TY - JOUR
T1 - Cre-inducible human CD59 mediates rapid cell ablation after intermedilysin administration
AU - Feng, Dechun
AU - Dai, Shen
AU - Liu, Fengming
AU - Ohtake, Yosuke
AU - Zhou, Zhou
AU - Wang, Hua
AU - Zhang, Yonggang
AU - Kearns, Alison
AU - Peng, Xiao
AU - Zhu, Faliang
AU - Hayat, Umar
AU - Li, Man
AU - He, Yong
AU - Xu, Mingjiang
AU - Zhao, Chunling
AU - Cheng, Min
AU - Zhang, Lining
AU - Wang, Hong
AU - Yang, Xiaofeng
AU - Ju, Cynthia
AU - Bryda, Elizabeth C.
AU - Gordon, Jennifer
AU - Khalili, Kamel
AU - Hu, Wenhui
AU - Li, Shuxin
AU - Qin, Xuebin
AU - Gao, Bin
N1 - Publisher Copyright:
© 2016, American Society for Clinical Investigation. All rights reserved.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - Cell ablation is a powerful tool for studying cell lineage and/or function; however, current cell-ablation models have limitations. Intermedilysin (ILY), a cytolytic pore-forming toxin that is secreted by Streptococcus intermedius, lyses human cells exclusively by binding to the human complement regulator CD59 (hCD59), but does not react with CD59 from nonprimates. Here, we took advantage of this feature of ILY and developed a model of conditional and targeted cell ablation by generating floxed STOP-CD59 knockin mice (ihCD59), in which expression of human CD59 only occurs after Cre-mediated recombination. The administration of ILY to ihCD59+ mice crossed with various Cre-driver lines resulted in the rapid and specific ablation of immune, epithelial, or neural cells without off-target effects. ILY had a large pharmacological window, which allowed us to perform dose-dependent studies. Finally, the ILY/ihCD59-mediated cell-ablation method was tested in several disease models to study immune cell functionalities, hepatocyte and/or biliary epithelial damage and regeneration, and neural cell damage. Together, the results of this study demonstrate the utility of the ihCD59 mouse model for studying the effects of cell ablation in specific organ systems in a variety of developmental and disease states.
AB - Cell ablation is a powerful tool for studying cell lineage and/or function; however, current cell-ablation models have limitations. Intermedilysin (ILY), a cytolytic pore-forming toxin that is secreted by Streptococcus intermedius, lyses human cells exclusively by binding to the human complement regulator CD59 (hCD59), but does not react with CD59 from nonprimates. Here, we took advantage of this feature of ILY and developed a model of conditional and targeted cell ablation by generating floxed STOP-CD59 knockin mice (ihCD59), in which expression of human CD59 only occurs after Cre-mediated recombination. The administration of ILY to ihCD59+ mice crossed with various Cre-driver lines resulted in the rapid and specific ablation of immune, epithelial, or neural cells without off-target effects. ILY had a large pharmacological window, which allowed us to perform dose-dependent studies. Finally, the ILY/ihCD59-mediated cell-ablation method was tested in several disease models to study immune cell functionalities, hepatocyte and/or biliary epithelial damage and regeneration, and neural cell damage. Together, the results of this study demonstrate the utility of the ihCD59 mouse model for studying the effects of cell ablation in specific organ systems in a variety of developmental and disease states.
UR - http://www.scopus.com/inward/record.url?scp=84974530576&partnerID=8YFLogxK
U2 - 10.1172/JCI84921
DO - 10.1172/JCI84921
M3 - Article
C2 - 27159394
AN - SCOPUS:84974530576
SN - 0021-9738
VL - 126
SP - 2321
EP - 2333
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 6
ER -