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The Instructive Role of the Bone Marrow Niche in Aging and Leukemia. 骨髓生态位在衰老和白血病中的指导作用。
IF 1.4 Q4 CELL & TISSUE ENGINEERING Pub Date : 2018-01-01 Epub Date: 2018-10-12 DOI: 10.1007/s40778-018-0143-7
Elisa Lazzari, Jason M Butler

Purpose of review: In this review, we aim to discuss the role of the bone marrow microenvironment in supporting hematopoiesis, with particular focus on the contribution of the endothelial niche in dictating hematopoietic stem cell (HSC) fate.

Recent findings: Evidence gathered in the past two decades revealed that specific cell types within the bone marrow niche influence the hematopoietic system. Endothelial cells have emerged as a key component of the HSC niche, directly affecting stem cell quiescence, self-renewal, and lineage differentiation. Physiological alterations of the bone marrow niche occurring in aging have been described to be sufficient to promote functional aging of young HSCs. Furthermore, a growing body of evidence suggests that aberrant activation of endothelial-derived signaling pathways can aid or trigger neoplastic transformation.

Summary: Several groups have contributed to the characterization of the different cell types that comprise the complex bone marrow environment, whose function was long perceived as an undiscernible sum of many parts. Further studies will need to uncover niche cell-type-specific pathways, in order to provide new targets and therapeutic options that aim at withdrawing the microenvironmental support to malignant cells while sparing normal HSCs.

综述目的:在这篇综述中,我们旨在讨论骨髓微环境在支持造血中的作用,特别关注内皮生态位在决定造血干细胞(HSC)命运中的贡献。最近的发现:在过去的二十年中收集的证据表明,骨髓生态位内的特定细胞类型影响造血系统。内皮细胞已成为造血干细胞生态位的关键组成部分,直接影响干细胞的静止、自我更新和谱系分化。在衰老过程中发生的骨髓生态位的生理改变已经被描述为足以促进年轻造血干细胞的功能衰老。此外,越来越多的证据表明,内皮源性信号通路的异常激活可以帮助或触发肿瘤转化。总结:几个研究小组对组成复杂骨髓环境的不同细胞类型的特征做出了贡献,长期以来,骨髓环境的功能被认为是许多部分的不可分辨的总和。进一步的研究将需要揭示特定于小生境细胞类型的途径,以便提供新的靶点和治疗选择,旨在撤回对恶性细胞的微环境支持,同时保留正常的造血干细胞。
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引用次数: 15
Human iPSC Models to Study Orphan Diseases: Muscular Dystrophies. 研究孤儿疾病的人类iPSC模型:肌肉萎缩症。
IF 1.4 Q4 CELL & TISSUE ENGINEERING Pub Date : 2018-01-01 Epub Date: 2018-10-04 DOI: 10.1007/s40778-018-0145-5
Guangbin Xia, Naohiro Terada, Tetsuo Ashizawa

Purpose of review: Muscular dystrophies (MDs) are a spectrum of muscle disorders, which are caused by a number of gene mutations. The studies of MDs are limited due to lack of appropriate models, except for Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1), facioscapulohumeral muscular dystrophy (FSHD), and certain type of limb-girdle muscular dystrophy (LGMD). Human induced pluripotent stem cell (iPSC) technologies are emerging to offer a useful model for mechanistic studies, drug discovery, and cell-based therapy to supplement in vivo animal models. This review will focus on current applications of iPSC as disease models of MDs for studies of pathogenic mechanisms and therapeutic development.

Recent findings: Many and more human disease-specific iPSCs have been or being established, which carry the natural mutation of MDs with human genomic background. These iPSCs can be differentiated into specific cell types affected in a particular MDs such as skeletal muscle progenitor cells, skeletal muscle fibers, and cardiomyocytes. Human iPSCs are particularly useful for studies of the pathogenicity at the early stage or developmental phase of MDs. High-throughput screening using disease-specific human iPSCs has become a powerful technology in drug discovery. While MD iPSCs have been generated for cell-based replacement therapy, recent advances in genome editing technologies enabled correction of genetic mutations in these cells in culture, raising hope for in vivo genome therapy, which offers a fundamental cure for these daunting inherited MDs.

Summary: Human disease-specific iPSC models for MDs are emerging as an additional tool to current disease models for elucidating disease mechanisms and developing therapeutic intervention.

综述目的:肌营养不良症(MDs)是一系列由基因突变引起的肌肉疾病。除了杜氏肌营养不良症(DMD)、1型肌强直性营养不良症(DM1)、面肩肱肌营养不良症(FSHD)和某些类型的肢带肌营养不良症(LGMD)外,MDs的研究由于缺乏合适的模型而受到限制。人类诱导多能干细胞(iPSC)技术正在兴起,为机制研究、药物发现和基于细胞的治疗提供了一个有用的模型,以补充体内动物模型。本文就iPSC作为MDs疾病模型在发病机制研究和治疗进展方面的应用现状进行综述。最近发现:许多人类疾病特异性iPSCs已经或正在建立,它们携带具有人类基因组背景的MDs的自然突变。这些iPSCs可以分化为受特定MDs影响的特定细胞类型,如骨骼肌祖细胞、骨骼肌纤维和心肌细胞。人类多能干细胞对于MDs早期或发育阶段的致病性研究特别有用。利用疾病特异性人类多能干细胞进行高通量筛选已成为药物发现中的一项强大技术。虽然已经为基于细胞的替代疗法产生了MD iPSCs,但基因组编辑技术的最新进展使这些细胞在培养中纠正基因突变成为可能,为体内基因组治疗提供了希望,这为这些令人生畏的遗传性MDs提供了根本的治疗方法。摘要:MDs的人类疾病特异性iPSC模型正在成为当前疾病模型的额外工具,用于阐明疾病机制和制定治疗干预措施。
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引用次数: 13
The Role of Interferon-Gamma in Hematopoietic Stem Cell Development, Homeostasis, and Disease. 干扰素γ在造血干细胞发育、体内平衡和疾病中的作用。
IF 1.4 Q4 CELL & TISSUE ENGINEERING Pub Date : 2018-01-01 Epub Date: 2018-07-23 DOI: 10.1007/s40778-018-0139-3
Daniel E Morales-Mantilla, Katherine Y King

Purpose of review: Interferon-gamma (IFN-γ) is a pro-inflammatory cytokine that participates in the regulation of hematopoietic stem cells (HSC) during development and under homeostatic conditions. IFN-γ also plays a key pathogenic role in several diseases that affect hematopoiesis including aplastic anemia, hemophagocytic lymphohistiocytosis, and cirrhosis of the liver.

Recent findings: Studies have shown that increased IFN-γ negatively affects HSC homeostasis, skewing HSC towards differentiation over self-renewal and eventually causing exhaustion of the HSC compartment.

Summary: Here, we explore the mechanisms by which IFN-γ regulates HSC in both normal and pathological conditions. We focus on the role of IFN-γ signaling in HSC fate decisions, and the transcriptional changes it elicits. Elucidating the mechanisms through which IFN-γ regulates HSCs may lead to new therapeutic options to prevent or treat adverse hematologic effects of the many diseases to which IFN-γ contributes.

综述目的:干扰素-γ (IFN-γ)是一种促炎细胞因子,参与造血干细胞(HSC)在发育和稳态条件下的调节。IFN-γ在影响造血的几种疾病中也起着关键的致病作用,包括再生障碍性贫血、噬血细胞性淋巴组织细胞增多症和肝硬化。最近的发现:研究表明,IFN-γ的增加对HSC稳态产生负面影响,使HSC向自我更新的分化方向倾斜,最终导致HSC室衰竭。摘要:在这里,我们探讨了IFN-γ在正常和病理条件下调节HSC的机制。我们关注IFN-γ信号在HSC命运决定中的作用,以及它引发的转录变化。阐明IFN-γ调节造血干细胞的机制可能会带来新的治疗选择,以预防或治疗IFN-γ导致的许多疾病的不良血液学效应。
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引用次数: 59
Stem Cell Therapies for the Resolution of Radiation Injury to the Brain. 干细胞治疗解决脑辐射损伤。
IF 1.4 Q4 CELL & TISSUE ENGINEERING Pub Date : 2017-12-01 Epub Date: 2017-10-11 DOI: 10.1007/s40778-017-0105-5
Sarah M Smith, Charles L Limoli

Purpose of review: To encapsulate past and current research efforts focused on stem cell transplantation strategies to resolve radiation-induced cognitive dysfunction.

Recent findings: Transplantation of human stem cells in the irradiated brain was first shown to resolve radiation-induced cognitive dysfunction in a landmark paper by Acharya et al., appearing in PNAS in 2009. Since that time, work from the same laboratory as well as other groups have reported on the beneficial (as well as detrimental) effects of stem cell grafting after cranial radiation exposure. Improved learning and memory found many months after engraftment has since been associated with a preservation of host neuronal morphology, a suppression of neuroinflammation, improved myelination and increased cerebral blood flow. Interestingly, many (if not all) of these beneficial effects can be demonstrated by substituting stem cells with microvesicles derived from human stem cells during transplantation, thereby eliminating many of the more long-standing concerns related to immunorejection and teratoma formation.

Summary: Stem cell and microvesicle transplantation into the irradiated brain of rodents has uncovered some unexpected benefits that hold promise for ameliorating many of adverse neurocognitive complications associated with major cancer treatments. Properly developed, such approaches may provide much needed clinical recourse to millions of cancer survivors suffering from the unintended side effects of their cancer therapies.

综述的目的:总结过去和现在的研究成果,集中在干细胞移植策略解决辐射诱导的认知功能障碍。最近的发现:2009年,Acharya等人发表在《美国科学院院刊》上的一篇具有里程碑意义的论文首次表明,在受辐射的大脑中移植人类干细胞可以解决辐射诱导的认知功能障碍。从那时起,来自同一实验室以及其他小组的工作报告了颅辐射暴露后干细胞移植的有益(以及有害)影响。植入数月后发现的学习和记忆的改善与宿主神经元形态的保存、神经炎症的抑制、髓鞘形成的改善和脑血流量的增加有关。有趣的是,许多(如果不是全部)这些有益效果可以通过移植过程中用人类干细胞衍生的微泡代替干细胞来证明,从而消除了许多长期存在的与免疫排斥和畸胎瘤形成相关的担忧。摘要:将干细胞和微泡移植到受辐照的啮齿动物大脑中,发现了一些意想不到的益处,有望改善许多与主要癌症治疗相关的不良神经认知并发症。如果发展得当,这些方法可能会为数百万遭受癌症治疗意外副作用的癌症幸存者提供急需的临床资源。
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引用次数: 7
Radiotherapy and Glioma Stem Cells: Searching for Chinks in Cellular Armor. 放射治疗与胶质瘤干细胞:寻找细胞盔甲的缝隙。
IF 1.4 Q4 CELL & TISSUE ENGINEERING Pub Date : 2017-12-01 Epub Date: 2017-10-02 DOI: 10.1007/s40778-017-0102-8
Seamus P Caragher, Sean Sachdev, Atique Ahmed

Purpose of the review: Radiation became a pillar of oncologic treatment in the last century and provided a powerful and effective locoregional treatment of solid malignancies. After achieving some of the first cures in lymphomas and skin cancers, it assumed a key role in curative treatment of epithelioid malignancies. Despite success across a variety of histologic types, glioblastoma (GBM), the most common primary brain tumor afflicting adults, remains ultimately resistant to current radiation strategies. While GBMs demonstrate an initial response, recurrence is essentially universal and fatal, and typically reoccur in the areas that received the most intense radiation.

Recent findings: Glioma stem cells (GSCs), a subpopulation of tumor cells with expression profiles similar to neural stem cells and marked self-renewal capacities, have been shown to drive tumor recurrence and preclude curative radiotherapy. Recent research has shown that these cells have enhanced DNA repair capacity, elevated resistance to cytotoxic ion fluxes and escape multi-modality therapies.

Summary: We will analyze the current understanding of GSCs and radiation by highlighting key discoveries probing their ability to withstand radiotherapy. We then speculate on novel mechanisms by which GSC can be made sensitive to or specifically targeted by radiation therapy.

回顾的目的:放射治疗在上个世纪成为肿瘤治疗的支柱,为实体恶性肿瘤提供了强大而有效的局部治疗。在首次治愈淋巴瘤和皮肤癌后,它在上皮样恶性肿瘤的治愈治疗中发挥了关键作用。胶质母细胞瘤(GBM)是困扰成年人的最常见的原发性脑肿瘤,尽管在各种组织学类型中都取得了成功,但目前的放射治疗策略最终仍具有耐药性。虽然GBMs表现出最初的反应,但复发基本上是普遍和致命的,并且通常在接受最强烈辐射的区域复发。胶质瘤干细胞(Glioma stem cells, GSCs)是一种肿瘤细胞亚群,其表达谱与神经干细胞相似,具有显著的自我更新能力,已被证明可驱动肿瘤复发并阻碍治愈性放疗。最近的研究表明,这些细胞具有增强的DNA修复能力,提高对细胞毒性离子通量的抵抗力,并逃避多模态治疗。摘要:我们将分析当前对GSCs和辐射的理解,重点介绍探索其耐受放射治疗能力的关键发现。然后,我们推测新的机制,通过这种机制,GSC可以对放射治疗敏感或特异性靶向。
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引用次数: 17
NK Cells and γδT Cells for Relapse Protection After Allogeneic Hematopoietic Cell Transplantation (HCT). NK细胞和γδT细胞对同种异体造血细胞移植术后复发的保护作用。
IF 1.4 Q4 CELL & TISSUE ENGINEERING Pub Date : 2017-12-01 Epub Date: 2017-10-16 DOI: 10.1007/s40778-017-0106-4
Moniek A de Witte, Jürgen Kuball, Jeffrey S Miller

Purpose of review: The outcome of allogeneic stem cell transplantation (allo-HCT) is still compromised by relapse and complications. NK cells and γδT cells, effectors which both function through MHC-unrestricted mechanisms, can target transformed and infected cells without inducing Graft-versus-Host Disease (GVHD). Allo-HCT platforms based on CD34+ selection or αβ-TCR depletion result in low grades of GVHD, early immune reconstitution (IR) of NK and γδT cells and minimal usage of GVHD prophylaxis. In this review we will discuss strategies to retain and expand the quantity, diversity and functionality of these reconstituting innate cell types.

Recent findings: Bisphosphonates, IL-15 cytokine administration, specific antibodies, checkpoint inhibitors and (CMV based) vaccination are currently being evaluated to enhance IR. All these approaches have shown to potentially enhance both NK and γδT cell immuno-repertoires.

Summary: Rapidly accumulating data linking innate biology to proposed clinical immune interventions, will give unique opportunities to unravel shared pathways which determine the Graft-versus-Tumor effects of NK and γδT cells.

回顾的目的:同种异体干细胞移植(allogeneic stem cell transplantation, allo-HCT)的预后仍然受到复发和并发症的影响。NK细胞和γδT细胞都是通过mhc不受限制的机制起作用的效应物,它们可以靶向转化和感染的细胞,而不会诱导移植物抗宿主病(GVHD)。基于CD34+选择或αβ-TCR消耗的Allo-HCT平台导致GVHD的低级别,NK和γδT细胞的早期免疫重建(IR)和极少使用GVHD预防措施。在这篇综述中,我们将讨论保留和扩大这些重组先天细胞类型的数量、多样性和功能的策略。最近的发现:目前正在评估双膦酸盐、IL-15细胞因子管理、特异性抗体、检查点抑制剂和(基于巨细胞病毒的)疫苗接种以增强IR。所有这些方法都显示出潜在地增强NK和γδT细胞的免疫功能。摘要:快速积累的数据将先天生物学与拟议的临床免疫干预联系起来,将为揭示确定NK细胞和γδT细胞移植物抗肿瘤作用的共享途径提供独特的机会。
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引用次数: 11
How Will the Hematopoietic System Deal with Space Radiation on the Way to Mars? 在前往火星的途中,造血系统将如何应对太空辐射?
IF 1.4 Q4 CELL & TISSUE ENGINEERING Pub Date : 2017-10-03 DOI: 10.1007/s40778-017-0104-6
R. Patel, S. Welford
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引用次数: 2
CAR T Cells for Solid Tumors CAR - T细胞用于实体瘤
IF 1.4 Q4 CELL & TISSUE ENGINEERING Pub Date : 2017-09-30 DOI: 10.1007/s40778-017-0101-9
B. Moghimi, D. Barrett
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引用次数: 13
The Axolotl Limb Regeneration Model as a Discovery Tool for Engineering the Stem Cell Niche. 将轴足类肢体再生模型作为干细胞利基工程的探索工具。
IF 1.4 Q4 CELL & TISSUE ENGINEERING Pub Date : 2017-09-01 Epub Date: 2017-07-27 DOI: 10.1007/s40778-017-0085-5
Negar Seyedhassantehrani, Takayoshi Otsuka, Shambhavi Singh, David M Gardiner

Purpose of review: Recent advances in genomics and gene editing have expanded the range of model organisms to include those with interesting biological capabilities such as regeneration. Among these are the classic models of regeneration biology, the salamander. Although stimulating endogenous regeneration in humans likely is many years away, with advances in stem cell biology and biomedical engineering (e.g. bio-inspired materials), it is evident that there is great potential to enhance regenerative outcomes by approaching the problem from an engineering perspective. The question at this point is what do we need to engineer?

Recent findings: The value of regeneration models is that they show us how regeneration works, which then can guide efforts to mimic these developmental processes therapeutically. Among these models, the Accessory Limb Model (ALM) was developed in the axolotl as a gain-of-function assay for the sequential steps that are required for successful regeneration. To date, this model has identified a number of proregenerative signals, including growth factor signaling associated with nerves, and signals associated with the extracellular matrix (ECM) that induce pattern formation.

Summary: Identification of these signals through the use of models in highly regenerative vertebrates (e.g. the axolotl) offers a wide range of possible modifications for engineering bio-inspired, biomimetic materials to create a dynamic stem cell niche for regeneration and scar-free repair.

综述的目的:基因组学和基因编辑的最新进展扩大了模式生物的范围,使其包括那些具有再生等有趣生物学能力的生物。其中包括再生生物学的经典模型--蝾螈。虽然刺激人类的内源性再生可能还需要很多年,但随着干细胞生物学和生物医学工程学(如生物启发材料)的进步,从工程学的角度来解决这个问题,显然有很大的潜力来提高再生效果。目前的问题是,我们需要设计什么?再生模型的价值在于它们向我们展示了再生是如何进行的,从而指导我们努力模仿这些发育过程进行治疗。在这些模型中,辅助肢体模型(ALM)是在腋肢中开发的,作为成功再生所需的连续步骤的功能增益试验。总结:通过使用高度再生脊椎动物(如腋毛蜥)的模型来识别这些信号,为工程生物启发、生物仿生材料提供了广泛的可能修改,以创建一个动态干细胞龛,促进再生和无疤痕修复。
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引用次数: 0
Integrating Biological and Mathematical Models to Explain and Overcome Drug Resistance in Cancer. Part 1: Biological Facts and Studies in Drug Resistance 整合生物学和数学模型来解释和克服癌症的耐药性。第一部分:耐药性的生物学事实和研究
IF 1.4 Q4 CELL & TISSUE ENGINEERING Pub Date : 2017-08-03 DOI: 10.1007/s40778-017-0097-1
A. Goldman, M. Kohandel, J. Clairambault
{"title":"Integrating Biological and Mathematical Models to Explain and Overcome Drug Resistance in Cancer. Part 1: Biological Facts and Studies in Drug Resistance","authors":"A. Goldman, M. Kohandel, J. Clairambault","doi":"10.1007/s40778-017-0097-1","DOIUrl":"https://doi.org/10.1007/s40778-017-0097-1","url":null,"abstract":"","PeriodicalId":37444,"journal":{"name":"Current Stem Cell Reports","volume":"3 1","pages":"253 - 259"},"PeriodicalIF":1.4,"publicationDate":"2017-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s40778-017-0097-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"52901470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 7
期刊
Current Stem Cell Reports
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