MicroRNA-122: a novel hepatocyte-enriched in vitro marker of drug-induced cellular toxicity.
MicroRNA-122: a novel hepatocyte-enriched in vitro marker of drug-induced cellular toxicity.
复制标题
DOI：
10.1093/toxsci/kfu269
复制
发表时间：
2015-03
期刊：
影响因子：
--
通讯作者：
Park BK
中科院分区：
文献类型：
--
作者：
Kia R;Kelly L;Sison-Young RL;Zhang F;Pridgeon CS;Heslop JA;Metcalfe P;Kitteringham NR;Baxter M;Harrison S;Hanley NA;Burke ZD;Storm MP;Welham MJ;Tosh D;Küppers-Munther B;Edsbagge J;Starkey Lewis PJ;Bonner F;Harpur E;Sidaway J;Bowes J;Fenwick SW;Malik H;Goldring CE;Park BK
用于研究药物诱导毒性的新兴肝脏模型包括多能干细胞衍生的肝细胞样细胞（HLC）和复杂的肝细胞-非实质细胞共培养物，以模拟复杂的多细胞相互作用，重现人类肝脏中的生态位环境。然而，目前缺乏区分肝细胞损伤与非肝细胞类型或未成熟分化细胞引起的非特异性细胞毒性所需的肝细胞扰动的特异性标志物，因为体外毒理学研究中常规使用的细胞毒性测定依赖于普遍存在于所有真核细胞类型中的细胞内分子。在这项研究中，我们证明了细胞培养基中的microRNA-122（miR-122）检测可用作肝细胞均质培养物中药物诱导毒性的肝细胞富集体外标志物，以及异质培养物（如各种分化方案和多能干细胞系产生的HLC）中肝细胞毒性的细胞特异性标志物，其中使用通用细胞标记物的常规细胞毒性测定可能不合适。我们表明，miR-122细胞毒性试验的灵敏度与传统的测定乳酸脱氢酶活性和细胞内腺苷三磷酸的试验相似，当应用于具有高水平细胞内miR-122的肝脏模型时，并且可以与其他试验复用。MiR-122作为生物标志物也有可能将体外实验的结果与使用相同测定的体内动物模型和人类样本联系起来，并将临床研究的发现与确定为药物诱导的肝损伤研究开发的体外模型的相关性联系起来。
Emerging hepatic models for the study of drug-induced toxicity include pluripotent stem cell-derived hepatocyte-like cells (HLCs) and complex hepatocyte-non-parenchymal cellular coculture to mimic the complex multicellular interactions that recapitulate the niche environment in the human liver. However, a specific marker of hepatocyte perturbation, required to discriminate hepatocyte damage from non-specific cellular toxicity contributed by non-hepatocyte cell types or immature differentiated cells is currently lacking, as the cytotoxicity assays routinely used in in vitro toxicology research depend on intracellular molecules which are ubiquitously present in all eukaryotic cell types. In this study, we demonstrate that microRNA-122 (miR-122) detection in cell culture media can be used as a hepatocyte-enriched in vitro marker of drug-induced toxicity in homogeneous cultures of hepatic cells, and a cell-specific marker of toxicity of hepatic cells in heterogeneous cultures such as HLCs generated from various differentiation protocols and pluripotent stem cell lines, where conventional cytotoxicity assays using generic cellular markers may not be appropriate. We show that the sensitivity of the miR-122 cytotoxicity assay is similar to conventional assays that measure lactate dehydrogenase activity and intracellular adenosine triphosphate when applied in hepatic models with high levels of intracellular miR-122, and can be multiplexed with other assays. MiR-122 as a biomarker also has the potential to bridge results in in vitro experiments to in vivo animal models and human samples using the same assay, and to link findings from clinical studies in determining the relevance of in vitro models being developed for the study of drug-induced liver injury.
登录
查看更多内容
影响因子：
13.5
作者：
Antoine, Daniel J.;Dear, James W.;Lewis, Philip Starkey;Platt, Vivien;Coyle, Judy;Masson, Moyra;Thanacoody, Ruben H.;Gray, Alasdair J.;Webb, David J.;Moggs, Jonathan G.;Bateman, D. Nicholas;Goldring, Christopher E.;Park, B. Kevin
通讯作者：
Park, B. Kevin
影响因子：
3.7
作者：
Liu, Dong;Fan, Jing;Chen, Huiping
通讯作者：
Chen, Huiping
影响因子：
6.1
作者：
Godoy, Patricio;Hewitt, Nicola J.;Albrecht, Ute;Andersen, Melvin E.;Ansari, Nariman;Bhattacharya, Sudin;Bode, Johannes Georg;Bolleyn, Jennifer;Borner, Christoph;Boettger, Jan;Braeuning, Albert;Budinsky, Robert A.;Burkhardt, Britta;Cameron, Neil R.;Camussi, Giovanni;Cho, Chong-Su;Choi, Yun-Jaie;Rowlands, J. Craig;Dahmen, Uta;Damm, Georg;Dirsch, Olaf;Teresa Donato, Maria;Dong, Jian;Dooley, Steven;Drasdo, Dirk;Eakins, Rowena;Ferreira, Karine Sa;Fonsato, Valentina;Fraczek, Joanna;Gebhardt, Rolf;Gibson, Andrew;Glanemann, Matthias;Goldring, Chris E. P.;Jose Gomez-Lechon, Maria;Groothuis, Geny M. M.;Gustavsson, Lena;Guyot, Christelle;Hallifax, David;Hammad, Seddik;Hayward, Adam;Haeussinger, Dieter;Hellerbrand, Claus;Hewitt, Philip;Hoehme, Stefan;Holzhuetter, Hermann-Georg;Houston, J. Brian;Hrach, Jens;Ito, Kiyomi;Jaeschke, Hartmut;Keitel, Verena;Kelm, Jens M.;Park, B. Kevin;Kordes, Claus;Kullak-Ublick, Gerd A.;LeCluyse, Edward L.;Lu, Peng;Luebke-Wheeler, Jennifer;Lutz, Anna;Maltman, Daniel J.;Matz-Soja, Madlen;McMullen, Patrick;Merfort, Irmgard;Messner, Simon;Meyer, Christoph;Mwinyi, Jessica;Naisbitt, Dean J.;Nussler, Andreas K.;Olinga, Peter;Pampaloni, Francesco;Pi, Jingbo;Pluta, Linda;Przyborski, Stefan A.;Ramachandran, Anup;Rogiers, Vera;Rowe, Cliff;Schelcher, Celine;Schmich, Kathrin;Schwarz, Michael;Singh, Bijay;Stelzer, Ernst H. K.;Stieger, Bruno;Stoeber, Regina;Sugiyama, Yuichi;Tetta, Ciro;Thasler, Wolfgang E.;Vanhaecke, Tamara;Vinken, Mathieu;Weiss, Thomas S.;Widera, Agata;Woods, Courtney G.;Xu, Jinghai James;Yarborough, Kathy M.;Hengstler, Jan G.
通讯作者：
Hengstler, Jan G.
影响因子：
4.1
作者：
Brolen, Gabriella;Sivertsson, Louise;Heins, Nico
通讯作者：
Heins, Nico
影响因子：
5.2
作者：
Hay, David C.;Zhao, Debiao;Cui, Wei
通讯作者：
Cui, Wei