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| 1 | Stem cell-based regenerative opportunities for the liver: State of the art and beyond显示文摘The existing mismatch between the great demand for liver transplants and the number of available donor organs highlights the urgent need for alternative therapeutic strategies in patients with acute or chronic liver failure. The rapidly growing knowledge on stem cell biology and the intrinsic repair processes of the liver has opened new avenues for using stem cells as a cell therapy platform in regenerative medicine for hepatic diseases. An impressive number of cell types have been investigated as sources of liver regeneration: adult and fetal liver hepatocytes,intrahepatic stem cell populations,annex stem cells,adult bone marrow-derived hematopoietic stem cells,endothelial progenitor cells,mesenchymal stromal cells,embryonic stem cells,and induced pluripotent stem cells. All these highly different cell types,used either as cell suspensions or,in combination with biomaterials as implantable liver tissue constructs,have generated great promise for liver regeneration. However,fundamental questions still need to be addressed and critical hurdles to be overcome before liver cell therapy emerges. In this review,we summarize the state-of-the-art in the field of stem cell-based therapies for the liver along with existing challenges and future perspectives towards a successful liver cell therapy that will ultimately deliver its demanding goals. | Eleftheria Tsolaki Evangelia Yannaki | 2015 | World Journal of Gastroenterology2015，21，43： | 16 |
| 2 | iPS细胞研究的新进展及应用显示文摘通过导入特定的转录因子可将分化的体细胞重编程为诱导性多能干细胞(Induced pluripotent stem cells,iPS cells),这项技术避免了干细胞研究领域的免疫排斥和伦理道德问题,是生命科学领域的一次巨大革命。与胚胎干细胞(Embryonic stem cells,ES cells)一样,iPS细胞能够自我更新并维持未分化状态,在体内可分化为3个胚层来源的所有细胞,进而参与形成机体所有组织和器官。在体外,iPS细胞可定向诱导分化出多种成熟细胞。因此,iPS细胞在理论研究和临床应用等方面都极具应用价值。文章对iPS细胞诱导的最新研究进展、iPS细胞诱导的不同方法,如何提高iPS细胞的制备效率和安全性,iPS细胞在基础研究以及临床研究等方面的应用进行了全面综述,并探讨了iPS细胞研究领域面临的问题以及该技术在转基因动物研究中的发展前景。 | 秦彤 苗向阳 | 2010 | 遗传2010，32，12： | 15 |
| 3 | Clinical translation of bioartificial liver support systems with human pluripotent stem cell-derived hepatic cells显示文摘There is currently a pressing need for alternative the-rapies to liver transplantation. The number of patients waiting for a liver transplant is substantially higher than the number of transplantable donor livers, resulting in a long waiting time and a high waiting list mortality. An extracorporeal liver support system is one possible approach to overcome this problem. However, the ideal cell source for developing bioartificial liver(BAL) support systems has yet to be determined. Recent advancements in stem cell technology allow researchers to generate highly functional hepatocyte-like cells from human pluripotent stem cells(h PSCs). In this mini-review, we summarize previous clinical trials with different BAL systems, and discuss advantages of and potential obstacles to utilizing h PSC-derived hepatic cells in clinical-scale BAL systems. | Ryoichi Sakiyama Brandon J Blau Toshio Miki | 2017 | World Journal of Gastroenterology2017，23，11： | 13 |
| 4 | Advances in cell sources of hepatocytes for bioartificial liver显示文摘BACKGROUND: Orthotopic liver transplantation (OLT) is the most effective therapy for liver failure. However, OLT is severely limited by the shortage of liver donors. Bioartificial liver (BAL) shows great potential as an alternative therapy for liver failure In recent years, progress has been made in BAL regarding genetically engineered cell lines, immortalized human hepatocytes, methods for preserving the phenotype of primary human hepatocytes, and other functional hepatocytes derived from stem cells. DATA SOURCES: A systematic search of PubMed and ISI Web of Science was performed to identify relevant studies in English language literature using the Key words such as liver failure bioartificial liver, hepatocyte, stem cells, differentiation, and immortalization. More than 200 articles related to the cell sources of hepatocyte in BAL were systematically reviewed. RESULTS: Methods for preserving the phenotype of primary human hepatocytes have been successfully developed. Many genetically engineered cell lines and immortalized human hepatocytes have also been established. Among these cell lines the incorporation of BAL with GS-HepG2 cells or alginate encapsulated HepG2 cells could prolong the survival time and improve pathophysiological parameters in an animal model of liver failure. The cBAL111 cells were evaluated using the AMC-BAL bioreactor, which could eliminate ammonia and lidocaine, and produce albumin. Importantly, BAL loading with HepLi-4 cells could significantly improve the blood biochemical parameters, and prolong the survival time in pigs with liver failure. Other functional hepatocytes differentiated from stem cells, such as human liver progenitor cells, have been successfully achieved. CONCLUSIONS: Aside from genetically modified liver cell lines and immortalized human hepatocytes, other functionalhepatocytes derived from stem cells show great potential as cell sources for BAL. BAL with safe and effective liver cells may be achieved for clinical liver failure in the near future. | Xiao-Ping Pan , Lan-Juan Li State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China | 2012 | Hepatobiliary & Pancreatic Diseases International2012，11，6： | 6 |
| 5 | Translational medicine in China Ⅰ:Perspectives from Chinese physicians and scientists显示文摘Ever since Dr.Elias Zerhouni,then director of the National Institutes of Health,proposed 'The NIH Roadmap' in 2003 [1],life sciences and medical fields worldwide have emphasized translational medical research.In this special topic,we have invited distinguished physicians and scientists to | JIANG ChengYu | 2011 | Science China(Life Sciences)2011，54，12： | 6 |
| 6 | 干细胞模型研究进展及商业化应用的现状显示文摘背景:干细胞是具有自我更新能力的潜在的'永生化'细胞,是挖掘人类发育与衰老奥秘的关键,也是实现再生医学的核心。目的:总结胚胎干细胞、成体干细胞和诱导多能干细胞的生物学特性,评述其在细胞治疗和药物筛选中的临床及商业化应用现状,并浅析干细胞产业所面临的问题和前景。方法:应用计算机检索1995至2017年PubMed数据库、CNKI数据库中有关干细胞模型的相关文献,检索词为'干细胞,胚胎干细胞,成体干细胞,诱导多能干细胞,干细胞研究进展,干细胞治疗,药物筛选,stem cells,embryonic stem cells,adult stem cells,induced pluripotent stem cells,stem cell therapy,drug screening'。结果与结论:①干细胞模型根据其来源分为胚胎干细胞、成体干细胞和诱导多能干细胞。不同来源的干细胞具有其独特的生物学优势;②胚胎干细胞具有发育全能性,但存在伦理道德争议;成体干细胞研究最为广泛和深入,应用最为普遍和成熟;诱导多能干细胞具有类似于胚胎干细胞的全能性,并且不受细胞来源、道德伦理等诸多限制,为干细胞应用带来了新的机遇;③干细胞在细胞治疗领域的应用技术最为成熟。目前已有多款成体干细胞商业化产品上市,用于细胞治疗;同时国际上也开展了多个利用胚胎干细胞和诱导多能干细胞进行细胞治疗的临床研究;此外,利用多能干细胞建立的细胞模型或疾病模型进行特异性药物筛选具有广泛的应用前景。 | 柯敏霞 纪猛 王皓 洪丹萍 吴月红 齐念民 | 2018 | 中国组织工程研究2018，22，5： | 6 |
| 7 | Thinking outside the liver: Induced pluripotent stem cells for hepatic applications显示文摘The discovery of induced pluripotent stem cells (iPSCs) unraveled a mystery in stem cell research, after identification of four re-programming factors for generating pluripotent stem cells without the need of embryos. This breakthrough in generating iPSCs from somatic cells has overcome the ethical issues and immune rejection involved in the use of human embryonic stem cells. Hence, iPSCs form a great potential source for developing disease models, drug toxicity screening and cell-based therapies. These cells have the potential to differentiate into desired cell types, including hepatocytes, under in vitro as well as under in vivo conditions given the proper microenvironment. iPSC-derived hepatocytes could be useful as an unlimited source, which can be utilized in disease modeling, drug toxicity testing and producing autologous cell therapies that would avoid immune rejection and enable correction of gene defects prior to cell transplantation. In this review, we discuss the induction methods, role of reprogramming factors, and characterization of iPSCs, along with hepatocyte differentiation from iPSCs and potential applications. Further, we discuss the location and detection of liver stem cells and their role in liver regeneration. Although tumor formation and genetic mutations are a cause of concern, iPSCs still form a promising source for clinical applications. | Mekala Subba Rao Mitnala Sasikala D Nageshwar Reddy | 2013 | World Journal of Gastroenterology2013，19，22： | 4 |
| 8 | 诱导多能干细胞研究进展——细胞的炼丹术显示文摘人的生命是从一个小小的受精卵开始,经过有丝分裂形成8个细胞卵裂球,进而分化成胚泡(blastocyst)。从胚泡内的内细胞团(inner cell mass,ICM)提取出来的人胚胎干细胞具有多向分化的潜能,能够参与全身机体的200多种组织的形成。 | 张琪 陈规划 | 2010 | 器官移植2010，1，1： | 4 |
| 9 | 骨髓间充质干细胞移植对大鼠急性肺损伤的保护作用及其机制研究显示文摘目的分析骨髓间充质干细胞(MSC)移植对脂多糖(LPS)急性肺损伤(ALI)大鼠模型中炎症因子的影响及其作用机制。方法选取4只4个月龄的无特定病原体(SPF)级雄性C57BL/6J小鼠,用于MSC培养。另选取45只SPF级雄性Sprague Dawley大鼠,随机分为5组,每组9只:MSC对照组(A组)、MSC低剂量组(B组)、MSC高剂量组(C组)、内毒素组(D组)、正常对照组(E组)。于6、24和72 h分别留取每组中3只大鼠的血液标本与肺组织,分别给予血气分析,并测定肺组织中的肿瘤坏死因子-α(TNF-α)和白细胞介素-1β(IL-1β)的含量,同时测定肺湿重/干重比值,观察肺组织病理学变化。结果 3个时间点比较,D组IL-1β、TNF-α水平及肺湿重/干重比值高于E组,差异有统计学意义(P<0.05);B组与C组的血气指标、IL-1β、TNF-α水平及肺组织结构改善优于D组,差异有统计学意义(P<0.05);A组与E组各项指标比较,差异无统计学意义(P>0.05)。结论 MSC移植对LPS ALI大鼠有明显保护作用,可明显降低组织中炎症因子水平,缓解炎症反应,改善血气指标,且无明显毒副作用。 | 沈鹏 | 2016 | 中国现代医学杂志2016，26，17： | 4 |
| 10 | 生物型人工肝的新种子细胞来源-诱导性多潜能干细胞显示文摘生物型人工肝在严重广泛肝细胞功能受损特别是急性肝衰竭的临床应用方面获得了一致认可,而肝细胞的获取是生物型人工肝的根本所在,无论是何种来源的肝细胞,获取后其功能正常高效发挥是所有工作的导向。因此,获取良好状态的人工肝种子细胞是一切工作的前提。由于分化、培养和增殖等方面的限制,获取人工肝种子细胞的常规途径并不能满足临床对种子细胞的需求。2006年日本学者通过重编程体细胞成功诱导成具有多分化潜能的iPS细胞,这为生物型人工肝在获取安全有效种子细胞来源方面带来了新的曙光,本文主要论述iPS细胞的来源、分化及其特性,以及将其应用于临床特别是生物型人工肝所面临的主要问题,并对其前景进行探讨。 | 杨照 周新民 樊代明 韩英 时永全 王敬博 张懿 | 2010 | 胃肠病学和肝病学杂志2010，19，3： | 4 |
| 11 | 诱导多能干细胞及其移植治疗脊髓损伤的研究进展显示文摘目前临床上对脊髓损伤(spinal cord injury,SCI)的治疗方法主要包括手术减压、神经营养药物治疗及康复功能锻炼,但疗效并不理想.常留有不同程度的神经功能永久缺失.致残率高。外伤性SCI除直接导致脊髓神经细胞破坏外.还会随着损伤时间的推移,出现继发性损伤,使病灶周围原来完整的组织发生自身破坏性病变,表现为自由基生成增多,兴奋性氨基酸过度释放以及炎症反应等。 | 唐超 钟德君 | 2017 | 中国脊柱脊髓杂志2017，27，4： | 4 |
| 12 | 诱导多潜能干细胞(iPSCs)的研究与应用进展显示文摘诱导多潜能干细胞(induced pluripotent stem cells,iPSCs)是体细胞在外源因子作用下,经直接细胞核程序重整而重新获得多潜能的干细胞.iPSCs在疾病的模型建立与机理研究、细胞治疗、药物的发现与评价等方面有着巨大的潜在应用价值.在过去几年中,科学家们致力于改进体细胞重编程技术并取得许多突破.然而,为实现其在临床上的应用,必须克服体细胞重编程效率低和iPSCs成瘤风险两大挑战,而且重编程机制有待进一步阐明.结合iPSCs最新研究成果,评述了有关领域国内外研究进展,重点讨论当前存在问题,并展望未来研究方向. | 付玉华 周秀梅 徐凤青 钱其军 | 2011 | 生物化学与生物物理进展2011，38，2： | 4 |
| 13 | Efficient derivation of functional hepatocytes from mouse induced pluripotent stem cells by a combination of cytokines and sodium butyrate显示文摘背景 Hepatocyte 移植作为整个器官的移植的一种选择被建议了支持许多形式肝 insufficiency.Unfortunately ,施主肝的缺乏使为 基于hepatocyte 的 therapies.Therefore 获得足够可行的人的 hepatocytes 困难,发现新方法提供宽大的 hepatocytes.Induced pluripotent 茎( iPS )房间是迫切的,在干细胞研究的突破,可以终止这些为房间 transplantation.For 妨碍 iPS | ZHANG Qi YANG Yang ZHANG Jian WANG Guo-ying LIU Wei QIU Dong-bo HEI Zi-qing YING Qi-long CHEN Gui-hua | 2011 | Chinese Medical Journal2011，，22： | 4 |
| 14 | Progress in human liver organoids显示文摘Understanding the development,regeneration,and disorders of the liver is the major goal in liver biology.Current mechanistic knowledge of human livers has been largely derived from mouse models and cell lines,which fall short in recapitulating the features of human liver cells or the structures and functions of human livers.Organoids as an in vitro system hold the promise to generate organ-like tissues in a dish.Recent advances in human liver organoids also facilitate the understanding of the biology and diseases in this complex organ.Here we review the progress in human liver organoids,mainly focusing on the methods to generate liver organoids,their applications,and possible future directions. | Lulu Sun Lijian Hui | 2020 | Journal of Molecular Cell Biology2020，12，8： | 4 |
| 15 | Human induced pluripotent stem cells derived hepatocytes:rising promise for disease modeling,drug development and cell therapy显示文摘Recent advances in the study of human hepatocytes derived from induced pluripotent stem cells(iPSC)represent new promises for liver disease study and drug discovery.Human hepatocytes or hepatocyte-like cells differentiated from iPSC recapitulate many func-tional properties of primary human hepatocytes and have been demonstrated as a powerful and efficient tool to model human liver metabolic diseases and fa-cilitate drug development process.In this review,we summarize the recent progress in this field and discuss the future perspective of the application of human iPSC derived hepatocytes. | Fei Yi Guang-Hui Liu Juan Carlos Izpisua Belmonte | 2012 | Protein & Cell2012，3，4： | 3 |
| 16 | Establishment of hepatic and neural differentiation platforms of Wilson’s disease specific induced pluripotent stem cells显示文摘The combination of disease-specific human induced pluripotent stem cells(iPSC)and directed cell differentiation offers an ideal platform for modeling and studying many inherited human diseases.Wilson’s disease(WD)is a monogenic disorder of toxic copper accumulation caused by pathologic mutations of the ATP7B gene.WD affects multiple organs with primary manifestations in the liver and central nervous system(CNS).In order to better investigate the cellular pathogenesis of WD and to develop novel therapies against various WD syndromes,we sought to establish a comprehensive platform to differentiate WD patient iPSC into both hepatic and neural lineages.Here we report the generation of patient iPSC bearing a Caucasian population hotspot mutation of ATP7B.Combining with directed cell differentiation strategies,we successfully differentiated WD iPSC into hepatocyte-like cells,neural stem cells and neurons.Gene expression analysis and cDNA sequencing confirmed the expression of the mutant ATP7B gene in all differentiated cells.Hence we established a platform for studying both hepatic and neural abnormalities of WD,which may provide a new tool for tissue-specific disease modeling and drug screening in the future. | Fei Yi Jing Qu Mo Li Keiichiro Suzuki Na Young Kim Guang-Hui Liu Juan Carlos Izpisua Belmonte | 2012 | Protein & Cell2012，3，11： | 3 |
| 17 | 通过hiPS细胞诱导生成类肝细胞建立肝毒性检测模型及其初步评价显示文摘目的探讨通过人诱导多能干细胞(human induced pluripotent stem cells,hiPS cells)诱导生成类肝细胞,建立肝毒性检测模型并用于中药毒性体外评价的可行性。方法采用细胞因子4步诱导分化方法,通过加入激活素A(Activin A)、骨形态发生蛋白-4(BMP-4)、成纤维细胞生长因子-2(FGF-2)、肝细胞生长因子(HGF)、制瘤素M(Oncostatin M)等细胞因子,连续培养23 d,将hiPS细胞诱导分化成类肝细胞。采用细胞免疫荧光法检测hiPS细胞向类肝细胞分化过程不同阶段的特异性标记:叉头框转录因子A2(FOXA2)、性别决定区Y框蛋白17(SOX17)、甲胎蛋白(AFP)、白蛋白(ALB)、肝细胞色素P4503A4酶(CYP3A4)和α1-抗胰蛋白酶(AAT)等蛋白的表达;采用q PCR法检测类肝细胞特异性基因:甲胎蛋白(AFP)、白蛋白(ALB)、细胞角蛋白8(CK8)、细胞角蛋白18(CK18)和细胞角蛋白19(CK19)的基因表达;采用吲哚青绿(ICG)摄取实验检测类肝细胞排泌功能。采用雷公藤冻干粉(1,2,4,8 mg·m L^(-1))对类肝细胞进行肝毒性实验,作用24 h后检测谷草转氨酶(AST)、谷丙转氨酶(ALT)、丙二醛(MDA)、谷胱甘肽(GSH)、超氧化物歧化酶(SOD)的含量或活性。结果检测到FOXA2、SOX17蛋白在内胚层诱导阶段有表达,AFP、ALB在肝细胞分化与扩增阶段有表达,CYP3A4、AAT在肝细胞成熟阶段有表达;肝细胞特异性基因AFP、CK19、ALB、CK8、CK18在类肝细胞中均有表达,诱导前后比较差异有统计学意义(P<0.05);ICG摄取实验显示类肝细胞具有肝细胞的特异性ICG摄取功能。与对照组比较,雷公藤各剂量组的ALT及AST活性显著升高、MDA浓度显著升高、GSH及SOD活性显著降低,差异均有统计学意义(P<0.05,P<0.01)。结论通过hiPS细胞诱导生成类肝细胞的方法具有可行性,诱导得到的类肝细胞具有人正常肝细胞的功能,可以作为中药肝毒性筛选的模型细胞。 | 胡秋艳 谭庆龙 徐雯星 刘春萍 曾星 | 2018 | 中药新药与临床药理2018，29，1： | 2 |
| 18 | 诱导多功能干细胞来源肝样细胞体内抗肝纤维化显示文摘背景:诱导多功能干细胞具有与胚胎干细胞相似的自我更新、增殖及分化能力,无来源限制,又不存在伦理问题,有望成为治疗肝病的细胞来源。目的:观察诱导多功能干细胞来源肝样细胞体内移植对肝纤维化的改善作用。方法:采用三步法将诱导多功能干细胞诱导分化为肝样细胞,采用糖原染色、LDL摄取实验、免疫组织化学法检测诱导分化细胞合成糖原能力、摄取LDL能力和甲胎蛋白、白蛋白、CK18蛋白表达。取成年雄性SD大鼠45只(由中南大学湘雅医学院附属海口医院医学实验动物中心提供),随机分为3组,分别为正常对照组、模型组、细胞移植组,每组15只。模型组、细胞移植组以腹腔注射四氯化碳方法建立肝纤维化模型,造模后第3天,细胞移植组尾静脉注射0.5 mL诱导分化21 d的肝样细胞,细胞浓度为2×10~9 L^(-1)。细胞移植后4周,取静脉血与肝组织标本,分析肝功能及肝纤维化指标变化与肝病理改变。结果与结论:(1)诱导分化21 d后,人诱导多能干细胞克隆团已经松散,以类圆形或多角形为主,呈铺路石样分布并密集排列,糖原染色可见细胞胞浆内有大量聚集的粉红色糖原,具备摄取LDL的能力,免疫组织化学法观察甲胎蛋白、白蛋白与CK18呈阳性表达;(2)细胞移植后4周,与正常组比较,模型组白蛋白水平显著降低(P <0.05),直接胆红素、间接胆红素、谷草转氨酶、谷丙转氨酶及Ⅳ型胶原、血清透明质酸酶、血清Ⅲ型前胶原水平均显著升高(P <0.05)。与模型组比较,细胞移植组白蛋白水平显著升高(P <0.05),直接胆红素、间接胆红素、谷草转氨酶、谷丙转氨酶及Ⅳ型胶原、血清透明质酸酶、血清Ⅲ型前胶原水平均显著降低(P <0.05);(3)细胞移植后4周,细胞移植组炎性细胞浸润、肝细胞变性与坏死程度较模型组均有不同程度的改善;(4)结果表明,诱导多功能干细胞来源的肝样细胞对大鼠肝纤维化具有明显改善作用。 | 程钢 黄邓高 梁颖 | 2019 | 中国组织工程研究2019，23，9： | 2 |
| 19 | 干细胞与肝脏病治疗研究进展显示文摘全球17亿人有各种不同类型的慢性肝病,其中25%~30%的人会发生严重纤维化并最终进展成肝硬化。最主要的致病原因是HCV、HBV感染,酗酒和非酒精性脂肪肝。肝硬化是85% ~ 90%原发性肝癌的病因,这些疾病给全球的医疗卫生增加了显著的负担。目前,对于终末期肝病和先天遗传性代谢性肝病,原位肝移植( OLT)一直被认为是最理想的方法,但由于缺乏供体、费用昂贵、免疫排斥而需要服用免疫抑制剂等因素,其在临床的广泛应用受到限制。有人尝试将生物人工肝(BAL)和肝细胞移植(LCT)[1]作为肝移植的辅助或替代疗法,原代肝细胞是理想供体,同样来源匮乏,且原代肝细胞体外培养或体内移植后的增殖及功能的维持状况均不甚理想。干细胞研究的兴起为应用干细胞移植治疗终末期肝病提供了新的治疗思路。 | 胡祥 | 2011 | 中国继续医学教育2011，3，6： | 2 |
| 20 | 我国诱导多能干细胞研究进展显示文摘关于细胞重编程问题的探讨可以追溯至20世纪30年代。从汉斯·斯佩曼提出'胚胎诱导'概念开始,到20世纪60年代,约翰·戈登成功获得了经过体细胞核移植发育而来的爪蟾,再到1996年世界首例克隆哺乳动物克隆羊'多莉'的诞生,生物学家终于证实了高等动物的体细胞核能够通过核移植的方式重新建立多能性,但这一方法面临着很多社会伦理学问题,无法应用于医学实践。直到2006年Yamanaka小组诱导多能干细胞(Induced pluripotent stem cells,i PS细胞),成功地绕过了这些伦理问题,诱导重编程才成为了当今干细胞生物学最为热门的研究方向。在诱导多能干细胞领域,我国一直位居世界前列,近年来更是在i PS技术的优化、机制研究和应用研究等方面作出了令世界瞩目的贡献,就这几方面做一综述。 | 许锴 陈霞 高绍荣 | 2015 | 生物技术通报2015，31，4： | 2 |
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