File Download
  Links for fulltext
     (May Require Subscription)
Supplementary

Article: A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes

TitleA Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Authors
KeywordsDevelopmental biology
Familial hypercholesterolemia
Hepatocytes
Human liver chimeric mice
Induced pluripotent stem cells
Issue Date2018
PublisherJournal of Visualized Experiments. The Journal's web site is located at http://www.jove.com
Citation
Journal of Visualized Experiments, 2018, v. 15 n. 139, p. article no. 57556 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/294106
ISSN
2020 Impact Factor: 1.355
2020 SCImago Journal Rankings: 0.596
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYANG, J-
dc.contributor.authorWong, LY-
dc.contributor.authorTian, XY-
dc.contributor.authorWEI, R-
dc.contributor.authorLai, KW-
dc.contributor.authorAu, KW-
dc.contributor.authorLuo, Z-
dc.contributor.authorWard, C-
dc.contributor.authorHo, WI-
dc.contributor.authorIbanez, DP-
dc.contributor.authorLIU, H-
dc.contributor.authorBao, X-
dc.contributor.authorQin, B-
dc.contributor.authorHuang, Y-
dc.contributor.authorEsteban, MA-
dc.contributor.authorTse, HF-
dc.date.accessioned2020-11-23T08:26:24Z-
dc.date.available2020-11-23T08:26:24Z-
dc.date.issued2018-
dc.identifier.citationJournal of Visualized Experiments, 2018, v. 15 n. 139, p. article no. 57556-
dc.identifier.issn1940-087X-
dc.identifier.urihttp://hdl.handle.net/10722/294106-
dc.description.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.-
dc.languageeng-
dc.publisherJournal of Visualized Experiments. The Journal's web site is located at http://www.jove.com-
dc.relation.ispartofJournal of Visualized Experiments-
dc.rightsJournal of Visualized Experiments. Copyright © Journal of Visualized Experiments.-
dc.subjectDevelopmental biology-
dc.subjectFamilial hypercholesterolemia-
dc.subjectHepatocytes-
dc.subjectHuman liver chimeric mice-
dc.subjectInduced pluripotent stem cells-
dc.titleA Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes-
dc.typeArticle-
dc.identifier.emailLai, KW: kwhlai@hku.hk-
dc.identifier.emailAu, KW: aukawing@hku.hk-
dc.identifier.emailTse, HF: hftse@hkucc.hku.hk-
dc.identifier.authorityTse, HF=rp00428-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.3791/57556-
dc.identifier.pmid30272645-
dc.identifier.pmcidPMC6235199-
dc.identifier.scopuseid_2-s2.0-85054377819-
dc.identifier.hkuros319724-
dc.identifier.volume15-
dc.identifier.issue139-
dc.identifier.spagearticle no. 57556-
dc.identifier.epagearticle no. 57556-
dc.identifier.isiWOS:000456210900032-
dc.publisher.placeUnited States-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats