Stem cell-derived polarized hepatocytes

Viet Loan Dao Thi (), Xianfang Wu (), Rachel L. Belote, Ursula Andreo, Constantin N. Takacs, Joseph P. Fernandez, Luis Andre Vale-Silva, Sarah Prallet, Charlotte C. Decker, Rebecca M. Fu, Bingqian Qu, Kunihiro Uryu, Henrik Molina, Mohsan Saeed, Eike Steinmann, Stephan Urban, Roshni R. Singaraja, William M. Schneider, Sanford M. Simon and Charles M. Rice ()
Additional contact information
Viet Loan Dao Thi: The Rockefeller University
Xianfang Wu: The Rockefeller University
Rachel L. Belote: The Rockefeller University
Ursula Andreo: The Rockefeller University
Constantin N. Takacs: The Rockefeller University
Joseph P. Fernandez: The Rockefeller University
Luis Andre Vale-Silva: New York University
Sarah Prallet: The Rockefeller University
Charlotte C. Decker: Cluster of Excellence CellNetworks
Rebecca M. Fu: Cluster of Excellence CellNetworks
Bingqian Qu: Cluster of Excellence CellNetworks
Kunihiro Uryu: The Rockefeller University
Henrik Molina: The Rockefeller University
Mohsan Saeed: The Rockefeller University
Eike Steinmann: Ruhr-University Bochum
Stephan Urban: Cluster of Excellence CellNetworks
Roshni R. Singaraja: National University of Singapore
William M. Schneider: The Rockefeller University
Sanford M. Simon: The Rockefeller University
Charles M. Rice: The Rockefeller University

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-15337-2

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