A familial hypercholesterolemia human liver chimeric mouse model using induced pluripotent stem cell-derived hepatocytes
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AbstractFamilial hypercholesterolemia (FH) is mostly caused by low-density lipoprotein receptor (LDLR) mutations and results in an increased risk of early-onset cardiovascular disease due to marked elevation of LDL cholesterol (LDL-C) in blood. Statins are the first line of lipid-lowering drugs for treating FH and other types of hypercholesterolemia, but new approaches are emerging, in particular PCSK9 antibodies, which are now being tested in clinical trials. To explore novel therapeutic approaches for FH, either new drugs or new formulations, we need appropriate in vivo models. However, differences in the lipid metabolic profiles compared to humans are a key problem of the available animal models of FH. To address this issue, we have generated a human liver chimeric mouse model using FH induced pluripotent stem cell (iPSC)-derived hepatocytes (iHeps). We used Ldlr-/-/Rag2-/-/Il2rg-/- (LRG) mice to avoid immune rejection of transplanted human cells and to assess the effect of LDLR-deficient iHeps in an LDLR null background. Transplanted FH iHeps could repopulate 5-10% of the LRG mouse liver based on human albumin staining. Moreover, the engrafted iHeps responded to lipid-lowering drugs and recapitulated clinical observations of increased efficacy of PCSK9 antibodies compared to statins. Our human liver chimeric model could thus be useful for preclinical testing of new therapies to FH. Using the same protocol, similar human liver chimeric mice for other FH genetic variants, or mutations corresponding to other inherited liver diseases, may also be generated.
All Author(s) ListJiayin YANG, Lai-Yung WONG, Xiao-Yu TIAN, Rui WEI, Wing-Hon LAI, Ka-Wing AU, Zhiwei LUO, Carl WARD, Wai-In HO, David P. IBANEZ, Hao LIU, Xichen BAO, Baoming QIN, Yu HUANG, Miguel A. ESTEBAN, Hung-Fat TSE
Journal nameJournal of Visualized Experiments
Year2018
Month9
Volume Number2018
Issue Number139
PublisherJournal of Visualized Experiments
Article numbere57556
ISSN1940-087X
LanguagesEnglish-United Kingdom
KeywordsHuman liver chimeric mice, Hepatocytes, Familial hypercholesterolemia, Developmental biology, Pcsk9 antibodies, Ldl-receptor, Issue 139, Induced pluripotent stem cells, Statins

Last updated on 2020-26-03 at 02:31