{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:23:12Z","timestamp":1790760192148,"version":"4.1.0"},"reference-count":54,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,14]],"date-time":"2020-04-14T00:00:00Z","timestamp":1586822400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Non-alcoholic fatty liver disease affects approximately one billion adults worldwide. Non-alcoholic steatohepatitis (NASH) is a progressive disease and underlies the advancement to liver fibrosis, cirrhosis, and hepatocellular carcinoma, for which there are no FDA-approved drug therapies. We developed a hetero-cellular spheroid system comprised of primary human hepatocytes (PHH) co-cultured with crude fractions of primary human liver non-parenchymal cells (NPC) from several matched or non-matched donors, to identify phenotypes with utility in investigating NASH pathogenesis and drug screening. Co-culture spheroids displayed stable expression of hepatocyte markers (albumin, CYP3A4) with the integration of stellate (vimentin, PDGFR\u03b2), endothelial (vWF, PECAM1), and CD68-positive cells. Several co-culture spheroids developed a fibrotic phenotype either spontaneously, primarily observed in PNPLA3 mutant donors, or after challenge with free fatty acids (FFA), as determined by COL1A1 and \u03b1SMA expression. This phenotype, as well as TGF\u03b21 expression, was attenuated with an ALK5 inhibitor. Furthermore, CYP2E1, which has a strong pro-oxidant effect, was induced by NPCs and FFA. This system was used to evaluate the effects of anti-NASH drug candidates, which inhibited fibrillary deposition following 7 days of exposure. In conclusion, we suggest that this system is suitable for the evaluation of NASH pathogenesis and screening of anti-NASH drug candidates.<\/jats:p>","DOI":"10.3390\/cells9040964","type":"journal-article","created":{"date-parts":[[2020,4,15]],"date-time":"2020-04-15T04:01:46Z","timestamp":1586923306000},"page":"964","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":81,"title":["Human Liver Spheroids as a Model to Study Aetiology and Treatment of Hepatic Fibrosis"],"prefix":"10.3390","volume":"9","author":[{"given":"Tracey","family":"Hurrell","sequence":"first","affiliation":[{"name":"Ingelman-Sundberg Group, Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, 171 65 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vlasia","family":"Kastrinou-Lampou","sequence":"additional","affiliation":[{"name":"Ingelman-Sundberg Group, Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, 171 65 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2797-6962","authenticated-orcid":false,"given":"Achilleas","family":"Fardellas","sequence":"additional","affiliation":[{"name":"Ingelman-Sundberg Group, Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, 171 65 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delilah F. G.","family":"Hendriks","sequence":"additional","affiliation":[{"name":"Ingelman-Sundberg Group, Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, 171 65 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c5sa","family":"Nordling","sequence":"additional","affiliation":[{"name":"Ingelman-Sundberg Group, Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, 171 65 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inger","family":"Johansson","sequence":"additional","affiliation":[{"name":"Ingelman-Sundberg Group, Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, 171 65 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Baze","sequence":"additional","affiliation":[{"name":"KaLy-Cell, 67115 Plobsheim, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Parmentier","sequence":"additional","affiliation":[{"name":"KaLy-Cell, 67115 Plobsheim, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lysiane","family":"Richert","sequence":"additional","affiliation":[{"name":"KaLy-Cell, 67115 Plobsheim, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magnus","family":"Ingelman-Sundberg","sequence":"additional","affiliation":[{"name":"Ingelman-Sundberg Group, Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, 171 65 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.jhep.2004.02.013","article-title":"The spectrum expanded: Cryptogenic cirrhosis and the natural history of non-Alcoholic fatty liver disease","volume":"40","author":"Caldwell","year":"2004","journal-title":"J. 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