Transcriptomic Analysis of Hepatic Cells in Multicellular Organotypic Liver Models

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dc.contributor.authorTegge, Allison N.en
dc.contributor.authorRodrigues, Richard R.en
dc.contributor.authorLarkin, Adam L.en
dc.contributor.authorVu, Lucas T.en
dc.contributor.authorMurali, T. M.en
dc.contributor.authorRajagopalan, Padmavathyen
dc.contributor.departmentChemical Engineeringen
dc.contributor.departmentComputer Scienceen
dc.contributor.departmentStatisticsen
dc.contributor.departmentInstitute for Critical Technology and Applied Scienceen
dc.contributor.departmentBiomedical Engineering and Sciencesen
dc.date.accessioned2018-12-11T17:55:44Zen
dc.date.available2018-12-11T17:55:44Zen
dc.date.issued2018-07-27en
dc.description.abstractLiver homeostasis requires the presence of both parenchymal and non-parenchymal cells (NPCs). However, systems biology studies of the liver have primarily focused on hepatocytes. Using an organotypic three-dimensional (3D) hepatic culture, we report the first transcriptomic study of liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs) cultured with hepatocytes. Through computational pathway and interaction network analyses, we demonstrate that hepatocytes, LSECs and KCs have distinct expression profiles and functional characteristics. Our results show that LSECs in the presence of KCs exhibit decreased expression of focal adhesion kinase (FAK) signaling, a pathway linked to LSEC dedifferentiation. We report the novel result that peroxisome proliferator-activated receptor alpha (PPAR alpha) is transcribed in LSECs. The expression of downstream processes corroborates active PPAR alpha signaling in LSECs. We uncover transcriptional evidence in LSECs for a feedback mechanism between PPAR alpha and farnesoid X-activated receptor (FXR) that maintains bile acid homeostasis; previously, this feedback was known occur only in HepG2 cells. We demonstrate that KCs in 3D liver models display expression patterns consistent with an anti-inflammatory phenotype when compared to monocultures. These results highlight the distinct roles of LSECs and KCs in maintaining liver function and emphasize the need for additional mechanistic studies of NPCs in addition to hepatocytes in liver-mimetic microenvironments.en
dc.description.notesGrants from the National Science Foundation (DMR-090750, CBET-0933225, DBI-1062380, DMR-1410341, and CBET-1510920), the National Institutes of Health (F32-ES024062), and the U.S. Environmental Protection Agency (RD-83499801) supported this research.en
dc.description.sponsorshipNational Science Foundation [DMR-090750, CBET-0933225, DBI-1062380, DMR-1410341, CBET-1510920]; National Institutes of Health [F32-ES024062]; U.S. Environmental Protection Agency [RD-83499801]en
dc.format.extent14 pagesen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s41598-018-29455-xen
dc.identifier.issn2045-2322en
dc.identifier.other11306en
dc.identifier.pmid30054499en
dc.identifier.urihttp://hdl.handle.net/10919/86345en
dc.identifier.volume8en
dc.language.isoenen
dc.publisherSpringer Natureen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectsinusoidal endothelial-cellsen
dc.subjectactivated receptor-alphaen
dc.subjectfatty-acid oxidationen
dc.subjectcultured primary hepatocytesen
dc.subjectphenotype in-vitroen
dc.subjectperoxisome-proliferatoren
dc.subjectppar-alphaen
dc.subjectkupffer cellsen
dc.subjectgene-expressionen
dc.subjectbeta-oxidationen
dc.titleTranscriptomic Analysis of Hepatic Cells in Multicellular Organotypic Liver Modelsen
dc.title.serialScientific Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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