种复杂的自身免疫性疾病,具有血管损伤、免疫紊乱和纤维化等临床症状,给治疗带来巨大挑战,而且治疗方案有限。大量研究表明,间充质干细胞衍生的细胞外囊泡(MSC-EVs)在治疗自身免疫性疾病方面比间充质干细胞更有效。最近的研究表明,间充质干细胞-细胞外小泡可明显改善SSc的症状,减轻血管损伤、免疫失调和纤维化等病理变化。这些发现凸显了间充质干细胞-EV 在治疗 SSc 方面的巨大潜力。间充质干细胞-EV可促进血管生成、调节免疫功能紊乱和抗纤维化。本文总结了间充质干细胞-EVs在治疗SSc方面的应用和可能的机制,从而为治疗SSc提供了一个新的治疗方向。
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引用次数: 0
Developmental bias as a cause and consequence of adaptive radiation and divergence. 发育偏差是适应性辐射和分化的原因和结果。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-16 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1453566
Corin Stansfield, Kevin J Parsons

Efforts to reconcile development and evolution have demonstrated that development is biased, with phenotypic variation being more readily produced in certain directions. However, how this "developmental bias" can influence micro- and macroevolution is poorly understood. In this review, we demonstrate that defining features of adaptive radiations suggest a role for developmental bias in driving adaptive divergence. These features are i) common ancestry of developmental systems; ii) rapid evolution along evolutionary "lines of least resistance;" iii) the subsequent repeated and parallel evolution of ecotypes; and iv) evolutionary change "led" by biased phenotypic plasticity upon exposure to novel environments. Drawing on empirical and theoretical data, we highlight the reciprocal relationship between development and selection as a key driver of evolutionary change, with development biasing what variation is exposed to selection, and selection acting to mold these biases to align with the adaptive landscape. Our central thesis is that developmental biases are both the causes and consequences of adaptive radiation and divergence. We argue throughout that incorporating development and developmental bias into our thinking can help to explain the exaggerated rate and scale of evolutionary processes that characterize adaptive radiations, and that this can be best achieved by using an eco-evo-devo framework incorporating evolutionary biology, development, and ecology. Such a research program would demonstrate that development is not merely a force that imposes constraints on evolution, but rather directs and is directed by evolutionary forces. We round out this review by highlighting key gaps in our understanding and suggest further research programs that can help to resolve these issues.

调和发育与进化的努力表明,发育是有偏差的,表型变异更容易在某些方向上产生。然而,人们对这种 "发育偏差 "如何影响微观和宏观进化还知之甚少。在这篇综述中,我们证明了适应性辐射的决定性特征表明了发育偏差在驱动适应性分化中的作用。这些特征是:i) 发育系统的共同祖先;ii) 沿着进化的 "最小阻力线 "快速进化;iii) 随后生态型的重复和平行进化;iv) 在暴露于新环境时,有偏向的表型可塑性 "引领 "进化变化。根据经验和理论数据,我们强调发育与选择之间的相互关系是进化变化的关键驱动力,发育会使哪些变异暴露于选择,而选择则会塑造这些偏差,使其与适应环境相一致。我们的中心论点是,发育偏差既是适应性辐射和分化的原因,也是其结果。我们自始至终认为,将发育和发育偏差纳入我们的思维,有助于解释作为适应性辐射特征的进化过程的夸张速度和规模。这样的研究计划将证明,发展不仅仅是对进化施加限制的一种力量,而是指导进化的力量,并被进化的力量所指导。在本综述的最后,我们强调了我们认识上的主要差距,并提出了有助于解决这些问题的进一步研究计划。
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引用次数: 0
Myocardial infarction in rats was alleviated by MSCs derived from the maternal segment of the human umbilical cord. 从人类脐带母体部分提取的间充质干细胞可缓解大鼠的心肌梗死。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-16 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1469541
Shuifen Sun, Linping Wang, Qisheng Tang, Jialian Yi, Xin Yu, Yu Cao, Lihong Jiang, Jie Liu

Background: Mesenchymal stem cells (MSCs) are safe and effective in treating myocardial infarction (MI) and have broad application prospects. However, the heterogeneity of MSCs may affect their therapeutic effect on the disease. We recently found that MSCs derived from different segments of the same umbilical cord (UC) showed significant difference in the expression of genes that are related to heart development and injury repair. We therefore hypothesized that those MSCs with high expression of above genes are more effective to treat MI and tested it in this study.

Methods: MSCs were isolated from 3 cm-long segments of the maternal, middle and fetal segments of the UC (maternal-MSCs, middle-MSCs and fetal-MSCs, respectively). RNA-seq was used to analyze and compare the transcriptomes. We verified the effects of MSCs on oxygen-glucose deprivation (OGD)-induced cardiomyocyte apoptosis in vitro. In vivo, a rat MI model was established by ligating the left anterior descending coronary artery, and MSCs were injected into the myocardium surrounding the MI site. The therapeutic effects of MSCs derived from different segments of the UC were evaluated by examining cardiac function, histopathology, cardiomyocyte apoptosis, and angiogenesis.

Results: Compared to fetal-MSCs and middle-MSCs, maternal-MSCs exhibited significantly higher expression of genes that are associated with heart development, such as GATA-binding protein 4 (GATA4), and myocardin (MYOCD). Coculture with maternal-MSCs reduced OGD-induced cardiomyocyte apoptosis. In rats with MI, maternal-MSCs significantly restored cardiac contractile function and reduced the infarct size. Mechanistic experiments revealed that maternal-MSCs exerted cardioprotective effects by decreasing cardiomyocyte apoptosis, and promoting angiogenesis.

Conclusion: Our data demonstrated that maternal segment-derived MSCs were a superior cell source for regenerative repair after MI. Segmental localization of the entire UC when isolating hUCMSCs was necessary to improve the effectiveness of clinical applications.

背景:间充质干细胞(MSCs)治疗心肌梗死(MI)安全有效,具有广阔的应用前景。然而,间充质干细胞的异质性可能会影响其对疾病的治疗效果。我们最近发现,来自同一脐带(UC)不同区段的间充质干细胞在与心脏发育和损伤修复相关的基因表达上有显著差异。因此,我们假设上述基因高表达的间充质干细胞对治疗心肌梗死更有效,并在本研究中进行了测试:方法:从 UC 母体、中段和胎儿 3 厘米长的节段中分离间充质干细胞(分别为母体间充质干细胞、中段间充质干细胞和胎儿间充质干细胞)。我们使用 RNA-seq 对转录组进行了分析和比较。我们在体外验证了间充质干细胞对氧糖剥夺(OGD)诱导的心肌细胞凋亡的影响。在体内,我们通过结扎左前降支冠状动脉建立了大鼠心肌梗死模型,并将间充质干细胞注射到心肌梗死部位周围的心肌中。通过检查心脏功能、组织病理学、心肌细胞凋亡和血管生成,评估了来自 UC 不同部位的间充质干细胞的治疗效果:结果:与胎儿间充质干细胞和中期间充质干细胞相比,母体间充质干细胞与心脏发育相关的基因,如GATA结合蛋白4(GATA4)和心肌蛋白(MYOCD)的表达量明显更高。与母体间充质干细胞共培养可减少 OGD 诱导的心肌细胞凋亡。在心肌梗死的大鼠中,母体间充质干细胞能明显恢复心脏收缩功能并缩小梗死面积。机理实验表明,母体间充质干细胞通过减少心肌细胞凋亡和促进血管生成发挥了保护心脏的作用:我们的数据表明,母体节段来源的间充质干细胞是心肌梗死后再生修复的优质细胞来源。结论:我们的数据表明,母体节段来源的间充质干细胞是心肌梗死后再生修复的上佳细胞来源。在分离 hUCMSCs 时,有必要对整个 UC 进行节段定位,以提高临床应用的有效性。
{"title":"Myocardial infarction in rats was alleviated by MSCs derived from the maternal segment of the human umbilical cord.","authors":"Shuifen Sun, Linping Wang, Qisheng Tang, Jialian Yi, Xin Yu, Yu Cao, Lihong Jiang, Jie Liu","doi":"10.3389/fcell.2024.1469541","DOIUrl":"10.3389/fcell.2024.1469541","url":null,"abstract":"<p><strong>Background: </strong>Mesenchymal stem cells (MSCs) are safe and effective in treating myocardial infarction (MI) and have broad application prospects. However, the heterogeneity of MSCs may affect their therapeutic effect on the disease. We recently found that MSCs derived from different segments of the same umbilical cord (UC) showed significant difference in the expression of genes that are related to heart development and injury repair. We therefore hypothesized that those MSCs with high expression of above genes are more effective to treat MI and tested it in this study.</p><p><strong>Methods: </strong>MSCs were isolated from 3 cm-long segments of the maternal, middle and fetal segments of the UC (maternal-MSCs, middle-MSCs and fetal-MSCs, respectively). RNA-seq was used to analyze and compare the transcriptomes. We verified the effects of MSCs on oxygen-glucose deprivation (OGD)-induced cardiomyocyte apoptosis <i>in vitro</i>. <i>In vivo</i>, a rat MI model was established by ligating the left anterior descending coronary artery, and MSCs were injected into the myocardium surrounding the MI site. The therapeutic effects of MSCs derived from different segments of the UC were evaluated by examining cardiac function, histopathology, cardiomyocyte apoptosis, and angiogenesis.</p><p><strong>Results: </strong>Compared to fetal-MSCs and middle-MSCs, maternal-MSCs exhibited significantly higher expression of genes that are associated with heart development, such as GATA-binding protein 4 (GATA4), and myocardin (MYOCD). Coculture with maternal-MSCs reduced OGD-induced cardiomyocyte apoptosis. In rats with MI, maternal-MSCs significantly restored cardiac contractile function and reduced the infarct size. Mechanistic experiments revealed that maternal-MSCs exerted cardioprotective effects by decreasing cardiomyocyte apoptosis, and promoting angiogenesis.</p><p><strong>Conclusion: </strong>Our data demonstrated that maternal segment-derived MSCs were a superior cell source for regenerative repair after MI. Segmental localization of the entire UC when isolating hUCMSCs was necessary to improve the effectiveness of clinical applications.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11521943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Roles of the Dbl family of RhoGEFs in mechanotransduction - a review. RhoGEFs的Dbl家族在机械传导中的作用--综述。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-16 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1485725
Kazumasa Ohashi, Aoi Kunitomi, Shuhei Chiba, Kensaku Mizuno

Rho guanine nucleotide exchange factors (RhoGEFs) comprise a wide range of proteins with a common domain responsible for the activation of the Rho family of small GTPases and various domains in other regions. The evolutionary divergence of RhoGEFs enables actin cytoskeletal reorganization, leading to complex cellular responses in higher organisms. In this review, we address the involvement of RhoGEFs in the mechanical stress response of mammalian cells. The cellular mechanical stress response is essential for the proper and orderly regulation of cell populations, including the maintenance of homeostasis, tissue morphogenesis, and adaptation to the mechanical environment. In particular, this review focuses on the recent findings regarding the Dbl family of RhoGEFs involved in mechanical stress responses at the cell-cell and cell-substrate adhesion sites, and their molecular mechanisms underlying actin cytoskeleton remodeling and signal transduction.

Rho 鸟嘌呤核苷酸交换因子(RhoGEFs)由多种蛋白质组成,其共同结构域负责激活 Rho 家族的小 GTP 酶,其他结构域则各不相同。RhoGEFs 的进化分化使肌动蛋白细胞骨架得以重组,从而导致高等生物体内复杂的细胞反应。在本综述中,我们将探讨 RhoGEFs 参与哺乳动物细胞机械应激反应的情况。细胞的机械应激反应对于细胞群的正常有序调节至关重要,包括维持稳态、组织形态发生和适应机械环境。本综述特别关注最近关于参与细胞-细胞和细胞-基质粘附位点机械应激反应的 RhoGEFs Dbl 家族的研究结果,以及它们作为肌动蛋白细胞骨架重塑和信号转导基础的分子机制。
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引用次数: 0
Interleukin-1 receptor-dependent and -independent caspase-1 activity in retinal cells mediated by receptor interacting protein 2. 视网膜细胞中由受体互作蛋白 2 介导的白细胞介素-1 受体依赖型和非依赖型 caspase-1 活性。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-16 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1467799
Brandon A Coughlin, Barbara Christian, Brett Trombley, Susanne Mohr

Introduction: Inflammation and cell death play an important role in the pathogenesis of diabetic retinopathy. Previously we observed sustained activation of pro-inflammatory caspase-1 in retinas of diabetic animals and patients. In this study, we aimed to look at mechanisms underlying chronic caspase-1 activation in vitro and in vivo.

Methods: Non-diabetic and diabetic wild type and IL-1 receptor (IL-1R1) knockout mice were used for in vivo experiments. Diabetes was induced using STZ (streptozotocin). Human Müller cells were used for in vitro studies. Cells were treated with either 5 mM or 25 mM glucose or interleukin-1beta (IL-1β) in the presence or absence of IL-1 receptor antagonist (IL-1ra) or siRNA against RIP2 (receptor interacting protein-2) for up to 96 h. Outcome measurements to assess Müller cell functions included measurements of caspase-1 activity using a fluorescence peptide substrate, production of IL-1β by Elisa, and cell death using trypan blue exclusion assays.

Results: Our in vivo results demonstrate that caspase-1 activation progresses from an IL-1R1 independent mechanism at 10 weeks of diabetes to an IL-1R1 dependent mechanism at 20 weeks indicating that feedback through IL-1R1 is crucial for sustained caspase-1 activity in retinas of mice. A similar hyperglycemia-mediated caspase-1/IL-1β/IL-1R1 feedback signaling was detected in vitro in human Müller cells which was prevented by treatment with IL-1ra. Our data also indicate that hyperglycemia induces caspase-1 activation initially but IL-1β sustains caspase-1 activation via caspase-1/IL-1β/IL-1R1 feedback and we identified RIP2 as mediator for both hyperglycemia- and IL-1β-induced caspase-1 activation. Activation of caspase-1/IL-1β/IL-1R1 feedback signaling caused Müller cell death which was prevented by RIP2 knockdown.

Discussion: We conclude that any intervention in caspase-1/IL-1β/IL-1R1 feedback signaling presents novel therapeutic options for the treatment of diabetic retinopathy.

导言:炎症和细胞死亡在糖尿病视网膜病变的发病机制中起着重要作用。此前,我们曾在糖尿病动物和患者的视网膜中观察到促炎性 caspase-1 的持续激活。在这项研究中,我们旨在研究体外和体内慢性 caspase-1 激活的机制:方法:使用非糖尿病和糖尿病野生型小鼠以及 IL-1 受体(IL-1R1)基因敲除小鼠进行体内实验。使用 STZ(链脲佐菌素)诱导糖尿病。人 Müller 细胞用于体外研究。在有或没有IL-1受体拮抗剂(IL-1ra)或针对RIP2(受体相互作用蛋白-2)的siRNA的情况下,用5 mM或25 mM葡萄糖或白细胞介素-1β(IL-1β)处理细胞长达96小时:我们的体内研究结果表明,在糖尿病10周时,caspase-1的激活从独立于IL-1R1的机制发展到20周时依赖于IL-1R1的机制,这表明通过IL-1R1的反馈对小鼠视网膜中持续的caspase-1活性至关重要。在体外人Müller细胞中也检测到了类似的高血糖介导的caspase-1/IL-1β/IL-1R1反馈信号传导,用IL-1ra处理可阻止这种信号传导。我们的数据还表明,高血糖最初会诱导 caspase-1 激活,但 IL-1β 会通过 caspase-1/IL-1β/IL-1R1 反馈维持 caspase-1 激活,我们还发现 RIP2 是高血糖和 IL-1β 诱导 caspase-1 激活的介质。Caspase-1/IL-1β/IL-1R1反馈信号的激活导致了Müller细胞的死亡,而RIP2的敲除可以阻止这种死亡:讨论:我们得出结论,任何对caspase-1/IL-1β/IL-1R1反馈信号的干预都为治疗糖尿病视网膜病变提供了新的治疗方案。
{"title":"Interleukin-1 receptor-dependent and -independent caspase-1 activity in retinal cells mediated by receptor interacting protein 2.","authors":"Brandon A Coughlin, Barbara Christian, Brett Trombley, Susanne Mohr","doi":"10.3389/fcell.2024.1467799","DOIUrl":"10.3389/fcell.2024.1467799","url":null,"abstract":"<p><strong>Introduction: </strong>Inflammation and cell death play an important role in the pathogenesis of diabetic retinopathy. Previously we observed sustained activation of pro-inflammatory caspase-1 in retinas of diabetic animals and patients. In this study, we aimed to look at mechanisms underlying chronic caspase-1 activation <i>in vitro</i> and <i>in vivo</i>.</p><p><strong>Methods: </strong>Non-diabetic and diabetic wild type and IL-1 receptor (IL-1R1) knockout mice were used for <i>in vivo</i> experiments. Diabetes was induced using STZ (streptozotocin). Human Müller cells were used for <i>in vitro</i> studies. Cells were treated with either 5 mM or 25 mM glucose or interleukin-1beta (IL-1β) in the presence or absence of IL-1 receptor antagonist (IL-1ra) or siRNA against RIP2 (receptor interacting protein-2) for up to 96 h. Outcome measurements to assess Müller cell functions included measurements of caspase-1 activity using a fluorescence peptide substrate, production of IL-1β by Elisa, and cell death using trypan blue exclusion assays.</p><p><strong>Results: </strong>Our <i>in vivo</i> results demonstrate that caspase-1 activation progresses from an IL-1R1 independent mechanism at 10 weeks of diabetes to an IL-1R1 dependent mechanism at 20 weeks indicating that feedback through IL-1R1 is crucial for sustained caspase-1 activity in retinas of mice. A similar hyperglycemia-mediated caspase-1/IL-1β/IL-1R1 feedback signaling was detected <i>in vitro</i> in human Müller cells which was prevented by treatment with IL-1ra. Our data also indicate that hyperglycemia induces caspase-1 activation initially but IL-1β sustains caspase-1 activation via caspase-1/IL-1β/IL-1R1 feedback and we identified RIP2 as mediator for both hyperglycemia- and IL-1β-induced caspase-1 activation. Activation of caspase-1/IL-1β/IL-1R1 feedback signaling caused Müller cell death which was prevented by RIP2 knockdown.</p><p><strong>Discussion: </strong>We conclude that any intervention in caspase-1/IL-1β/IL-1R1 feedback signaling presents novel therapeutic options for the treatment of diabetic retinopathy.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11525982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Corrigendum: Pyroptosis and gasdermins-Emerging insights and therapeutic opportunities in metabolic dysfunction-associated steatohepatitis. 更正:新陈代谢功能障碍相关性脂肪性肝炎的新见解和治疗机会。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-16 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1461581
Christian Stoess, Aleksandra Leszczynska, Lin Kui, Ariel E Feldstein

[This corrects the article DOI: 10.3389/fcell.2023.1218807.].

[此处更正了文章 DOI:10.3389/fcell.2023.1218807]。
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引用次数: 0
Extra-cerebral recombination activity of Emx1-Cre and nestin-Cre in the kidney. 肾脏中 Emx1-Cre 和 nestin-Cre 的脑外重组活性。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-16 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1480217
Min Wang, Xiaojuan Liu, Yin Fang, Qintong Li

Individuals with neurodevelopmental disorders (NDDs) are frequently diagnosed with comorbidities in other organs, indicating that NDD risk genes may have extra-cerebral functions. The engineered mouse models are pivotal in understanding the functions of candidate NDD genes. Here, we report that Emx1-Cre and nestin-Cre mouse strains, the popular tools to study brain development, also exhibit recombination activity in the kidney. We find that both Emx1-Cre and nestin-Cre can drive recombination in epithelial cells lining proximal and distal convoluted tubules of the nephron. Additionally, nestin-Cre drives recombination in the glomerulus of the nephron. Furthermore, we use Emx1-Cre and nestin-Cre to knock out Larp7, a gene linked to a human NDD called Alazami syndrome. We find that Larp7 knockout using nestin-Cre, but not Emx1-Cre, results in elevated blood urea nitrogen. This result suggests a compromised kidney function, reminiscent of recently revealed renal anomalies in Alazami syndrome patients. Many genes have been knocked out using Emx1-Cre and nestin-Cre to study their roles during embryonic neurogenesis. It will be of great interest to reinvestigate whether the renal development and function is affected in these existing mouse models.

神经发育障碍(NDDs)患者经常被诊断出合并其他器官的疾病,这表明NDD风险基因可能具有脑外功能。工程小鼠模型对于了解候选 NDD 基因的功能至关重要。在这里,我们报告了 Emx1-Cre 和 nestin-Cre 小鼠品系,它们是研究大脑发育的常用工具,在肾脏中也表现出重组活性。我们发现,Emx1-Cre 和 nestin-Cre 都能驱动肾小管近端和远端曲小管上皮细胞的重组。此外,nestin-Cre 还能驱动肾小球中的重组。此外,我们还利用 Emx1-Cre 和 nestin-Cre 基因敲除 Larp7。我们发现,使用 nestin-Cre 而不是 Emx1-Cre 敲除 Larp7 会导致血尿素氮升高。这一结果表明肾功能受损,这与最近发现的阿拉扎米综合征患者的肾脏异常现象相似。利用 Emx1-Cre 和 nestin-Cre 基因敲除了许多基因,以研究它们在胚胎神经发生过程中的作用。重新研究这些现有小鼠模型的肾脏发育和功能是否受到影响将是非常有意义的。
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引用次数: 0
Advances in understanding the regulation of pluripotency fate transition in embryonic stem cells. 了解胚胎干细胞多能性命运转变调控的进展。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-16 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1494398
Yong Kang Jia, Yang Yu, Li Guan

Embryonic stem cells (ESCs) sourced from the inner cell mass of blastocysts, are akin to this tissue in function but lack the capacity to form all extraembryonic structures. mESCs are transient cell populations that express high levels of transcripts characteristic of 2-cell (2C) embryos and are identified as "2-cell-like cells" (2CLCs). Previous studies have shown that 2CLCs can contribute to both embryonic and extraembryonic tissues upon reintroduction into early embryos. Approximately 1% of mESCs dynamically transition from pluripotent mESCs into 2CLCs. Nevertheless, the scarcity of mammalian embryos presents a significant challenge to the molecular characterization of totipotent cells. To date, Previous studies have explored various methods for reprogramming pluripotent cells into totipotent cells. While there is a good understanding of the molecular regulatory network maintaining ES pluripotency, the process by which pluripotent ESCs reprogram into totipotent cells and the associated molecular mechanisms of totipotent regulation remain poorly understood. This review synthesizes recent insights into the regulatory pathways of ESC reprogramming into 2CLC, exploring molecular mechanisms modulated by transcriptional regulators, small molecules, and epigenetic changes. The objective is to construct a theoretical framework for the field of researchers.

胚胎干细胞(ESC)来源于胚泡的内细胞团,在功能上与胚泡组织相似,但缺乏形成所有胚外结构的能力。先前的研究表明,2CLCs 在重新导入早期胚胎后,可对胚胎组织和胚外组织做出贡献。约有 1% 的 mESCs 可从多能 mESCs 动态转变为 2CLCs 。然而,哺乳动物胚胎的稀缺性给全能细胞的分子鉴定带来了巨大挑战。迄今为止,以往的研究探索了将多能细胞重编程为全能细胞的各种方法。虽然人们对维持 ES 多能性的分子调控网络有了很好的了解,但对多能性 ESC 重编程为全能细胞的过程以及全能性调控的相关分子机制仍然知之甚少。这篇综述综述了ESC重编程为2CLC的调控途径的最新见解,探讨了由转录调控因子、小分子和表观遗传变化调控的分子机制。目的是为该领域的研究人员构建一个理论框架。
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Frontiers in Cell and Developmental Biology
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