Stem cell-derived polarized hepatocytes.
Antiviral Agents
/ pharmacology
Cell Culture Techniques
/ methods
Cell Differentiation
Cell Polarity
Cells, Cultured
Drug Evaluation, Preclinical
/ methods
Drug Interactions
Hepatitis A Virus, Human
/ physiology
Hepatitis E virus
/ physiology
Hepatocytes
/ physiology
Humans
Induced Pluripotent Stem Cells
/ physiology
Liver
/ cytology
Membrane Transport Proteins
/ metabolism
Microscopy, Electron, Transmission
Proof of Concept Study
Virion
/ metabolism
Virus Release
Virus Replication
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
03 04 2020
03 04 2020
Historique:
received:
09
01
2019
accepted:
03
03
2020
entrez:
5
4
2020
pubmed:
5
4
2020
medline:
1
8
2020
Statut:
epublish
Résumé
Human stem cell-derived hepatocyte-like cells (HLCs) offer an attractive platform to study liver biology. Despite their numerous advantages, HLCs lack critical in vivo characteristics, including cell polarity. Here, we report a stem cell differentiation protocol that uses transwell filters to generate columnar polarized HLCs with clearly defined basolateral and apical membranes separated by tight junctions. We show that polarized HLCs secrete cargo directionally: Albumin, urea, and lipoproteins are secreted basolaterally, whereas bile acids are secreted apically. Further, we show that enterically transmitted hepatitis E virus (HEV) progeny particles are secreted basolaterally as quasi-enveloped particles and apically as naked virions, recapitulating essential steps of the natural infectious cycle in vivo. We also provide proof-of-concept that polarized HLCs can be used for pharmacokinetic and drug-drug interaction studies. This novel system provides a powerful tool to study hepatocyte biology, disease mechanisms, genetic variation, and drug metabolism in a more physiologically relevant setting.
Identifiants
pubmed: 32245952
doi: 10.1038/s41467-020-15337-2
pii: 10.1038/s41467-020-15337-2
pmc: PMC7125181
doi:
Substances chimiques
Antiviral Agents
0
Membrane Transport Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1677Subventions
Organisme : NIAID NIH HHS
ID : K99 AI141742
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA243126
Pays : United States
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