Cholesterol-Secreting and Statin-Responsive Hepatocytes from Human ES and iPS Cells to Model Hepatic Involvement in Cardiovascular Health.docVIP

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Cholesterol-Secreting and Statin-Responsive Hepatocytes from Human ES and iPS Cells to Model Hepatic Involvement in Cardiovascular Health.doc

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Cholesterol-Secreting and Statin-Responsive Hepatocytes from Human ES and iPS Cells to Model Hepatic Involvement in Cardiovascular Health

Cholesterol-SecretingandStatin-Responsive HepatocytesfromHumanESandiPSCellstoModel HepaticInvolvementinCardiovascularHealth WinfriedH.Krueger1,2*,BorkoTanasijevic1,2,VanessaBarber1,AnthonyFlamier1,XinshengGu1, JoseManautou1,TheodoreP.Rasmussen1,2,3 1Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut, United States of America, 2University of Connecticut Stem Cell Institute, Farmington,Connecticut,UnitedStatesofAmerica,3DepartmentofMolecularandCellBiology,UniversityofConnecticut,Storrs,Connecticut,UnitedStatesofAmerica Abstract Hepatocytes play a central and crucial role in cholesterol and lipid homeostasis, and their proper function is of key importanceforcardiovascularhealth.Inparticular,hepatocytes(especiallyperiportalhepatocytes)endogenouslysynthesize large amounts of cholesterol and secrete it into circulating blood via apolipoprotein particles. Cholesterol-secreting hepatocytesarealsotheclinically-relevantcellstargetedbystatintreatmentinvivo.Thestudyofcholesterolhomeostasisis largely restricted to the use of animal models and immortalized cell lines that do not recapitulate those key aspects of normalhumanhepatocytefunctionthatresultfromgeneticvariationofindividualswithinapopulation.Hepatocyte-like cells(HLCs)derivedfromhumanembryonicandinducedpluripotentstemcellscanprovide acellculturemodelforthe study of cholesterol homeostasis, dyslipidemias, the action of statins and other pharmaceuticals important for cardiovascularhealth.Wehaveanalyzedexpressionofcorecomponentsforcholesterolhomeostasisinuntreatedhuman iPS cells and in response to pravastatin. Here we show the production of differentiated cells resembling periportal hepatocytesfromhumanpluripotentstemcells.Thesecellsexpressabroadrangeofapolipoproteinsrequiredforsecretion and elimination of serum cholesterol, actively secrete cholesterol into the medium, and respond functionally to statin treatmentbyreducedcholesterolsecretion.OurresearchshowsthatHLCsderivedfromh