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Recent Advances for Enhancing Drug Metabolizing Functions of Hepatocyte- like Cells Derived from Human Pluripotent Stem Cells 增强人多能干细胞衍生的肝细胞样细胞药物代谢功能的研究进展
Pub Date : 2015-11-01 DOI: 10.7599/HMR.2015.35.4.196
Jiyou Han, Jong Hoon Kim
Clinical treatment for chronic liver failure using human embryonic stem cell (hESC) and human-induced pluripotent stem cell (hiPSC)-derived hepatocyte-like cells (HLCs) is considered a promising alternative method to organ transplantation. In addition to their use for treatment in liver failure, stem cell-derived HLCs have been considered for in vitro drug screening and toxicology researches [1]. Therefore, HLCs directly induced from hESCs have been intensively studied, resulting in a significant improvement in the efficiency of hepatic differentiation using human pluripotent stem cells. Albumin-positive HLCs can now be produced at the end of in vitro hepatic differentiation at levels up to 90% [2,3]. However, in spite of efforts to induce further maturation of HLCs derived from human pluripotent stem cells, the phenotype of most HLCs is more similar to fetal hepatocytes rather than fully mature hepatocytes. Critical inducing mature hepatocyte functions, such as phase I and II enzyme activity, tend to be significantly reduced in 2D-cultured HLCs (approximately <1% of human primary hepatocytes) [4,5]. Furthermore, under in vitro culture conditions, hepatobiliary transporter expression rapidly decreases [6], and most HLCs are spontaneously differentiate into various cell lineages, regardless of the differentiation protocol. Thus, at the final stage of hepatic differentiation, purification is needed to obtain highly homogenous HLCs. These key differences between HLCs and human primary hepatocytes result in limited use of HLCs as Hanyang Med Rev 2015;35:196-206 http://dx.doi.org/10.7599/hmr.2015.35.4.196
使用人胚胎干细胞(hESC)和人诱导多能干细胞(hiPSC)衍生的肝细胞样细胞(HLCs)治疗慢性肝衰竭被认为是器官移植的一种有前途的替代方法。除了用于治疗肝功能衰竭外,干细胞来源的HLCs也被考虑用于体外药物筛选和毒理学研究[1]。因此,由hESCs直接诱导的HLCs得到了广泛的研究,从而显著提高了利用人多能干细胞进行肝脏分化的效率。白蛋白阳性的HLCs现在可以在体外肝分化结束时产生,其水平高达90%[2,3]。然而,尽管人们努力诱导人类多能干细胞衍生的肝细胞进一步成熟,但大多数肝细胞的表型更类似于胎儿肝细胞,而不是完全成熟的肝细胞。关键的成熟肝细胞诱导功能,如I期和II期酶活性,在2d培养的HLCs(约<1%的人原代肝细胞)中往往显著降低[4,5]。此外,在体外培养条件下,肝胆转运蛋白表达迅速下降[6],大多数HLCs自发分化为各种细胞系,无论分化方案如何。因此,在肝分化的最后阶段,需要纯化以获得高度均质的肝细胞。hlc与人原代肝细胞之间的这些关键差异导致hlc的使用受到限制。Hanyang Med Rev 2015;35:196-206 http://dx.doi.org/10.7599/hmr.2015.35.4.196
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引用次数: 1
The Current Status of Directed Differentiation Technology 定向分化技术的现状
Pub Date : 2015-11-01 DOI: 10.7599/HMR.2015.35.4.215
Seung-Eun Lee, D. Choi
This work was carried out with the support of “Cooperative Research Program for Agriculture Science & Technology Development (Project No. PJ0110022015)” Rural Development Administration, Republic of Korea.
本工作是在“农业科技发展合作研究计划”(项目编号:No. 8111111)的支持下进行的。PJ0110022015)“韩国农村振兴厅”。
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引用次数: 1
Induced Pluripotent Stem Cells: Next Generation Stem Cells to Clinical Applications 诱导多能干细胞:下一代干细胞的临床应用
Pub Date : 2015-11-01 DOI: 10.7599/HMR.2015.35.4.190
Ji-Man Cha, Sunhoo Park, Seung Bum Lee
Induced pluripotent stem cells (iPSC) are specially manipulated cells from somatic cells by the introduction of four factors that are reprogrammed. The properties of iPSC are similar to embryonic stem cells (ESC) characteristic of self-renewal and pluripotency. The technology of reprogramming somatic cells to iPSC enables the generation of patient-specific cells that can be used as powerful tools for drug screening, in vitro models for human disease and autologous transplantation. The iPSC technology provides a priceless resource for regenerative medicine but there are still changing obstacles over the safety of iPSC in avoiding induction of tumorigenicity and maintaining high purity of re-differentiated cells from iPSC to produce more functional cells for cell therapy. A variety of methods to overcome the limitation of iPSC application applied in the clinical setting have been developed. In this review, we summarize the recent progress in iPSC generation and differentiation techniques to facilitate clinical application of iPSC with future potential in regenerative medicine.
诱导多能干细胞(iPSC)是通过引入四种重编程因子从体细胞中获得的特殊操纵细胞。iPSC具有与胚胎干细胞(ESC)相似的自我更新和多能性。体细胞重编程为iPSC的技术能够产生患者特异性细胞,这些细胞可作为药物筛选、人类疾病体外模型和自体移植的有力工具。iPSC技术为再生医学提供了宝贵的资源,但在避免诱导致瘤性和保持iPSC再分化细胞的高纯度以产生更多功能细胞用于细胞治疗方面,iPSC的安全性仍存在不断变化的障碍。为了克服iPSC在临床应用中的局限性,人们开发了多种方法。本文就诱导多能干细胞的生成和分化技术的最新进展进行综述,以期促进诱导多能干细胞在再生医学中的临床应用。
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引用次数: 1
Advanced Research on Stem Cell Therapy for Hepatic Diseases: Potential Implications of a Placenta-derived Mesenchymal Stem Cell-based Strategy 肝脏疾病干细胞治疗的最新研究:基于胎盘源性间充质干细胞策略的潜在意义
Pub Date : 2015-11-01 DOI: 10.7599/HMR.2015.35.4.207
G. Kim
Stem cells are unique undifferentiated cells that have the potential for self-renewal activity while also possessing the ability to differentiate into multiple-lineages. They are categorized into embryonic stem cells (ESCs) and adult stem cells (ASCs), which include hematopoietic stem cells (HSCs) and non-hematopoietic stem cells (e.g. mesenchymal stem cells, or MSCs). ESCs that are reintroduced into blastocysts can participate in the development of all organs and tissues in the adult animal, confirming their intrinsic potency [1]. This demonstrated plasticity has made ESCs the benchmark against which stem cell potency is measured. Although ESCs have great potential, problems related to ethics, politics, and safety remain challenges to their future applications in regenerative medicine. Recently, there has been an explosion in the number of adult stem cells that have been isolated and characterized [2]. Every tissue or organ apparently contains a stem cell population; therefore, stem cells can be easily harvested, and stem cells with low immuHanyang Med Rev 2015;35:207-214 http://dx.doi.org/10.7599/hmr.2015.35.4.207
干细胞是一种独特的未分化细胞,具有自我更新活动的潜力,同时也具有分化成多谱系的能力。它们分为胚胎干细胞(ESCs)和成体干细胞(ASCs),其中包括造血干细胞(hsc)和非造血干细胞(如间充质干细胞或MSCs)。被重新引入囊胚的ESCs可以参与成年动物所有器官和组织的发育,证实了它们的内在潜能bb0。这种已证实的可塑性使ESCs成为衡量干细胞效力的基准。尽管ESCs具有巨大的潜力,但伦理、政治和安全问题仍然是其未来在再生医学中应用的挑战。最近,分离和鉴定的成体干细胞数量呈爆炸式增长。每个组织或器官显然都含有干细胞群;因此,干细胞可以很容易地收获,和低免疫的干细胞。汉阳医学,2015;35:207-214 http://dx.doi.org/10.7599/hmr.2015.35.4.207
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引用次数: 5
New Horizons in Stem Cell Research 干细胞研究的新视野
Pub Date : 2015-11-01 DOI: 10.7599/HMR.2015.35.4.187
D. Choi
generate injured tissues and organs in the body. Therefore, this special issue has been published to review the clinical implication of using various stem cell types (from pluripotent to adult including direct differentiated cells) to heal patients suffering from chronic human disorders such as cerebrovascular diseases, chronic liver diseases, cardiovascular disorders, musculoskeletal diseases, and fatal cancers. The emergence of human embryonic stem cell (ESC) lines is one of the most important achievements in the biological sciences during the previous century and has raised a broad scientific and social interest as it is believed embryonic stem cells can be utilized in the near future as a powerful source of material for cell transplantation in regenerative medicine. Studies with human ESC have enabled us to elucidate the gene expression patterns related to pluripotency and to initiate basic research allowing medical scientists to create induced pluripotent stem cells by several methods. Understanding genetic manipulation that can direct stem cells to develop into various lineages of terminally differentiated cells enable us directly to make differentiated cells from various cell sources. In terms of clinical application, adult stem cells including mesenchymal stem cells have become a central focus in the real world. The establishment of an outstanding research laboratory for stem cell research and regenerative medicine involves translational research including the development of Good Manufacturing Practice (GMP) and clean room facilities in companies and medical schools. Further development and the establishment of systems for the production of autologous adult stem cells for clinical usage increase our capabilities for treating patients who have suffered from chronic diseases.
在体内产生受伤的组织和器官。因此,本期特刊将回顾利用各种干细胞类型(从多能干细胞到成人干细胞,包括直接分化细胞)治疗慢性人类疾病(如脑血管疾病、慢性肝病、心血管疾病、肌肉骨骼疾病和致命癌症)的临床意义。人类胚胎干细胞(ESC)系的出现是上个世纪生物科学领域最重要的成就之一,并引起了广泛的科学和社会兴趣,因为人们相信胚胎干细胞在不久的将来可以作为再生医学中细胞移植的强大材料来源。对人类ESC的研究使我们能够阐明与多能性相关的基因表达模式,并启动基础研究,使医学科学家能够通过几种方法创建诱导多能性干细胞。了解基因操纵可以指导干细胞发育成各种终末分化细胞谱系,使我们能够直接从各种细胞来源制造分化细胞。在临床应用方面,包括间充质干细胞在内的成体干细胞已成为现实世界的中心焦点。建立一个卓越的干细胞研究和再生医学研究实验室涉及转化研究,包括在公司和医学院开发良好生产规范(GMP)和无尘室设施。进一步发展和建立用于临床的自体成体干细胞生产系统,提高了我们治疗慢性疾病患者的能力。
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引用次数: 1
Adult Stem Cell Therapy in Chronic Liver Diseases 慢性肝病的成体干细胞治疗
Pub Date : 2015-11-01 DOI: 10.7599/HMR.2015.35.4.236
Y. Eom, S. Baik
The transplantation of mesenchymal stem cells (MSCs) represents a potentially effective therapy for chronic liver diseases. The potential of MSCs in the treatment of chronic liver disease is based on their ability to differentiate into multiple cell types including hepatocytes, their immunosuppressive properties, and their ability to secrete various trophic factors. This potential has been investigated in clinical and pre-clinical studies. Although the therapeutic mechanisms of MSC transplantation are still not fully characterized, accumulating evidence has revealed that various trophic factors secreted by MSCs play key therapeutic roles in regeneration. These trophic factors not only reduce inflammation, apoptosis, and fibrosis in damaged tissues but also stimulate angiogenesis and tissue regeneration in the impaired liver. In this review, we summarize the basic and therapeutic properties of MSCs, their therapeutic mechanisms of action, and potential transplantation routes for the treatment of chronic liver disease. We also discuss several risks associated with the use of MSCs in therapy, such as their fibrogenic potential and capacity to promote pre-existing tumor cell growth.
间充质干细胞(MSCs)移植是一种潜在的有效治疗慢性肝病的方法。MSCs在慢性肝病治疗中的潜力是基于它们分化为多种细胞类型的能力,包括肝细胞,它们的免疫抑制特性,以及它们分泌各种营养因子的能力。这种可能性已经在临床和临床前研究中进行了调查。尽管间充质干细胞移植的治疗机制尚未完全明确,但越来越多的证据表明,间充质干细胞分泌的各种营养因子在再生中起着关键的治疗作用。这些营养因子不仅能减少受损组织的炎症、细胞凋亡和纤维化,还能刺激受损肝脏的血管生成和组织再生。本文综述了间充质干细胞的基本特性和治疗特性,其治疗作用机制,以及治疗慢性肝病的潜在移植途径。我们还讨论了与在治疗中使用MSCs相关的几个风险,例如它们的纤维化潜力和促进已有肿瘤细胞生长的能力。
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引用次数: 2
Current Concepts in Stem Cell Therapy for Cardiovascular Diseases: What We Know and Don't Know 干细胞治疗心血管疾病的当前概念:我们知道的和不知道的
Pub Date : 2015-11-01 DOI: 10.7599/HMR.2015.35.4.242
K. Jeon
Medical therapies and mechanical interventions for the treatment of myocardial infarction (MI) and ischemic heart failure have seen great progress. However, current therapies only slow the progression to heart failure, but do not stimulate regeneration to recover the loss of functional myocytes. Stem cell-based therapy is a novel modality that can potentially be used for the treatment of ischemic cardiac injury and heart failure wherein cardiac tissue is regenerated thereby improving cardiac function and reducing the morbidity and mortality of patients. Many preclinical and clinical trials have employed various types of stem cells including bone marrow-derived mononuclear cells, skeletal myoblasts, resident cardiac stem cells, mesenchymal stem cells, and endothelial progenitor cells, and these studies have suggested great potential for the clinical application of stem cell therapy for cardiac disease. Here we will review and summarize the current evidence indicating the potential of stem cell therapy, focusing on the clinical trials conducted to date.
心肌梗死(MI)和缺血性心力衰竭的医学治疗和机械干预已经取得了很大进展。然而,目前的治疗方法只能减缓心力衰竭的进展,而不能刺激再生以恢复失去的功能性肌细胞。干细胞为基础的治疗是一种新的模式,可以潜在地用于缺血性心脏损伤和心力衰竭的治疗,其中心脏组织再生,从而改善心脏功能,降低患者的发病率和死亡率。许多临床前和临床试验使用了各种类型的干细胞,包括骨髓来源的单个核细胞、骨骼肌母细胞、常驻心脏干细胞、间充质干细胞和内皮祖细胞,这些研究表明干细胞治疗心脏病的临床应用潜力巨大。在这里,我们将回顾和总结当前的证据表明干细胞治疗的潜力,重点是迄今为止进行的临床试验。
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引用次数: 1
Recent Advances in Skeletal Muscle Stem Cells for Duchenne Muscular Dystrophy Treatment 骨骼肌干细胞治疗杜氏肌营养不良的最新进展
Pub Date : 2015-11-01 DOI: 10.7599/HMR.2015.35.4.222
Jin Young Yang, Jaemin Jeong
About 50 years ago, the satellite cell was discovered through electron microscopic inspection of skeletal muscle. Satellite cells are mono-nucleated and located in the edge of the skeletal myofibers. These cells were imposed for their association with muscle regeneration. Satellite cells maintain dormant state in the mature muscle and are activated mitotically during muscle injuries, and finally differentiated to myoblasts. It contributes to the myofibrils resulting in muscle recovery from the injury [1]. Collins proved that satellite cells have both differentiation and self-renewal ability [2]. Sequentially, Kuang et al. established that the muscle stem cells achieve self-renewal through asymmetrical divisions. Also, satellite cells did not consist of only adult stem cells, rather both adult stem cells and committed progenitor cells [3]. Muscular dystrophies include many diseases, which have skeletal muscle wasting and limit mobility of patients. Among that, Duchenne muscular dystrophy (DMD), fragility of respiratory muscles and absence of dystrophin protein in the cardiac muscle results in respiratory or cardiac failure and early death [4]. The underlying pathogenesis is already investigated, but the treatment has not been established yet. However, research has accumulated these days and clinical trials are also being performed now. There are roughly four methods to research DMD treatments, 1) gene therapy replacing the mutated gene, 2) cell therapy which replace affected cells or using bone marrow-derived stem cells and mesoangioblasts, 3) repairing the endogenous gene using exon skipping, skipping premature termination, and 4) drug therapy which compensates for lack of dystrophin, promotes function in dystrophic muscle, improves muscle hypertrophy and minimizes muscle wasting, uses histone deacetylase inhibitors or NO-releasing anti-inflammatory drugs [5]. In this article, cell therapies in DMD are focused in a review and current clinical trials using cell therapy are introduced. Hanyang Med Rev 2015;35:222-228 http://dx.doi.org/10.7599/hmr.2015.35.4.222 pISSN 1738-429X eISSN 2234-4446
大约50年前,通过对骨骼肌的电子显微镜检查发现了卫星细胞。卫星细胞是单核的,位于骨骼肌纤维的边缘。这些细胞与肌肉再生有关。卫星细胞在成熟肌肉中保持休眠状态,在肌肉损伤过程中被有丝分裂激活,最终分化为成肌细胞。它有助于肌原纤维从损伤中恢复肌肉[1]。Collins证明卫星细胞既具有分化能力,又具有自我更新能力[2]。随后,Kuang等人证实肌肉干细胞通过不对称分裂实现自我更新。此外,卫星细胞并非仅由成体干细胞组成,而是既有成体干细胞,也有承托祖细胞[3]。肌肉萎缩症包括许多疾病,这些疾病导致骨骼肌萎缩并限制患者的活动能力。其中,杜氏肌营养不良(Duchenne muscular dystrophy, DMD),呼吸肌脆弱,心肌中缺乏肌营养不良蛋白,可导致呼吸或心力衰竭和早期死亡[4]。潜在的发病机制已被研究,但治疗尚未确定。但是,最近积累了研究成果,正在进行临床试验。研究DMD治疗的方法大致有四种,1)基因疗法替代突变基因,2)细胞疗法替代受损细胞或使用骨髓来源的干细胞和间质血管母细胞,3)使用外显子跳跃修复内源性基因,跳跃式过早终止,4)药物疗法补偿营养不良蛋白的缺乏,促进营养不良肌肉的功能,改善肌肉肥大,减少肌肉萎缩。使用组蛋白去乙酰化酶抑制剂或no释放抗炎药物[5]。本文对DMD的细胞治疗进行了综述,并介绍了目前使用细胞治疗的临床试验。汉阳医学杂志2015;35:222-228 http://dx.doi.org/10.7599/hmr.2015.35.4.222 pISSN 1738-429X eISSN 2234-4446
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引用次数: 2
Cancer Stem Cells: Biological Features and Targeted Therapeutics 癌症干细胞:生物学特征和靶向治疗
Pub Date : 2015-11-01 DOI: 10.7599/HMR.2015.35.4.250
Se Yong Song, Daekwan Seo
Advance in stem cells (SCs) has become significant by the isolation of the tissue-specific SCs in a tissue, because it is the beginning of using SC utility for regenerative medicine. Likewise in SCs, a small subpopulation of cancer cells, named cancer stem cells (CSCs), also have similar properties. These properties include indefinite self-renewal potential and sharing similar signaling pathways with normal SCs, because the originality of CSCs is from the mutation of normal SCs. Hierarchically, CSCs in solid tumors may organize from the normal SCs in the highest cellular hierarchy of these cancer cells. The functional assay techniques to assess the differentiation frequency of normal SCs are similarly used in CSCs to sustain tumor growth and recurrence after therapy. In this review, we discuss the different parallels between adult SCs and CSCs in solid cancer disease and applications toward targeted therapy in use of molecular level on CSCs.
从组织中分离出具有组织特异性的干细胞是干细胞应用于再生医学的开端,因此干细胞的研究进展具有重要意义。同样,在干细胞中,癌细胞的一个小亚群,称为癌症干细胞(CSCs),也具有类似的特性。这些特性包括无限的自我更新潜力和与正常SCs共享相似的信号通路,因为CSCs的原创性来自正常SCs的突变。从层次上看,实体肿瘤中的CSCs可能是从这些癌细胞的最高细胞层次的正常SCs组织而来的。评估正常SCs分化频率的功能测定技术同样用于CSCs在治疗后维持肿瘤生长和复发。在这篇综述中,我们讨论了成人SCs和CSCs在实体癌症疾病中的不同相似之处,以及在CSCs分子水平上靶向治疗的应用。
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引用次数: 2
Disaster Medical Assistance Team 灾难医疗援助小组
Pub Date : 2015-08-01 DOI: 10.7599/HMR.2015.35.3.152
K. Lee
A modern Disaster Medical Assistance Team (DMAT) is a group of professional and paraprofessional medical personnel organized to provide rapid-response medical care during a disaster situation. DMAT is a part of the disaster response system that acts as a trained, mobile, self-contained medical team in the acute phase of a disaster to provide necessary services such as triage, treatment, and transportation of injured patients in the devastated disaster area. The timeliness of DMAT response is critical to the administration of medical care and reduction of immediate mortality in disaster. While the number of members in a DMAT may vary between different nations. A small-scale DMAT is often composed of five to six people and there is good reason to consider this an effective unit for early disaster medical responses. An adequate structure and training system should be provided for Korean DMAT development in the near future.
现代灾害医疗援助队(DMAT)是由专业和准专业医务人员组成的一组,在灾害情况下提供快速反应医疗护理。DMAT是灾害应对系统的一部分,在灾难的急性阶段充当一支训练有素的、机动的、独立的医疗队,在受灾地区提供必要的服务,如分流、治疗和运送受伤病人。灾害应急反应的及时性对医疗保健管理和减少灾害中立即死亡至关重要。虽然DMAT的成员人数在不同的国家可能会有所不同。小规模的DMAT通常由五到六人组成,有充分的理由认为这是早期灾害医疗反应的有效单位。在不久的将来,应该为韩国的DMAT发展提供适当的结构和培训体系。
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引用次数: 5
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Hanyang Medical Reviews
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