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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。
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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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引用次数: 0
Revisiting the role of MicroRNAs in the pathogenesis of idiopathic pulmonary fibrosis. 重新审视 MicroRNA 在特发性肺纤维化发病机制中的作用。
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.2024.1470875
Zhimin Zhou, Yuhong Xie, Qianru Wei, Xinyue Zhang, Zhihao Xu

Idiopathic pulmonary fibrosis (IPF) is a prevalent chronic pulmonary fibrosis disease characterized by alveolar epithelial cell damage, fibroblast proliferation and activation, excessive extracellular matrix deposition, and abnormal epithelial-mesenchymal transition (EMT), resulting in tissue remodeling and irreversible structural distortion. The mortality rate of IPF is very high, with a median survival time of 2-3 years after diagnosis. The exact cause of IPF remains unknown, but increasing evidence supports the central role of epigenetic changes, particularly microRNA (miRNA), in IPF. Approximately 10% of miRNAs in IPF lung tissue exhibit differential expression compared to normal lung tissue. Diverse miRNA phenotypes exert either a pro-fibrotic or anti-fibrotic influence on the progression of IPF. In the context of IPF, epigenetic factors such as DNA methylation and long non-coding RNAs (lncRNAs) regulate differentially expressed miRNAs, which in turn modulate various signaling pathways implicated in this process, including transforming growth factor-β1 (TGF-β1)/Smad, mitogen-activated protein kinase (MAPK), and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. Therefore, this review presents the epidemiology of IPF, discusses the multifaceted regulatory roles of miRNAs in IPF, and explores the impact of miRNAs on IPF through various pathways, particularly the TGF-β1/Smad pathway and its constituent structures. Consequently, we investigate the potential for targeting miRNAs as a treatment for IPF, thereby contributing to advancements in IPF research.

特发性肺纤维化(IPF)是一种流行的慢性肺纤维化疾病,其特点是肺泡上皮细胞损伤、成纤维细胞增殖和活化、细胞外基质过度沉积以及异常的上皮-间质转化(EMT),从而导致组织重塑和不可逆的结构扭曲。IPF 的死亡率非常高,确诊后的中位生存时间为 2-3 年。IPF 的确切病因尚不清楚,但越来越多的证据支持表观遗传学变化,尤其是微 RNA(miRNA)在 IPF 中的核心作用。与正常肺组织相比,IPF 肺组织中约有 10% 的 miRNA 表现出不同的表达。不同的 miRNA 表型会对 IPF 的进展产生促纤维化或抗纤维化的影响。就 IPF 而言,DNA 甲基化和长非编码 RNA(lncRNA)等表观遗传因素可调控不同表达的 miRNA,而 miRNA 又可调节与此过程有关的各种信号通路,包括转化生长因子-β1(TGF-β1)/Smad、丝裂原活化蛋白激酶(MAPK)和磷脂酰肌醇-3-激酶/蛋白激酶 B(PI3K/AKT)通路。因此,本综述介绍了 IPF 的流行病学,讨论了 miRNA 在 IPF 中的多方面调控作用,并探讨了 miRNA 通过各种途径,尤其是 TGF-β1/Smad 途径及其组成结构对 IPF 的影响。因此,我们研究了以 miRNAs 为靶点治疗 IPF 的潜力,从而推动 IPF 研究的进步。
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引用次数: 0
Modification of Lhx2 activity for ex vivo amplification of human iPSC-derived hematopoietic stem/progenitor cells. 修改 Lhx2 活性,实现人 iPSC 衍生造血干细胞/祖细胞的体内外扩增。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-15 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1482989
Kenji Kitajima, Yuna Takahashi, Hikaru Ando, Minako Shingai, Mako Hamasaki, Miyu Tanikawa, Mai Kanokoda, Marino Nakajima, Yasumasa Nishito, Takahiko Hara

Hematopoietic stem cells (HSCs) obtained from patient-derived human induced pluripotent stem cells (iPSCs) are a promising tool for curing various hematological disorders. We previously demonstrated that enforced expression of the LIM-homeobox transcription factor Lhx2, which is essential for mouse embryonic hematopoiesis, leads to generation of engraftable and expandable hematopoietic stem cells (HSCs) from mouse iPSCs. However, it remained unknown whether Lhx2 can induce HSCs from human iPSCs. Here, we investigated the effect of Lhx2 overexpression on hematopoietic differentiation of human iPSCs. Unexpectedly, Lhx2 severely inhibited proliferation of human iPSC-derived hematopoietic cells. Thus, Lhx2 exhibited differential effects on mouse and human hematopoietic cells. Further studies implied that the inhibitory effect of Lhx2 on human iPSC-derived hematopoietic cells was due to insufficient transcriptional activation ability. Therefore, we modified Lhx2 to strengthen its activity as a transcriptional activator. This modified Lhx2 could induce ex vivo amplification of human iPSC-derived hematopoietic stem/progenitor cells (HSPCs). We believe that these findings will facilitate the development of a method to efficiently produce HSCs from human iPSCs.

从源自患者的人类诱导多能干细胞(iPSCs)中获得的造血干细胞(HSCs)是治疗各种血液病的一种很有前景的工具。我们以前曾证实,小鼠胚胎造血过程中必不可少的LIM-homeobox转录因子Lhx2的强制表达可导致小鼠iPSCs产生可移植和可扩增的造血干细胞(HSCs)。然而,Lhx2能否诱导人iPSCs产生造血干细胞仍是未知数。在这里,我们研究了Lhx2过表达对人类iPSCs造血分化的影响。意想不到的是,Lhx2 严重抑制了人 iPSC 衍生造血细胞的增殖。因此,Lhx2 对小鼠和人类造血细胞具有不同的影响。进一步的研究表明,Lhx2 对人 iPSC 衍生造血细胞的抑制作用是由于转录激活能力不足造成的。因此,我们对Lhx2进行了改造,以增强其作为转录激活剂的活性。经过改造的Lhx2可以诱导人iPSC衍生造血干细胞/祖细胞(HSPCs)的体内外扩增。我们相信,这些发现将有助于开发一种从人类 iPSCs 高效生产造血干细胞的方法。
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引用次数: 0
Tensions on the actin cytoskeleton and apical cell junctions in the C. elegans spermatheca are influenced by spermathecal anatomy, ovulation state and activation of myosin. 秀丽隐杆线虫精巢中肌动蛋白细胞骨架和顶端细胞连接的张力受精巢解剖、排卵状态和肌球蛋白活化的影响。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-15 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1490803
Fereshteh Sadeghian, Noa W F Grooms, Samuel H Chung, Erin J Cram

Introduction: Cells generate mechanical forces mainly through myosin motor activity on the actin cytoskeleton. In C. elegans, actomyosin stress fibers drive contractility of the smooth muscle-like cells of the spermatheca, a distensible, tube-shaped tissue in the hermaphrodite reproductive system and the site of oocyte fertilization. Stretching of the spermathecal cells by oocyte entry triggers activation of the small GTPase Rho. In this study, we asked how forces are distributed in vivo, and explored how spermathecal tissue responds to alterations in myosin activity.

Methods: In animals expressing GFP labeled actin or apical membrane complexes, we severed these structures using femtosecond laser ablation and quantified retractions. RNA interference was used to deplete key contractility regulators.

Results: We show that the basal actomyosin fibers are under tension in the occupied spermatheca. Reducing actomyosin contractility by depletion of the phospholipase C-ε/PLC-1 or non-muscle myosin II/NMY-1, leads to distended spermathecae occupied by one or more embryos, but does not alter tension on the basal actomyosin fibers. However, activating myosin through depletion of the Rho GAP SPV-1 increases tension on the actomyosin fibers, consistent with earlier studies showing Rho drives spermathecal contractility. On the inner surface of the spermathecal tube, tension on the apical junctions is decreased by depletion of PLC-1 and NMY-1. Surprisingly, when basal contractility is increased through SPV-1 depletion, the tension on apical junctions also decreases, with the most significant effect on the junctions aligned in perpendicular to the axis of the spermatheca.

Discussion: Our results suggest that much of the tension on the basal actin fibers in the occupied spermatheca is due to the presence of the embryo. Additionally, increased tension on the outer basal surface may compress the apical side, leading to lower tensions apically. The three dimensional shape of the spermatheca plays a role in force distribution and contractility during ovulation.

引言细胞主要通过肌动蛋白细胞骨架上的肌球蛋白运动产生机械力。在秀丽隐杆线虫中,肌动蛋白应力纤维驱动精囊平滑肌样细胞收缩,精囊是雌雄同体生殖系统中一个可扩张的管状组织,也是卵细胞受精的场所。卵母细胞进入精囊时会拉伸精囊细胞,从而引发小 GTPase Rho 的活化。在这项研究中,我们询问了力在体内是如何分布的,并探讨了精巢组织如何对肌球蛋白活性的改变做出反应:方法:在表达 GFP 标记的肌动蛋白或顶端膜复合物的动物中,我们使用飞秒激光烧蚀法切断这些结构并量化回缩。结果:我们发现基底肌动蛋白和顶端膜复合物的活性与肌球蛋白的活性相似:结果:我们发现,在被占据的精囊中,基底肌动蛋白纤维处于紧张状态。通过消耗磷脂酶C-ε/PLC-1或非肌球蛋白II/NMY-1来降低肌动蛋白的收缩力,会导致精巢被一个或多个胚胎占据,但不会改变基础肌动蛋白纤维的张力。然而,通过消耗 Rho GAP SPV-1 激活肌球蛋白会增加肌动蛋白纤维的张力,这与早先的研究显示 Rho 驱动精巢收缩力一致。在精巢管内表面,消耗 PLC-1 和 NMY-1 会降低顶端连接处的张力。令人惊讶的是,当通过消耗 SPV-1 增加基础收缩力时,顶端连接的张力也会降低,其中对垂直于精巢轴线的连接影响最大:讨论:我们的研究结果表明,被占据精囊中基底肌动蛋白纤维的张力主要是由于胚胎的存在。此外,基底外表面张力的增加可能会压缩顶端一侧,导致顶端张力降低。精囊的三维形状在排卵期间对力的分布和收缩性起作用。
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引用次数: 0
Corrigendum: A role for TRPC3 in mammalian testis development. 更正:TRPC3在哺乳动物睾丸发育中的作用。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-15 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1484634
Zhenhua Ming, Stefan Bagheri-Fam, Emily R Frost, Janelle M Ryan, Brittany Vining, Vincent R Harley

[This corrects the article DOI: 10.3389/fcell.2024.1337714.].

[此处更正了文章 DOI:10.3389/fcell.2024.1337714]。
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引用次数: 0
Cellular and transcriptomic changes by the supplementation of aged rat serum in human pluripotent stem cell-derived myogenic progenitors. 补充老龄大鼠血清后人多能干细胞肌原性祖细胞的细胞和转录组变化
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-15 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1481491
Sin-Ruow Tey, Ryan S Anderson, Clara H Yu, Samantha Robertson, Heidi Kletzien, Nadine P Connor, Kaori Tanaka, Yasuyuki Ohkawa, Masatoshi Suzuki

Introduction: The changing composition of non-cell autonomous circulating factors in blood as humans age is believed to play a role in muscle mass and strength loss. The mechanisms through which these circulating factors act in age-related skeletal muscle changes is not fully understood. In this study, we used human myogenic progenitors derived from human pluripotent stem cells to study non-cell autonomous roles of circulating factors during the process of myogenic differentiation.

Methods: Myogenic progenitors from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) were supplemented with serum samples from aged or young Fischer 344 × Brown Norway F1-hybrid rats. The effect of aged or young serum supplementation on myogenic progenitor proliferation, myotube formation capacity, differentiation, and early transcriptomic profiles were analyzed.

Results: We found that aged rat serum supplementation significantly reduced cell proliferation and increased cell death in both ESC- and iPSC-derived myogenic progenitors. Next, we found that the supplementation of aged rat serum inhibited myotube formation and maturation during terminal differentiation from progenitors to skeletal myocytes when compared to the cells treated with young adult rat serum. Lastly, we identified that gene expression profiles were affected following serum supplementation in culture.

Discussion: Together, aged serum supplementation caused cellular and transcriptomic changes in human myogenic progenitors. The current data from our in vitro model possibly simulate non-cell autonomous contributions of blood composition to age-related processes in human skeletal muscle.

简介随着年龄的增长,血液中的非细胞自主循环因子的组成不断变化,这被认为是导致肌肉质量和力量下降的原因之一。这些循环因子在与年龄相关的骨骼肌变化中的作用机制尚未完全明了。在这项研究中,我们利用从人类多能干细胞中提取的人类肌原祖细胞来研究循环因子在肌原分化过程中的非细胞自主作用:方法:将人胚胎干细胞(ESCs)和诱导多能干细胞(iPSCs)的成肌祖细胞加入老年或年轻的Fischer 344 × Brown Norway F1-杂交大鼠的血清样本中。分析了补充老年或年轻血清对肌原细胞增殖、肌管形成能力、分化和早期转录组谱的影响:结果:我们发现,补充老龄大鼠血清会显著降低ESC和iPSC衍生的肌原细胞的细胞增殖,增加细胞死亡。接着,我们发现与使用年轻成年大鼠血清处理的细胞相比,补充老年大鼠血清抑制了从祖细胞向骨骼肌细胞终极分化过程中肌管的形成和成熟。最后,我们还发现,在培养过程中补充血清后,基因表达谱也会受到影响:总之,补充老年血清会导致人类肌原细胞和转录组发生变化。我们体外模型的现有数据可能模拟了血液成分对人体骨骼肌年龄相关过程的非细胞自主贡献。
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引用次数: 0
Integrating clinical and genomic landscape analysis of perineural invasion identify ACTA1 as an oncogene for oral squamous cell carcinoma. 综合临床和神经周围侵袭基因组图谱分析发现 ACTA1 是口腔鳞状细胞癌的致癌基因。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-15 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1458879
Sheng Chen, Tongchao Zhao, Yuxian Song, Xiaofeng Huang, Yanhong Ni, Liang Ding, Yong Fu, Qingang Hu, Yi Wang

Background: Perineural invasion (PNI) has been shown to be a key pathological feature of several types of cancer, including oral squamous epithelial carcinoma (OSCC). However, the overall clinical and genomic landscape of PNI+ OSCC are still unclear, and the molecular mechanism of PNI remains to be further investigated.

Methods: 279 OSCC samples were extracted from the TCGA database and grouped according to PNI. The clinicopathological information, prognostic and survival analyses were performed. The Cibersort algorithm and ESTIMATE algorithm was used to estimate the impacts on proportion of immune cells, immune score and stromal score by PNI. Immunotherapy prediction analysis was also performed. 167 differentially expressed genes were screened for functional enrichment analysis. Actin α1 (ACTA1) protein, which was significantly upregulated in the PNI+ group, was selected for validation in our OSCC patient's cohort (n = 70). We next analyzed the ratio and absolute number of key immunocytes in peripheral blood of OSCC patients according to Actin α1 expression by flow cytometry.

Results: PNI was more likely to occur in patients with advanced tumors and worse prognosis. Immunomodulation analyses showed that T cells follicular helper and cells were significantly lower, but M2 macrophages and total stromal score was significantly higher in PNI+ OSCC. Immunotherapy prediction analyses showed that PNI+ OSCC may be more sensitive to CTLA4 inhibitor treatment. 167 differentially expressed genes were identified and enriched in muscle structure and cell movement-related pathway. Among them, Actin α1 (ACTA1) was significantly upregulated in PNI+ advanced OSCC with worse clinical outcome whose had relatively low ratio of CD3+CD8+ circulating cytotoxic T cells.

Conclusion: PNI+ OSCC patients with upregulated of Actin α1 could benefit from cytotoxic T cell-mediated immunotherapy.

背景:神经周围侵犯(PNI)已被证明是包括口腔鳞状上皮癌(OSCC)在内的多种类型癌症的一个关键病理特征。方法:从 TCGA 数据库中提取 279 例 OSCC 样本,并根据 PNI 进行分组。方法:从 TCGA 数据库中提取 279 例 OSCC 样本,根据 PNI 进行分组,并进行临床病理信息、预后和生存分析。使用 Cibersort 算法和 ESTIMATE 算法估算 PNI 对免疫细胞比例、免疫评分和基质评分的影响。此外,还进行了免疫治疗预测分析。筛选了 167 个差异表达基因进行功能富集分析。肌动蛋白α1(ACTA1)蛋白在PNI+组中显著上调,我们选择了该蛋白在我们的OSCC患者队列(n = 70)中进行验证。接下来,我们通过流式细胞术分析了OSCC患者外周血中关键免疫细胞与Actin α1表达的比例和绝对数量:结果:PNI更容易发生在肿瘤晚期和预后较差的患者中。免疫调节分析显示,在PNI+ OSCC患者中,T细胞滤泡辅助细胞和细胞显著降低,但M2巨噬细胞和基质总分显著升高。免疫治疗预测分析表明,PNI+ OSCC可能对CTLA4抑制剂治疗更敏感。在肌肉结构和细胞运动相关通路中发现了167个差异表达基因。其中,肌动蛋白α1(ACTA1)在PNI+晚期OSCC中显著上调,而PNI+晚期OSCC的临床预后较差,其CD3+CD8+循环细胞毒性T细胞的比例相对较低:结论:Actin α1上调的PNI+ OSCC患者可从细胞毒性T细胞介导的免疫疗法中获益。
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Frontiers in Cell and Developmental Biology
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