Please wait a minute...

中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2023, Vol. 43 Issue (8): 20-29    DOI: 10.13523/j.cb.2304008
类器官构建与应用专题     
人源肝脏类器官的研究及应用进展
朱翔1,张静引2,王丽蕊3,*()
1 中国药科大学基础医学与临床药学学院 南京 211112
2 东南大学附属中大医院 南京 210009
3 南京大学现代生物研究院 南京 210008
Research and Applications of Human Liver Organoids: Progress and Developments
ZHU Xiang1,ZHANG Jing-yin2,WANG Li-rui3,*()
1 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211112, China
2 Obstetrics and Gynecology Department, Zhongda Hospital Southeast University, Nanjing 210009, China
3 Institute of Modern Biology, Nanjing University, Nanjing 210008, China
 全文: PDF(1043 KB)   HTML
摘要：

肝脏是人体的主要代谢器官,在维持人体内环境稳态过程中起着关键调控作用。近年来,肝脏疾病严重威胁着人类健康,然而使用目前体外培养的细胞系和体内动物模型均无法深入揭示人肝脏疾病的发病机制,探索出有效潜在治疗靶点。人源肝脏类器官(human liver organoids, HLOs)是从人源细胞经体外3D分化培养得到的细胞团,能在体外模拟人肝脏的结构和功能,为人们理解肝脏生理结构、体外模拟肝脏疾病和开发治疗肝脏疾病药物提供了新模型。总结近年来具有代表性的HLOs模型的建立策略及应用,探讨目前HLOs模型存在的缺陷,以期为推动HLOs向临床应用提供参考。
关键词： 肝脏;  肝脏疾病;  人源肝脏类器官;  3D培养    
Abstract:

The liver is the major metabolic organ in the body and it plays a crucial regulatory role in maintaining homeostasis. In recent years, liver diseases have seriously threatened human health. However, the in vitro cultured cell lines or in vivo animal models cannot thoroughly reveal pathogenesis of human liver diseases and explore potential therapeutic targets effectively. Human liver organoids (HLOs), which are cell clusters differentiated from human cells through 3D culture in vitro, can mimic the structures and functions of the human liver in vitro. HLOs provide a new model for understanding the physiological structures and functions of the liver, simulating liver diseases in vitro, and exploring drugs for liver disease treatment. This review summarizes establishment strategies and applications of HLO models in recent years, and also discusses the defects of these models, which aim to provide a theoretical basis for the clinical applications of HLOs.
Key words: Liver    Liver diseases    Human liver organoids    Three dimensional culture
收稿日期: 2023-04-04 出版日期: 2023-09-05
ZTFLH:  Q819  
通讯作者: *电子信箱:wanglirui@nju.edu.cn   
服务　　
把本文推荐给朋友
加入引用管理器
E-mail Alert
RSS
作者相关文章　　
朱翔
张静引
王丽蕊

引用本文:

朱翔, 张静引, 王丽蕊. 人源肝脏类器官的研究及应用进展[J]. 中国生物工程杂志, 2023, 43(8): 20-29.

ZHU Xiang, ZHANG Jing-yin, WANG Li-rui. Research and Applications of Human Liver Organoids: Progress and Developments. China Biotechnology, 2023, 43(8): 20-29.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2304008    或    https://manu60.magtech.com.cn/biotech/CN/Y2023/V43/I8/20

细胞名称 细胞因子 肝脏类器官特点 参考文献
人脐静脉内皮细胞、人间充质干细胞、人诱导肝脏内胚层细胞 激活素A、碱性成纤维细胞生长因子(bFGF)、骨形态发生蛋白4(BMP4)、抑瘤素M (OSM) 血管化的人肝芽组织 [24]
人肝内胆管上皮细胞 R-spondin1蛋白、表皮生长因子(EGF)、成纤维细胞生长因子10(FGF10)、肝细胞生长因子(HGF), 骨形态发生蛋白7(BMP7)、成纤维细胞生长因子19(FGF19)、胃泌素 外观呈规则囊泡状,且具有人肝实质细胞特征 [37]
人肝癌细胞 R-spondin1蛋白、Wnt3A蛋白、表皮生长因子(EGF)、成纤维细胞生长因子10(FGF10)、肝细胞生长因子(HGF)、Noggin蛋白、骨形态发生蛋白7(BMP7)、成纤维细胞生长因子19(FGF19)、胃泌素 致密球状或不规则囊泡状结构 [21]
人诱导性多能干细胞 激活素A、骨形态发生蛋白4(BMP4)、肝细胞生长因子(HGF)、表皮生长因子(EGF)、抑瘤素M (OSM)、 成纤维细胞生长因子10(FGF10) 同时具有人肝实质细胞和胆管上皮细胞两种特征 [38]
人诱导性多能干细胞分化而来的间充质细胞、内皮细胞和肝向内胚层细胞 激活素A、Wnt3A蛋白、碱性成纤维细胞生长因子(bFGF)、骨形态发生蛋白4(BMP4)、血管内皮细胞生长因子(VEGF)、血小板衍生生长因子BB(PDGFBB)、成纤维细胞生长因子(FGF2) 血管化的人肝芽结构 [25]
人肝母细胞 R-spondin1蛋白、表皮生长因子(EGF)、肝细胞生长因子(HGF)、成纤维细胞生长因子7(FGF7)、成纤维细胞生长因子10(FGF10)、转化生长因子-α(TGF-α)、抑瘤素M (OSM) 呈葡萄串状,具有人肝实质细胞特征 [20]
人胚胎肝祖细胞 催乳素、表皮生长因子(EGF)、肝细胞生长因子(HGF)、抑瘤素M(OSM) 同时具有人肝实质细胞和胆管上皮细胞两种特征 [23]
人诱导性多能干细胞 激活素A、碱性成纤维细胞生长因子(bFGF)、肝细胞生长因子(HGF)、抑瘤素M(OSM) 在微流控系统内衍生而来,同时具有人肝实质细胞和胆管上皮细胞两种特征 [26]
人诱导性多能干细胞 胃泌素、表皮生长因子(EGF)、R-spondin1蛋白,成纤维细胞生长因子10(FGF10)、肝细胞生长因子(HGF)、Noggin蛋白、Wnt3A蛋白 同时具有人肝实质细胞和胆管上皮细胞两种特征 [39]
人胚胎干细胞、人诱导性多能干细胞 激活素A、骨形态发生蛋白4(BMP4)、成纤维细胞生长因子4(FGF4)、Noggin蛋白 同时具有人肝、胆、胰特征的人肝-胆-胰类器官 [31]
人胚胎干细胞、人诱导性多能干细胞 激活素A、骨形态发生蛋白4(BMP4)、成纤维细胞生长因子4(FGF4)、肝细胞生长因子(HGF)、抑瘤素M(OSM) 同时具有人肝实质细胞样细胞、人星状细胞样细胞和人库普弗样细胞 [27]
人胚胎干细胞 激活素A、Wnt3A蛋白、表皮生长因子(EGF)、成纤维细胞生长因子2(FGF2)、骨形态发生蛋白4(BMP4)、胃泌素、R-spondin1蛋白 呈规则囊泡状,具有向人肝实质细胞和胆管上皮细胞双向分化潜能 [28]
人诱导性多能干细胞 激活素A、骨形态发生蛋白4(BMP4)、成纤维细胞生长因子4(FGF4)、骨形态发生蛋白2(BMP2)、角质细胞生长因子(KGF)、抑瘤素M(OSM) 同时具有2D水平的人肝实质样细胞和3D水平的囊泡状胆管类器官的肝胆类器官 [29]
人胚胎干细胞、人诱导性多能干细胞 骨形态发生蛋白4(BMP4)、碱性成纤维细胞生长因子(bFGF)、表皮生长因子(EGF)、肝细胞生长因子(HGF)、成纤维细胞生长因子7(FGF7)、骨形态发生蛋白7(BMP7)、成纤维细胞生长因子19(FGF19) 同时具有人肝实质细胞和胆管上皮细胞特征,且具有功能性的胆管结构 [32]
人诱导性多能干细胞 激活素A、碱性成纤维细胞生长因子(bFGF)、肝细胞生长因子(HGF)、骨形态发生蛋白4(BMP4)、抑瘤素M(OSM) 在微流控系统内衍生而来,同时具有人肝实质细胞和胆管上皮细胞两种特征 [33]
人诱导性多能干细胞 激活素A、骨形态发生蛋白2(BMP2)、成纤维细胞生长因子4(FGF4)、肝细胞生长因子(HGF)、角质细胞生长因子(KGF)、胃泌素、表皮生长因子(EGF)、转化生长因子-α(TGF-α)、成纤维细胞生长因子7(FGF7)、成纤维细胞生长因子10(FGF10)、抑瘤素M(OSM) 具有人肝实质细胞特征 [35]
人肝内胆管上皮细胞 R-spondin1蛋白、表皮生长因子(EGF)、成纤维细胞生长因子10(FGF10)、肝细胞生长因子(HGF)、骨形态发生蛋白7(BMP7)、成纤维细胞生长因子19(FGF19)、胃泌素 呈规则囊泡状结构,具有人肝实质细胞特征 [35]
人胚胎干细胞、人诱导性多能干细胞 激活素A、骨形态发生蛋白4(BMP4)、成纤维细胞生长因子4(FGF4)、表皮生长因子(EGF)、血管内皮细胞生长因子(VEGF)、成纤维细胞生长因子2(FGF2)、肝细胞生长因子(HGF)、抑瘤素M(OSM) 同时具有人肝实质细胞样细胞、人星状细胞样细胞和人库普弗样细胞 [34,36]
人诱导性多能干细胞 激活素A、碱性成纤维细胞生长因子(bFGF)、肝细胞生长因子(HGF)、抑瘤素M(OSM) 在微流控系统内衍生而来,同时具有人肝实质细胞和胆管上皮细胞两种特征 [40]
人肝母细胞 肝细胞生长因子(HGF)、表皮生长因子(EGF)、胃泌素、成纤维细胞生长因子10(FGF10)、R-spondin1蛋白 呈规则囊泡状结构,具有人肝实质细胞特征 [41]
表1  建立不同类型人源肝脏类器官使用的细胞及生长因子
图1  正常肝脏组织来源的人源肝脏类器官建立策略
图2  hPSCs来源的HLOs建立策略
[1] Trefts E, Gannon M, Wasserman D H. The liver. Current Biology: CB, 2017, 27(21): R1147-R1151.
doi: 10.1016/j.cub.2017.09.019
[2] Jalan-Sakrikar N, Brevini T, Huebert R C, et al. Organoids and regenerative hepatology. Hepatology (Baltimore, Md), 2023, 77(1): 305-322.
doi: 10.1002/hep.32583
[3] Xia S W, Wang Z M, Sun S M, et al. Endoplasmic reticulum stress and protein degradation in chronic liver disease. Pharmacological Research, 2020, 161: 105218.
doi: 10.1016/j.phrs.2020.105218
[4] Karlsen T H, Sheron N, Zelber-Sagi S, et al. The EASL-Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality. Lancet (London, England), 2022, 399(10319): 61-116.
doi: 10.1016/S0140-6736(21)01701-3
[5] Cvetkovski F, Hexham J M, Berglund E. Strategies for liver transplantation tolerance. International Journal of Molecular Sciences, 2021, 22(5): 2253.
doi: 10.3390/ijms22052253
[6] Takebe T, Taniguchi H. Human iPSC-derived miniature organs: a tool for drug studies. Clinical Pharmacology & Therapeutics, 2014, 96(3): 310-313.
[7] Nagarajan S R, Paul-Heng M, Krycer J R, et al. Lipid and glucose metabolism in hepatocyte cell lines and primary mouse hepatocytes: a comprehensive resource for in vitro studies of hepatic metabolism. American Journal of Physiology Endocrinology and Metabolism, 2019, 316(4): E578-E589.
doi: 10.1152/ajpendo.00365.2018
[8] Boyer J L, Soroka C J. Bile formation and secretion: an update. Journal of Hepatology, 2021, 75(1): 190-201.
doi: 10.1016/j.jhep.2021.02.011 pmid: 33617926
[9] Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nature Reviews Gastroenterology & Hepatology, 2021, 18(3): 151-166.
[10] Gracia-Sancho J, Caparrós E, Fernández-Iglesias A, et al. Role of liver sinusoidal endothelial cells in liver diseases. Nature Reviews Gastroenterology & Hepatology, 2021, 18(6): 411-431.
[11] Li W Y, Chang N, Li L Y. Heterogeneity and function of Kupffer cells in liver injury. Frontiers in Immunology, 2022, 13: 940867.
doi: 10.3389/fimmu.2022.940867
[12] Aizarani N, Saviano A, Sagar, et al. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature, 2019, 572(7768): 199-204.
doi: 10.1038/s41586-019-1373-2
[13] Ben-Moshe S, Itzkovitz S. Spatial heterogeneity in the mammalian liver. Nature Reviews Gastroenterology & Hepatology, 2019, 16(7): 395-410.
[14] Manco R, Itzkovitz S. Liver zonation. Journal of Hepatology, 2021, 74(2): 466-468.
doi: 10.1016/j.jhep.2020.09.003 pmid: 33317845
[15] Paris J, Henderson N C. Liver zonation, revisited. Hepatology (Baltimore, Md), 2022, 76(4): 1219-1230.
doi: 10.1002/hep.32408
[16] Corrò C, Novellasdemunt L, Li V S W. A brief history of organoids. American Journal of Physiology Cell Physiology, 2020, 319(1): C151-C165.
doi: 10.1152/ajpcell.00120.2020
[17] Prior N, Inacio P, Huch M. Liver organoids: from basic research to therapeutic applications. Gut, 2019, 68(12): 2228-2237.
doi: 10.1136/gutjnl-2019-319256 pmid: 31300517
[18] Huch M, Dorrell C, Boj S F, et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature, 2013, 494(7436): 247-250.
doi: 10.1038/nature11826
[19] Huch M, Gehart H, Van Boxtel R, et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell, 2015, 160(1-2): 299-312.
doi: 10.1016/j.cell.2014.11.050 pmid: 25533785
[20] Hu H L, Gehart H, Artegiani B, et al. Long-term expansion of functional mouse and human hepatocytes as 3D organoids. Cell, 2018, 175(6): 1591-1606.e19.
doi: S0092-8674(18)31505-8 pmid: 30500538
[21] Broutier L, Mastrogiovanni G, Verstegen M M, et al. Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. Nature Medicine, 2017, 23(12): 1424-1435.
doi: 10.1038/nm.4438 pmid: 29131160
[22] Peng W C, Logan C Y, Fish M, et al. Inflammatory cytokine TNF-α promotes the long-term expansion of primary hepatocytes in 3D culture. Cell, 2018, 175(6): 1607-1619.e15.
doi: 10.1016/j.cell.2018.11.012
[23] Vyas D, Baptista P M, Brovold M, et al. Self-assembled liver organoids recapitulate hepatobiliary organogenesis in vitro. Hepatology, 2018, 67(2): 750-761.
doi: 10.1002/hep.29483
[24] Takebe T, Sekine K, Enomura M, et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature, 2013, 499(7459): 481-484.
doi: 10.1038/nature12271
[25] Takebe T, Sekine K, Kimura M, et al. Massive and reproducible production of liver buds entirely from human pluripotent stem cells. Cell Reports, 2017, 21(10): 2661-2670.
doi: S2211-1247(17)31625-X pmid: 29212014
[26] Wang Y Q, Wang H, Deng P W, et al. In situ differentiation and generation of functional liver organoids from human iPSCs in a 3D perfusable chip system. Lab on a Chip, 2018, 18(23): 3606-3616.
doi: 10.1039/C8LC00869H
[27] Ouchi R E, Togo S, Kimura M, et al. Modeling steatohepatitis in humans with pluripotent stem cell-derived organoids. Cell Metabolism, 2019, 30(2): 374-384.e6.
doi: S1550-4131(19)30247-5 pmid: 31155493
[28] Wang S Y, Wang X, Tan Z L, et al. Human ESC-derived expandable hepatic organoids enable therapeutic liver repopulation and pathophysiological modeling of alcoholic liver injury. Cell Research, 2019, 29(12): 1009-1026.
doi: 10.1038/s41422-019-0242-8 pmid: 31628434
[29] Wu F F, Wu D, Ren Y, et al. Generation of hepatobiliary organoids from human induced pluripotent stem cells. Journal of Hepatology, 2019, 70(6): 1145-1158.
doi: S0168-8278(19)30002-9 pmid: 30630011
[30] de l’Hortet A C, Takeishi K, Guzman-Lepe J, et al. Generation of human fatty livers using custom-engineered induced pluripotent stem cells with modifiable SIRT1 metabolism. Cell Metabolism, 2019, 30(2): 385-401.e9.
doi: S1550-4131(19)30320-1 pmid: 31390551
[31] Koike H, Iwasawa K, Ouchi R E, et al. Modelling human hepato-biliary-pancreatic organogenesis from the foregut-midgut boundary. Nature, 2019, 574(7776): 112-116.
doi: 10.1038/s41586-019-1598-0
[32] Bin Ramli M N, Lim Y S, Koe C T, et al. Human pluripotent stem cell-derived organoids as models of liver disease. Gastroenterology, 2020, 159(4): 1471-1486.e12.
doi: 10.1053/j.gastro.2020.06.010 pmid: 32553762
[33] Wang Y Q, Wang H, Deng P W, et al. Modeling human nonalcoholic fatty liver disease (NAFLD) with an organoids-on-a-chip system. ACS Biomaterials Science & Engineering, 2020, 6(10): 5734-5743.
[34] Shinozawa T, Kimura M, Cai Y Q, et al. High-fidelity drug-induced liver injury screen using human pluripotent stem cell-derived organoids. Gastroenterology, 2021, 160(3): 831-846.e10.
doi: 10.1053/j.gastro.2020.10.002 pmid: 33039464
[35] Guo J Y, Duan L F, He X Y, et al. A combined model of human iPSC-derived liver organoids and hepatocytes reveals ferroptosis in DGUOK mutant mtDNA depletion syndrome. Advanced Science, 2021, 8(10): 2004680.
doi: 10.1002/advs.v8.10
[36] Kimura M, Iguchi T, Iwasawa K, et al. En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH. Cell, 2022, 185(22): 4216-4232.e16.
doi: 10.1016/j.cell.2022.09.031
[37] Broutier L, Andersson-Rolf A, Hindley C J, et al. Culture and establishment of self-renewing human and mouse adult liver and pancreas 3D organoids and their genetic manipulation. Nature Protocols, 2016, 11(9): 1724-1743.
doi: 10.1038/nprot.2016.097 pmid: 27560176
[38] Guan Y, Xu D, Garfin P M, et al. Human hepatic organoids for the analysis of human genetic diseases. JCI Insight, 2017, 2(17): e94954.
doi: 10.1172/jci.insight.94954
[39] Akbari S, Sevinç G G, Ersoy N, et al. Robust, long-term culture of endoderm-derived hepatic organoids for disease modeling. Stem Cell Reports, 2019, 13(4): 627-641.
doi: S2213-6711(19)30301-7 pmid: 31522975
[40] Tao T T, Deng P W, Wang Y Q, et al. Microengineered multi-organoid system from hiPSCs to recapitulate human liver-islet axis in normal and type 2 diabetes. Advanced Science, 2022, 9(5): 2103495.
doi: 10.1002/advs.v9.5
[41] Simoneau C R, Erickson A L, Meyers N L, et al. Modelling T-cell immunity against hepatitis C virus with liver organoids in a microfluidic coculture system. Open Biology, 2022, 12(3): 210320.
doi: 10.1098/rsob.210320
[42] Prior N, Hindley C J, Rost F, et al. Lgr5+ stem and progenitor cells reside at the apex of a heterogeneous embryonic hepatoblast pool. Development (Cambridge, England), 2019, 146(12): dev174557.
[43] McCarron S, Bathon B, Conlon D M, et al. Functional characterization of organoids derived from irreversibly damaged liver of patients with NASH. Hepatology (Baltimore, Md), 2021, 74(4): 1825-1844.
doi: 10.1002/hep.31857
[44] Sorrentino G, Rezakhani S, Yildiz E, et al. Mechano-modulatory synthetic niches for liver organoid derivation. Nature Communications, 2020, 11(1): 1-10.
doi: 10.1038/s41467-019-13993-7
[45] Illath K, Kar S, Gupta P, et al. Microfluidic nanomaterials: from synthesis to biomedical applications. Biomaterials, 2022, 280: 121247.
doi: 10.1016/j.biomaterials.2021.121247
[46] Filippi M, Buchner T, Yasa O, et al. Microfluidic tissue engineering and bio-actuation. Advanced Materials, 2022, 34(23): 2108427.
doi: 10.1002/adma.v34.23
[47] Liu Y, Yang G Z, Hui Y, et al. Microfluidic nanoparticles for drug delivery. Small, 2022, 18(36): 2106580.
doi: 10.1002/smll.v18.36
[48] Hur J, Chung A J. Microfluidic and nanofluidic intracellular delivery. Advanced Science, 2021, 8(15): 2004595.
doi: 10.1002/advs.v8.15
[49] Kong M Y, Zhou D. Establishment of universal human embryonic stem cell lines. Immunology Letters, 2021, 230: 59-62.
doi: 10.1016/j.imlet.2020.12.001 pmid: 33309828
[50] Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 2006, 126(4): 663-676.
doi: 10.1016/j.cell.2006.07.024 pmid: 16904174
[51] Cyranoski D. Woman is first to receive cornea made from ‘reprogrammed’ stem cells.[2022-09-05]. https://www.nature.com/articles/d41586-019-02597-2.
[52] Poetsch M S, Strano A, Guan K M. Human induced pluripotent stem cells: from cell origin, genomic stability, and epigenetic memory to translational medicine. Stem Cells (Dayton, Ohio), 2022, 40(6): 546-555.
doi: 10.1093/stmcls/sxac020
[53] Bonnardel J, T’Jonck W, Gaublomme D, et al. Stellate cells, hepatocytes, and endothelial cells imprint the kupffer cell identity on monocytes colonizing the liver macrophage niche. Immunity, 2019, 51(4): 638-654.e9.
doi: S1074-7613(19)30368-1 pmid: 31561945
[54] Si-Tayeb K, Lemaigre F P, Duncan S A. Organogenesis and development of the liver. Developmental Cell, 2010, 18(2): 175-189.
doi: 10.1016/j.devcel.2010.01.011 pmid: 20159590
[55] Joshi M, Patil P B, He Z, et al. Fetal liver-derived mesenchymal stromal cells augment engraftment of transplanted hepatocytes. Cytotherapy, 2012, 14(6): 657-669.
doi: 10.3109/14653249.2012.663526 pmid: 22424216
[56] Mederacke I, Hsu C C, Troeger J S, et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nature Communications, 2013, 4(1): 1-11.
[57] Li Y, Zhao D Y, Qian M Y, et al. Amlodipine, an anti-hypertensive drug, alleviates non-alcoholic fatty liver disease by modulating gut microbiota. British Journal of Pharmacology, 2022, 179(9): 2054-2077.
doi: 10.1111/bph.v179.9
[58] Zandi Shafagh R, Youhanna S, Keulen J, et al. Bioengineered pancreas-liver crosstalk in a microfluidic coculture chip identifies human metabolic response signatures in prediabetic hyperglycemia. Advanced Science, 2022, 9(34): 2203368.
doi: 10.1002/advs.v9.34
[59] Wu Y R, Wong C W, Chiles E N, et al. Glycerate from intestinal fructose metabolism induces islet cell damage and glucose intolerance. Cell Metabolism, 2022, 34(7): 1042-1053.e6.
doi: 10.1016/j.cmet.2022.05.007 pmid: 35688154
[60] Svegliati-Baroni G, Patrício B, Lioci G, et al. Gut-pancreas-liver axis as a target for treatment of NAFLD/NASH. International Journal of Molecular Sciences, 2020, 21(16): 5820.
doi: 10.3390/ijms21165820
[61] Garber K. RIKEN suspends first clinical trial involving induced pluripotent stem cells. Nature Biotechnology, 2015, 33(9): 890-891.
doi: 10.1038/nbt0915-890 pmid: 26348942
[62] Rouhani F J, Zou X Q, Danecek P, et al. Substantial somatic genomic variation and selection for BCOR mutations in human induced pluripotent stem cells. Nature Genetics, 2022, 54(9): 1406-1416.
doi: 10.1038/s41588-022-01147-3 pmid: 35953586
[1] 郭超婧,朱琼,张新,李磊,张令强. 去泛素化酶OTUB1肝脏特异性基因敲除小鼠模型的构建与表型分析 *[J]. 中国生物工程杂志, 2019, 39(5): 80-87.
[2] 徐竹, 诸葛启钏, 黄李洁. 干细胞3D支架的研究进展[J]. 中国生物工程杂志, 2017, 37(9): 112-117.
[3] 满善晴; 孔祥祯; 董小明; 陈慧; 詹轶群; 李长燕; 杨晓明. [J]. 中国生物工程杂志, 2015, 35(4): 30-41.
[4] 胡燕珍, 卫军营, 罗光明. 谷胱甘肽在肝脏疾病相关信号通路中的作用及研究进展[J]. 中国生物工程杂志, 2015, 35(10): 72-77.
[5] 王佃亮. 组织工程的临床研究——组织工程连载之五[J]. 中国生物工程杂志, 2014, 34(10): 114-120.
[6] 田文洪, 胡键阳, 董小岩, 李明皓, 吴小兵. 用生物传感器方法测定正常小鼠肝脏中miR-21活性[J]. 中国生物工程杂志, 2013, 33(1): 60-66.
[7] 李文博, 张伟峰, 陈胤伯, 王东阳, 张琛, 夏海滨. 携带不同数量增强子的嵌合型肝脏特异性启动子的构建及其体外实验研究[J]. 中国生物工程杂志, 2012, 32(01): 15-20.
[8] 于晓明,张维冰,张丽华,张玉奎. 利用氨甲蝶呤－琼脂糖凝胶进行噬菌体展示人肝脏cDNA文库筛选的方法研究[J]. 中国生物工程杂志, 2007, 27(10): 70-74.
[9] PierreTiollais, 王豪. 乙型肝炎病毒(续)[J]. 中国生物工程杂志, 1987, 7(5): 35-40.
[10] R.D.Palmiter, R.L.Brinster, R.E.Hammer, M.E.Trumbauer, M.G.Rosenfeld, N.C.Birnberg, 戴宗汉. 由显微注射了金属巯基组氨酸三甲内盐—生长激素融合基因的受精卵发育而戍的小鼠生长显著[J]. 中国生物工程杂志, 1984, 4(3): 27-31.
主管：中国科学院 　主办：中国科学院文献情报中心 　中国生物技术发展中心 　中国生物工程学会