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Neural crest precursors from the skin are the primary source of directly reprogrammed neurons. 来自皮肤的神经嵴前体是直接重编程神经元的主要来源。
IF 5.9 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-11-12 Epub Date: 2024-10-31 DOI: 10.1016/j.stemcr.2024.10.003
Justin J Belair-Hickey, Ahmed Fahmy, Wenbo Zhang, Rifat S Sajid, Brenda L K Coles, Michael W Salter, Derek van der Kooy

Direct reprogramming involves the conversion of differentiated cell types without returning to an earlier developmental state. Here, we explore how heterogeneity in developmental lineage and maturity of the starting cell population contributes to direct reprogramming using the conversion of murine fibroblasts into neurons. Our hypothesis is that a single lineage of cells contributes to most reprogramming and that a rare elite precursor with intrinsic bias is the source of reprogrammed neurons. We find that nearly all reprogrammed neurons are derived from the neural crest (NC) lineage. Moreover, when rare proliferating NC precursors are selectively ablated, there is a large reduction in the number of reprogrammed neurons. Previous interpretations of this paradigm are that it demonstrates a cell fate conversion across embryonic germ layers (mesoderm to ectoderm). Our interpretation is that this is actually directed differentiation of a neural lineage stem cell in the skin that has intrinsic bias to produce neuronal progeny.

直接重编程涉及已分化细胞类型的转换,而无需回到早期的发育状态。在这里,我们通过将小鼠成纤维细胞转化为神经元的实验,探讨了起始细胞群在发育谱系和成熟度方面的异质性是如何促进直接重编程的。我们的假设是,单系细胞促成了大多数重编程,而具有内在偏向性的稀有精英前体是重编程神经元的来源。我们发现,几乎所有重编程神经元都来自神经嵴(NC)系。此外,当选择性地消减稀有增殖的 NC 前体时,重编程神经元的数量会大幅减少。以往对这一范例的解释是,它展示了胚胎胚层(中胚层到外胚层)之间的细胞命运转换。我们的解释是,这实际上是皮肤中神经系干细胞的定向分化,其内在偏向于产生神经元后代。
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引用次数: 0
Lineage-specific dynamics of loss of X upregulation during inactive-X reactivation. 无活性-X 再激活过程中 X 缺失上调的特定系动态。
IF 5.9 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-11-12 Epub Date: 2024-10-31 DOI: 10.1016/j.stemcr.2024.10.001
Hemant Chandru Naik, Deepshikha Chandel, Sudeshna Majumdar, Maniteja Arava, Runumi Baro, Harshavardhan Bv, Kishore Hari, Parichitran Ayyamperumal, Avinchal Manhas, Mohit Kumar Jolly, Srimonta Gayen

In mammals, X chromosome dosage is balanced between sexes through the silencing of one X chromosome in females. Recent single-cell RNA sequencing analysis demonstrated that the inactivation of the X chromosome is accompanied by the upregulation of the active X chromosome (Xa) during mouse embryogenesis. Here, we have investigated if the reactivation of inactive-X (Xi) leads to the loss of Xa upregulation in different cellular or developmental contexts. We find that while Xi reactivation and loss of Xa upregulation are tightly coupled in mouse embryonic epiblast and induced pluripotent stem cells, that is not the case in germ cells. Moreover, we demonstrate that partial reactivation of Xi in mouse extra-embryonic endoderm stem cells and human B cells does not result in the loss of Xa upregulation. Finally, we have established a mathematical model for the transcriptional coordination of two X chromosomes. Together, we conclude that the reactivation of Xi is not always synchronized with the loss of Xa upregulation.

在哺乳动物中,X 染色体的剂量通过雌性的一条 X 染色体沉默而在两性之间实现平衡。最近的单细胞 RNA 测序分析表明,在小鼠胚胎发育过程中,X 染色体的失活伴随着活性 X 染色体(Xa)的上调。在此,我们研究了非活性-X(Xi)的再激活是否会导致 Xa 在不同细胞或发育环境中失去上调。我们发现,在小鼠胚胎上胚层和诱导多能干细胞中,Xi 的再激活和 Xa 上调的丧失是紧密联系在一起的,但在生殖细胞中却不是这样。此外,我们还证明,在小鼠胚外内胚层干细胞和人类 B 细胞中,Xi 的部分再激活不会导致 Xa 上调的丧失。最后,我们建立了两个 X 染色体转录协调的数学模型。综上所述,我们得出结论:Xi 的重新激活并不总是与 Xa 上调的丧失同步进行。
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引用次数: 0
Abnormal synaptic architecture in iPSC-derived neurons from a multi-generational family with genetic Creutzfeldt-Jakob disease. 遗传性克雅氏病多代家族 iPSC 衍生神经元的异常突触结构。
IF 5.9 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-08 Epub Date: 2024-09-26 DOI: 10.1016/j.stemcr.2024.08.010
Aldana D Gojanovich, Nhat T T Le, Robert C C Mercer, Seonmi Park, Bei Wu, Alice Anane, Janelle S Vultaggio, Gustavo Mostoslavsky, David A Harris

Genetic prion diseases are caused by mutations in PRNP, which encodes the prion protein (PrPC). Why these mutations are pathogenic, and how they alter the properties of PrPC are poorly understood. We have consented and accessed 22 individuals of a multi-generational Israeli family harboring the highly penetrant E200K PRNP mutation and generated a library of induced pluripotent stem cells (iPSCs) representing nine carriers and four non-carriers. iPSC-derived neurons from E200K carriers display abnormal synaptic architecture characterized by misalignment of postsynaptic NMDA receptors with the cytoplasmic scaffolding protein PSD95. Differentiated neurons from mutation carriers do not produce PrPSc, the aggregated and infectious conformer of PrP, suggesting that loss of a physiological function of PrPC may contribute to the disease phenotype. Our study shows that iPSC-derived neurons can provide important mechanistic insights into the pathogenesis of genetic prion diseases and can offer a powerful platform for testing candidate therapeutics.

遗传性朊病毒疾病是由编码朊病毒蛋白(PrPC)的 PRNP 基因突变引起的。人们对这些突变为何致病以及它们如何改变 PrPC 的特性知之甚少。我们同意并访问了一个以色列多代家族中携带高渗透性 E200K PRNP 突变的 22 个个体,并生成了一个诱导多能干细胞(iPSC)库,其中 9 个为携带者,4 个为非携带者。来自 E200K 携带者的 iPSC 衍生神经元显示出异常的突触结构,其特征是突触后 NMDA 受体与细胞质支架蛋白 PSD95 错位。突变携带者的分化神经元不会产生 PrPSc(PrP 的聚集和感染性构象),这表明 PrPC 生理功能的缺失可能是导致疾病表型的原因之一。我们的研究表明,iPSC衍生神经元可为遗传性朊病毒疾病的发病机制提供重要的机理见解,并可为测试候选疗法提供一个强大的平台。
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引用次数: 0
SMAD3 mediates the specification of human induced pluripotent stem cell-derived epicardium into progenitors for the cardiac pericyte lineage. SMAD3介导人类诱导多能干细胞衍生的心外膜向心脏周细胞系祖细胞的分化。
IF 5.9 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-08 Epub Date: 2024-09-26 DOI: 10.1016/j.stemcr.2024.08.008
Yutaro Miyoshi, Antonio Lucena-Cacace, Yu Tian, Yasuko Matsumura, Kanae Tani, Misato Nishikawa, Megumi Narita, Takeshi Kimura, Koh Ono, Yoshinori Yoshida

Understanding the molecular mechanisms of epicardial epithelial-to-mesenchymal transition (EMT), particularly in directing cell fate toward epicardial derivatives, is crucial for regenerative medicine using human induced pluripotent stem cell (iPSC)-derived epicardium. Although transforming growth factor β (TGF-β) plays a pivotal role in epicardial biology, orchestrating EMT during embryonic development via downstream signaling through SMAD proteins, the function of SMAD proteins in the epicardium in maintaining vascular homeostasis or mediating the differentiation of various epicardial-derived cells (EPDCs) is not yet well understood. Our study reveals that TGF-β-independent SMAD3 expression autonomously predicts epicardial cell specification and lineage maintenance, acting as a key mediator in promoting the angiogenic-oriented specification of the epicardium into cardiac pericyte progenitors. This finding uncovers a novel role for SMAD3 in the human epicardium, particularly in generating cardiac pericyte progenitors that enhance cardiac microvasculature angiogenesis. This insight opens new avenues for leveraging epicardial biology in developing more effective cardiac regeneration strategies.

了解心外膜上皮细胞向间质转化(EMT)的分子机制,特别是将细胞命运导向心外膜衍生物的机制,对于利用诱导多能干细胞(iPSC)衍生的心外膜进行再生医学至关重要。尽管转化生长因子β(TGF-β)在心外膜生物学中起着关键作用,它通过SMAD蛋白的下游信号在胚胎发育过程中协调EMT,但SMAD蛋白在心外膜中维持血管稳态或介导各种心外膜衍生细胞(EPDCs)分化的功能还不十分清楚。我们的研究揭示,独立于 TGF-β 的 SMAD3 表达可自主预测心外膜细胞的规格化和系谱维持,是促进心外膜以血管生成为导向的心脏周细胞祖细胞规格化的关键介质。这一发现揭示了 SMAD3 在人类心外膜中的新作用,尤其是在产生能增强心脏微血管血管生成的心脏周细胞祖细胞方面。这一发现为利用心外膜生物学开发更有效的心脏再生策略开辟了新途径。
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引用次数: 0
Scaled and efficient derivation of loss-of-function alleles in risk genes for neurodevelopmental and psychiatric disorders in human iPSCs. 在人类 iPSCs 中大规模、高效地衍生神经发育和精神疾病风险基因的功能缺失等位基因。
IF 5.9 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-08 Epub Date: 2024-09-12 DOI: 10.1016/j.stemcr.2024.08.003
Hanwen Zhang, Ada McCarroll, Lilia Peyton, Sol Díaz de León-Guerrerro, Siwei Zhang, Prarthana Gowda, David Sirkin, Mahmoud ElAchwah, Alexandra Duhe, Whitney G Wood, Brandon Jamison, Gregory Tracy, Rebecca Pollak, Ronald P Hart, Carlos N Pato, Jennifer G Mulle, Alan R Sanders, Zhiping P Pang, Jubao Duan

Translating genetic findings for neurodevelopmental and psychiatric disorders (NPDs) into actionable disease biology would benefit from large-scale and unbiased functional studies of NPD genes. Leveraging the cytosine base editing (CBE) system, we developed a pipeline for clonal loss-of-function (LoF) allele mutagenesis in human induced pluripotent stem cells (hiPSCs) by introducing premature stop codons (iSTOP) that lead to mRNA nonsense-mediated decay (NMD) or protein truncation. We tested the pipeline for 23 NPD genes on 3 hiPSC lines and achieved highly reproducible, efficient iSTOP editing in 22 genes. Using RNA sequencing (RNA-seq), we confirmed their pluripotency, absence of chromosomal abnormalities, and NMD. Despite high editing efficiency, three schizophrenia risk genes (SETD1A, TRIO, and CUL1) only had heterozygous LoF alleles, suggesting their essential roles for cell growth. We found that CUL1-LoF reduced neurite branches and synaptic puncta density. This iSTOP pipeline enables a scaled and efficient LoF mutagenesis of NPD genes, yielding an invaluable shareable resource.

将神经发育障碍和精神障碍(NPD)的基因研究成果转化为可操作的疾病生物学研究,将受益于对NPD基因进行大规模、无偏见的功能研究。利用胞嘧啶碱基编辑(CBE)系统,我们开发了一种在人类诱导多能干细胞(hiPSC)中进行克隆性功能缺失(LoF)等位基因诱变的方法,通过引入过早终止密码子(iSTOP)导致mRNA无义介导衰变(NMD)或蛋白质截断。我们在 3 个 hiPSC 株系上对 23 个 NPD 基因进行了测试,在 22 个基因中实现了高度重复、高效的 iSTOP 编辑。通过 RNA 测序(RNA-seq),我们证实了它们的多能性、无染色体异常和 NMD。尽管编辑效率很高,但三个精神分裂症风险基因(SETD1A、TRIO 和 CUL1)只有杂合的 LoF 等位基因,这表明它们对细胞生长起着至关重要的作用。我们发现,CUL1-LoF 减少了神经元分支和突触点密度。这种 iSTOP 管道能够对 NPD 基因进行规模化和高效的 LoF 诱变,从而产生宝贵的可共享资源。
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引用次数: 0
Astrocytes originated from neural stem cells drive the regenerative remodeling of pathologic CSPGs in spinal cord injury. 源自神经干细胞的星形胶质细胞推动了脊髓损伤中病理性 CSPG 的再生重塑。
IF 5.9 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-08 Epub Date: 2024-09-19 DOI: 10.1016/j.stemcr.2024.08.007
Seyed Mojtaba Hosseini, Shiva Nemati, Soheila Karimi-Abdolrezaee

Neural degeneration is a hallmark of spinal cord injury (SCI). Multipotent neural precursor cells (NPCs) have the potential to reconstruct the damaged neuron-glia network due to their tri-lineage capacity to generate neurons, astrocytes, and oligodendrocytes. However, astrogenesis is the predominant fate of resident or transplanted NPCs in the SCI milieu adding to the abundant number of resident astrocytes in the lesion. How NPC-derived astrocytes respond to the inflammatory milieu of SCI and the mechanisms by which they contribute to the post-injury recovery processes remain largely unknown. Here, we uncover that activated NPC-derived astrocytes exhibit distinct molecular signature that is immune modulatory and foster neurogenesis, neuronal maturity, and synaptogenesis. Mechanistically, NPC-derived astrocytes perform regenerative matrix remodeling by clearing inhibitory chondroitin sulfate proteoglycans (CSPGs) from the injury milieu through LAR and PTP-σ receptor-mediated endocytosis and the production of ADAMTS1 and ADAMTS9, while most resident astrocytes are pro-inflammatory and contribute to the pathologic deposition of CSPGs. These novel findings unravel critical mechanisms of NPC-mediated astrogenesis in SCI repair.

神经变性是脊髓损伤(SCI)的标志。多能神经前体细胞(NPCs)具有生成神经元、星形胶质细胞和少突胶质细胞的三系能力,因此有可能重建受损的神经元-胶质细胞网络。然而,在 SCI 环境中,星形胶质细胞的形成是常住或移植 NPC 的主要命运,这使得病变部位常住星形胶质细胞的数量更加丰富。NPC衍生的星形胶质细胞如何对SCI的炎症环境做出反应以及它们对损伤后恢复过程做出贡献的机制在很大程度上仍是未知数。在这里,我们发现活化的 NPC 衍生星形胶质细胞表现出独特的分子特征,具有免疫调节作用并能促进神经发生、神经元成熟和突触生成。从机制上讲,NPC衍生的星形胶质细胞通过LAR和PTP-σ受体介导的内吞作用以及ADAMTS1和ADAMTS9的产生,清除损伤环境中的抑制性硫酸软骨素蛋白多糖(CSPGs),从而进行再生基质重塑,而大多数常驻星形胶质细胞则具有促炎作用,并导致CSPGs的病理性沉积。这些新发现揭示了在 SCI 修复中 NPC 介导的星形胶质细胞生成的关键机制。
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引用次数: 0
Guidelines for managing and using the digital phenotypes of pluripotent stem cell lines. 多能干细胞系数字表型的管理和使用指南。
IF 5.9 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-08 Epub Date: 2024-09-26 DOI: 10.1016/j.stemcr.2024.08.009
Christine A Wells, Anke Guhr, Amos Bairoch, Ying Chen, Mengqi Hu, Peter Löser, Tenneille E Ludwig, Nancy Mah, Sabine C Mueller, Andrea E M Seiler Wulczyn, Stefanie Seltmann, Bella Rossbach, Andreas Kurtz

Each pluripotent stem cell line has a physical entity as well as a digital phenotype, but linking the two unambiguously is confounded by poor naming practices and assumed knowledge. Registration gives each line a unique and persistent identifier that links to phenotypic data generated over the lifetime of that line. Registration is a key recommendation of the 2023 ISSCR Standards for the use of human stem cells in research. Here we consider how community adoption of stem cell line registration could facilitate the establishment of integrated digital phenotypes of specific human pluripotent stem cell (hPSC) lines.

每个多能干细胞系都有一个物理实体和一个数字表型,但由于命名方法不当和假定的知识,无法明确地将两者联系起来。注册可为每个品系提供一个唯一、持久的标识符,并与该品系生命周期内生成的表型数据相链接。注册是2023年ISSCR标准中关于在研究中使用人类干细胞的一项重要建议。在此,我们考虑社区采用干细胞系注册如何促进建立特定人类多能干细胞(hPSC)系的综合数字表型。
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引用次数: 0
Functionally redundant roles of ID family proteins in spermatogonial stem cells. ID家族蛋白在精原干细胞中的功能冗余作用
IF 5.9 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-08 Epub Date: 2024-09-26 DOI: 10.1016/j.stemcr.2024.08.011
Hue M La, Ai-Leen Chan, Ashlee M Hutchinson, Bianka Y M Su, Fernando J Rossello, Ralf B Schittenhelm, Robin M Hobbs

Spermatogonial stem cells (SSCs) are essential for sustained sperm production, but SSC regulatory mechanisms and markers remain poorly defined. Studies have suggested that the Id family transcriptional regulator Id4 is expressed in SSCs and involved in SSC maintenance. Here, we used reporter and knockout models to define the expression and function of Id4 in the adult male germline. Within the spermatogonial pool, Id4 reporter expression and inhibitor of DNA-binding 4 (ID4) protein are found throughout the GFRα1+ fraction, comprising the self-renewing population. However, Id4 deletion is tolerated by adult SSCs while revealing roles in meiotic spermatocytes. Cultures of undifferentiated spermatogonia could be established following Id4 deletion. Importantly, ID4 loss in undifferentiated spermatogonia triggers ID3 upregulation, and both ID proteins associate with transcription factor partner TCF3 in wild-type cells. Combined inhibition of IDs in cultured spermatogonia disrupts the stem cell state and blocks proliferation. Our data therefore demonstrate critical but functionally redundant roles of IDs in SSC function.

精原干细胞(SSC)对精子的持续生成至关重要,但SSC的调控机制和标志物仍不十分明确。研究表明,Id家族转录调节因子Id4在SSC中表达并参与SSC的维持。在这里,我们使用报告基因和基因敲除模型来确定Id4在成年男性生殖系中的表达和功能。在精原细胞池中,Id4报告基因的表达和DNA结合抑制因子4(ID4)蛋白在整个GFRα1+部分中都能发现,GFRα1+部分是自我更新的群体。然而,成体造血干细胞能耐受Id4缺失,同时还能显示减数分裂精母细胞的作用。Id4缺失后,未分化精原细胞的培养可以建立。重要的是,未分化精原细胞中ID4的缺失会引发ID3的上调,而在野生型细胞中,这两种ID蛋白都与转录因子伙伴TCF3相关联。在培养的精原细胞中联合抑制ID会破坏干细胞状态并阻碍增殖。因此,我们的数据证明了IDs在干细胞功能中的关键但功能冗余的作用。
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引用次数: 0
EZH2 Protects Glioma Stem Cells from Radiation-Induced Cell Death in a MELK/FOXM1-Dependent Manner. EZH2 以 MELK/FOXM1 依赖性方式保护胶质瘤干细胞免受辐射诱导的细胞死亡。
IF 5.9 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-08 Epub Date: 2024-09-15 DOI: 10.1016/j.stemcr.2024.09.003
Sung-Hak Kim, Kaushal Joshi, Ravesanker Ezhilarasan, Toshia R Myers, Jason Siu, Chunyu Gu, Mariko Nakano-Okuno, David Taylor, Mutsuko Minata, Erik P Sulman, Jeongwu Lee, Krishna P L Bhat, Anna Elisabetta Salcini, Ichiro Nakano
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引用次数: 0
Rod-shaped micropatterning enhances the electrophysiological maturation of cardiomyocytes derived from human induced pluripotent stem cells. 棒状微图案化可增强人类诱导多能干细胞心肌细胞的电生理成熟。
IF 5.9 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-08 Epub Date: 2024-09-19 DOI: 10.1016/j.stemcr.2024.08.005
Zeina R Al Sayed, Charlène Jouve, Magali Seguret, Andrea Ruiz-Velasco, Céline Pereira, David-Alexandre Trégouët, Jean-Sébastien Hulot

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer great potential for drug screening and disease modeling. However, hiPSC-CMs remain immature compared to the adult cardiac cells. Cardiomyocytes isolated from adult human hearts have a typical rod-shaped morphology. Here, we sought to develop a simple method to improve the architectural maturity of hiPSC-CMs by using a rod-shaped cell micropatterned substrate consisting of repeated rectangles (120 μm long × 30 μm wide) surrounded by a chemical cell repellent. The generated hiPSC-CMs exhibit numerous characteristics similar to adult human cardiomyocytes, including elongated cell shape, well-organized sarcomeres, and increased myofibril density. The improvement in structural properties correlates with the enrichment of late ventricular action potentials characterized by a more hyperpolarized resting membrane potential and an enhanced depolarization consistent with an increased sodium current density. The more mature hiPSC-CMs generated by this method may serve as a useful in vitro platform for characterizing cardiovascular disease.

人类诱导多能干细胞衍生的心肌细胞(hiPSC-CMs)为药物筛选和疾病建模提供了巨大的潜力。然而,与成体心脏细胞相比,hiPSC-CMs 仍未成熟。从成人心脏分离的心肌细胞具有典型的杆状形态。在此,我们试图开发一种简单的方法,通过使用由重复矩形(长 120 μm × 宽 30 μm)组成的棒状细胞微图案基底,并用化学细胞驱避剂包围,来提高 hiPSC-CMs 的结构成熟度。生成的 hiPSC-CMs 表现出许多与成人人类心肌细胞相似的特征,包括细胞形状拉长、肌节组织良好和肌原纤维密度增加。结构特性的改善与心室晚期动作电位的丰富有关,其特点是静息膜电位更加超极化,去极化增强,与钠离子电流密度的增加一致。用这种方法生成的更成熟的 hiPSC-CMs 可作为表征心血管疾病的有用体外平台。
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引用次数: 0
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