Generation of Hepatic Stellate Cells from Human Pluripotent Stem Cells Enables In Vitro Modeling of Liver Fibrosis

Publication date: Available online 28 June 2018

Source: Cell Stem Cell

Author(s): Mar Coll, Luis Perea, Ruben Boon, Sofia B. Leite, Julia Vallverdú, Inge Mannaerts, Ayla Smout, Adil El Taghdouini, Delia Blaya, Daniel Rodrigo-Torres, Isabel Graupera, Beatriz Aguilar-Bravo, Christophe Chesne, Mustapha Najimi, Etienne Sokal, Juan José Lozano, Leo A. van Grunsven, Catherine M. Verfaillie, Pau Sancho-Bru

Summary

The development of complex in vitro hepatic systems and artificial liver devices has been hampered by the lack of reliable sources for relevant cell types, such as hepatic stellate cells (HSCs). Here we report efficient differentiation of human pluripotent stem cells into HSC-like cells (iPSC-HSCs). iPSC-HSCs closely resemble primary human HSCs at the transcriptional, cellular, and functional levels and possess a gene expression profile intermediate between that of quiescent and activated HSCs. Functional analyses revealed that iPSC-HSCs accumulate retinyl esters in lipid droplets and are activated in response to mediators of wound healing, similar to their in vivo counterparts. When maintained as 3D spheroids with HepaRG hepatocytes, iPSC-HSCs exhibit a quiescent phenotype but mount a fibrogenic response and secrete pro-collagen in response to known stimuli and hepatocyte toxicity. Thus, this protocol provides a robust in vitro system for studying HSC development, modeling liver fibrosis, and drug toxicity screening.

Graphical Abstract

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