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Patient iPSC models reveal glia-intrinsic phenotypes in multiple sclerosis. 患者 iPSC 模型揭示了多发性硬化症的神经胶质内表型。
Pub Date : 2024-11-07 Epub Date: 2024-08-26 DOI: 10.1016/j.stem.2024.08.002
Benjamin L L Clayton, Lilianne Barbar, Maria Sapar, Kriti Kalpana, Chandrika Rao, Bianca Migliori, Tomasz Rusielewicz, Daniel Paull, Katie Brenner, Dorota Moroziewicz, Ilana Katz Sand, Patrizia Casaccia, Paul J Tesar, Valentina Fossati

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS), resulting in neurological disability that worsens over time. While progress has been made in defining the immune system's role in MS pathophysiology, the contribution of intrinsic CNS cell dysfunction remains unclear. Here, we generated a collection of induced pluripotent stem cell (iPSC) lines from people with MS spanning diverse clinical subtypes and differentiated them into glia-enriched cultures. Using single-cell transcriptomic profiling and orthogonal analyses, we observed several distinguishing characteristics of MS cultures pointing to glia-intrinsic disease mechanisms. We found that primary progressive MS-derived cultures contained fewer oligodendrocytes. Moreover, MS-derived oligodendrocyte lineage cells and astrocytes showed increased expression of immune and inflammatory genes, matching those of glia from MS postmortem brains. Thus, iPSC-derived MS models provide a unique platform for dissecting glial contributions to disease phenotypes independent of the peripheral immune system and identify potential glia-specific targets for therapeutic intervention.

多发性硬化症(MS)是中枢神经系统(CNS)的一种炎症和神经退行性疾病,会导致神经系统残疾,并随着时间的推移而恶化。虽然在确定免疫系统在多发性硬化症病理生理学中的作用方面取得了进展,但中枢神经系统内在细胞功能障碍的作用仍不清楚。在这里,我们从不同临床亚型的多发性硬化症患者身上收集了一系列诱导多能干细胞(iPSC),并将它们分化成胶质丰富的培养物。利用单细胞转录组分析和正交分析,我们观察到多发性硬化症培养物的几个显著特征,这些特征指向胶质细胞内在疾病机制。我们发现,原发性进行性多发性硬化症衍生培养物含有较少的少突胶质细胞。此外,多发性硬化症衍生的少突胶质细胞系细胞和星形胶质细胞显示免疫和炎症基因表达增加,与多发性硬化症死后大脑胶质细胞的表达相匹配。因此,iPSC衍生的多发性硬化症模型提供了一个独特的平台,可用于剖析神经胶质对疾病表型的贡献,而不受外周免疫系统的影响,并确定潜在的神经胶质特异性治疗干预靶点。
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引用次数: 0
Hallmarks of regeneration. 再生的标志
Pub Date : 2024-09-05 Epub Date: 2024-08-19 DOI: 10.1016/j.stem.2024.07.007
Kenneth D Poss, Elly M Tanaka

Regeneration is a heroic biological process that restores tissue architecture and function in the face of day-to-day cell loss or the aftershock of injury. Capacities and mechanisms for regeneration can vary widely among species, organs, and injury contexts. Here, we describe "hallmarks" of regeneration found in diverse settings of the animal kingdom, including activation of a cell source, initiation of regenerative programs in the source, interplay with supporting cell types, and control of tissue size and function. We discuss these hallmarks with an eye toward major challenges and applications of regenerative biology.

再生是一个英勇的生物过程,它能在日常细胞损失或损伤后恢复组织结构和功能。不同物种、器官和损伤情况下的再生能力和机制差异很大。在这里,我们描述了在动物王国不同环境中发现的再生 "标志",包括细胞源的激活、细胞源再生程序的启动、与支持细胞类型的相互作用以及组织大小和功能的控制。我们在讨论这些特征时将着眼于再生生物学的主要挑战和应用。
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引用次数: 0
Integrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells. 单细胞综合分析确定了耐阉割前列腺管腔细胞的表观遗传学基础。
Pub Date : 2024-08-01 Epub Date: 2024-06-14 DOI: 10.1016/j.stem.2024.05.008
Jason S Kirk, Jie Wang, Mark Long, Spencer Rosario, Amanda Tracz, Yibing Ji, Rahul Kumar, Xiaozhuo Liu, Anmbreen Jamroze, Prashant K Singh, Igor Puzanov, Gurkamal Chatta, Qing Cheng, Jiaoti Huang, Jeffrey L Wrana, Jonathan Lovell, Han Yu, Song Liu, Michael M Shen, Tao Liu, Dean G Tang

Understanding prostate response to castration and androgen receptor signaling inhibitors (ARSI) is critical to improving long-term prostate cancer (PCa) patient survival. Here, we use a multi-omics approach on 229,794 single cells to create a mouse single-cell reference atlas for interpreting mouse prostate biology and castration response. Our reference atlas refines single-cell annotations and provides a chromatin context, which, when coupled with mouse lineage tracing, demonstrates that castration-resistant luminal cells are distinct from the pre-existent urethra-proximal stem/progenitor cells. Molecular pathway analysis and therapeutic studies further implicate AP1 (JUN/FOS), WNT/β-catenin, FOXQ1, NF-κB, and JAK/STAT pathways as major drivers of castration-resistant luminal populations with relevance to human PCa. Our datasets, which can be explored through an interactive portal (https://visportal.roswellpark.org/data/tang/), can aid in developing combination treatments with ARSI for advanced PCa patients.

了解前列腺对阉割和雄激素受体信号抑制剂(ARSI)的反应对于提高前列腺癌(PCa)患者的长期生存率至关重要。在这里,我们采用多组学方法对 229,794 个单细胞进行研究,建立了小鼠单细胞参考图谱,用于解释小鼠前列腺生物学和阉割反应。我们的参考图谱完善了单细胞注释并提供了染色质背景,结合小鼠系谱追踪,证明了耐阉割管腔细胞有别于之前存在的尿道近端干细胞/祖细胞。分子通路分析和治疗研究进一步表明,AP1(JUN/FOS)、WNT/β-catenin、FOXQ1、NF-κB 和 JAK/STAT 通路是阉割耐药管腔细胞的主要驱动因素,与人类 PCa 相关。我们的数据集可通过互动门户网站(https://visportal.roswellpark.org/data/tang/)进行浏览,有助于开发针对晚期PCa患者的ARSI联合疗法。
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引用次数: 0
Oscillation steers differentiation. 震荡引导分化。
Pub Date : 2024-07-05 DOI: 10.1016/j.stem.2024.06.008
Kyle A LaBella, Efren A Reyes, Louis Vermeulen

The differentiation trajectories defining enteroendocrine (EE) cell heterogeneity remain obscure. In this issue of Cell Stem Cell, Singh et al.1 map the differentiation landscape of EE cells, identifying early oscillating cell progenitor states, which play a critical role in generating terminal EE cell diversity.

定义肠内分泌(EE)细胞异质性的分化轨迹仍然模糊不清。在本期《细胞干细胞》(Cell Stem Cell)杂志上,辛格等人1绘制了肠内分泌细胞的分化图谱,确定了早期振荡细胞祖细胞状态,这种状态在产生终端肠内分泌细胞多样性方面发挥着关键作用。
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引用次数: 0
Monkey see, monkey do: Tracking iPS-cardiomyocyte survival and maturation in autografts. 猴子看,猴子干:跟踪 iPS 心肌细胞在自体移植物中的存活和成熟。
Pub Date : 2024-07-05 DOI: 10.1016/j.stem.2024.06.006
Xiaoqian Ji, Qiyuan Wang, Nan Cao

Induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) therapy has emerged as a highly promising field of heart repair. Lin et al.1 presented compelling evidence on the long-term engraftment and maturation of autologous iPSC-CMs in two rhesus macaques, demonstrating unprecedented cardiac autografting data in large animal models without the need of immunosuppressants.

诱导多能干细胞衍生心肌细胞(iPSC-CM)疗法已成为极具前景的心脏修复领域。Lin等人1提出了令人信服的证据,证明自体iPSC-CMs在两只猕猴体内的长期移植和成熟,在大型动物模型中展示了前所未有的心脏自体移植数据,且无需使用免疫抑制剂。
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引用次数: 0
Cultivating awareness of donation in cutting-edge allogenic cell therapies. 在最前沿的异基因细胞疗法中培养捐赠意识。
Pub Date : 2024-07-05 DOI: 10.1016/j.stem.2024.06.002
Oscar Andrusier, Aviad Raz, Jusaku Minari
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引用次数: 0
Activation of fetal-like molecular programs during regeneration in the intestine and beyond. 在肠道再生及其他过程中激活胎儿样分子程序
Pub Date : 2024-07-05 DOI: 10.1016/j.stem.2024.05.009
Sara Viragova, Dong Li, Ophir D Klein

Tissue regeneration after damage is generally thought to involve the mobilization of adult stem cells that divide and differentiate into progressively specialized progeny. However, recent studies indicate that tissue regeneration can be accompanied by reversion to a fetal-like state. During this process, cells at the injury site reactivate programs that operate during fetal development but are typically absent in adult homeostasis. Here, we summarize our current understanding of the molecular signals and epigenetic mediators that orchestrate "fetal-like reversion" during intestinal regeneration. We also explore evidence for this phenomenon in other organs and species and highlight open questions that merit future examination.

损伤后的组织再生通常被认为涉及成体干细胞的动员,这些干细胞分裂并分化成逐渐特化的后代。然而,最近的研究表明,组织再生可能伴随着恢复到类似胎儿的状态。在这一过程中,损伤部位的细胞会重新激活在胎儿发育过程中运行、但在成人稳态中通常不存在的程序。在此,我们总结了目前我们对在肠道再生过程中协调 "类胎儿还原 "的分子信号和表观遗传介质的理解。我们还探讨了这一现象在其他器官和物种中的证据,并强调了值得未来研究的开放性问题。
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引用次数: 0
Unraveling the function of FGF signaling in human hypoblast specialization. 揭示 FGF 信号在人类低分化母细胞特化过程中的功能。
Pub Date : 2024-07-05 DOI: 10.1016/j.stem.2024.06.010
Hao Wu, Jinglei Zhai, Hongmei Wang

Dattani et al.1 developed a method for inducing hypoblast-like cells from human naive pluripotent stem cells. They elucidated the requirement for FGF signaling in human hypoblast specialization at a specific time window, which was previously controversial.

Dattani 等人1 开发了一种从人类幼稚多能干细胞中诱导出低分化母细胞样细胞的方法。他们阐明了在特定的时间窗口内,人的低母细胞特化需要 FGF 信号,而这在以前是有争议的。
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引用次数: 0
Subventricular zone stem cell niche injury is associated with intestinal perforation in preterm infants and predicts future motor impairment. 脑室下区干细胞龛损伤与早产儿肠穿孔有关,并可预测未来的运动障碍。
Pub Date : 2024-04-04 Epub Date: 2024-03-26 DOI: 10.1016/j.stem.2024.03.001
Adrian A Epstein, Sara N Janos, Luca Menozzi, Kelly Pegram, Vaibhav Jain, Logan C Bisset, Joseph T Davis, Samantha Morrison, Aswathy Shailaja, Yingqiu Guo, Agnes S Chao, Khadar Abdi, Blaire Rikard, Junjie Yao, Simon G Gregory, Kimberley Fisher, Rick Pittman, Al Erkanli, Kathryn E Gustafson, Caroline W T Carrico, William F Malcolm, Terrie E Inder, C Michael Cotten, Trevor D Burt, Mari L Shinohara, Charles M Maxfield, Eric J Benner

Brain injury is highly associated with preterm birth. Complications of prematurity, including spontaneous or necrotizing enterocolitis (NEC)-associated intestinal perforations, are linked to lifelong neurologic impairment, yet the mechanisms are poorly understood. Early diagnosis of preterm brain injuries remains a significant challenge. Here, we identified subventricular zone echogenicity (SVE) on cranial ultrasound in preterm infants following intestinal perforations. The development of SVE was significantly associated with motor impairment at 2 years. SVE was replicated in a neonatal mouse model of intestinal perforation. Examination of the murine echogenic subventricular zone (SVZ) revealed NLRP3-inflammasome assembly in multiciliated FoxJ1+ ependymal cells and a loss of the ependymal border in this postnatal stem cell niche. These data suggest a mechanism of preterm brain injury localized to the SVZ that has not been adequately considered. Ultrasound detection of SVE may serve as an early biomarker for neurodevelopmental impairment after inflammatory disease in preterm infants.

脑损伤与早产关系密切。早产并发症,包括自发性或坏死性小肠结肠炎(NEC)相关的肠穿孔,与终生神经功能损伤有关,但其机制却鲜为人知。早产儿脑损伤的早期诊断仍是一项重大挑战。在这里,我们通过头颅超声波确定了肠穿孔早产儿脑室下区回声(SVE)。SVE的出现与2岁时的运动障碍有明显关联。SVE在新生小鼠肠穿孔模型中得到了复制。对小鼠室管膜下区(SVZ)的回声检查发现,在多纤毛FoxJ1+上皮细胞中组装了NLRP3-炎症小体,并且在这个产后干细胞龛中丧失了上皮细胞边界。这些数据表明,早产儿脑损伤的机制定位在SVZ,而这一点尚未得到充分考虑。超声检测SVE可作为早产儿炎症后神经发育受损的早期生物标志物。
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引用次数: 0
Lung repair and regeneration: Advanced models and insights into human disease. 肺修复与再生:先进的模型和对人类疾病的见解。
Pub Date : 2024-04-04 Epub Date: 2024-03-15 DOI: 10.1016/j.stem.2024.02.009
Maria C Basil, Konstantinos-Dionysios Alysandratos, Darrell N Kotton, Edward E Morrisey

The respiratory system acts as both the primary site of gas exchange and an important sensor and barrier to the external environment. The increase in incidences of respiratory disease over the past decades has highlighted the importance of developing improved therapeutic approaches. This review will summarize recent research on the cellular complexity of the mammalian respiratory system with a focus on gas exchange and immunological defense functions of the lung. Different models of repair and regeneration will be discussed to help interpret human and animal data and spur the investigation of models and assays for future drug development.

呼吸系统既是气体交换的主要场所,也是外界环境的重要传感器和屏障。过去几十年来,呼吸系统疾病发病率的上升凸显了开发更好的治疗方法的重要性。本综述将总结哺乳动物呼吸系统细胞复杂性的最新研究,重点关注肺的气体交换和免疫防御功能。将讨论不同的修复和再生模型,以帮助解释人类和动物数据,并促进对未来药物开发模型和检测方法的研究。
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引用次数: 0
期刊
Cell stem cell
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