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Stem Cell Reports. 2018 Mar 13;10(3):693-702. doi: 10.1016/j.stemcr.2018.01.025. Epub 2018 Mar 1.

Imaging-Based Screen Identifies Laminin 411 as a Physiologically Relevant Niche Factor with Importance for i-Hep Applications.

Author information

1
Centre for Stem Cells and Regenerative Medicine & Institute for Liver Studies, King's College London, London SE1 9RT, UK.
2
The Gurdon Institute Imaging Facility, Cambridge University, Cambridge CB2 1QN, UK.
3
Target Discovery Institute, Oxford University, Oxford OX3 7FZ, UK.
4
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
5
Perkin Elmer, Houston, TX 77055, USA.
6
Centre for Stem Cells and Regenerative Medicine & Institute for Liver Studies, King's College London, London SE1 9RT, UK; The Gurdon Institute Imaging Facility, Cambridge University, Cambridge CB2 1QN, UK. Electronic address: tamir.rashid@kcl.ac.uk.

Abstract

Use of hepatocytes derived from induced pluripotent stem cells (i-Heps) is limited by their functional differences in comparison with primary cells. Extracellular niche factors likely play a critical role in bridging this gap. Using image-based characterization (high content analysis; HCA) of freshly isolated hepatocytes from 17 human donors, we devised and validated an algorithm (Hepatocyte Likeness Index; HLI) for comparing the hepatic properties of cells against a physiological gold standard. The HLI was then applied in a targeted screen of extracellular niche factors to identify substrates driving i-Heps closer to the standard. Laminin 411, the top hit, was validated in two additional induced pluripotent stem cell (iPSC) lines, primary tissue, and an in vitro model of α1-antitrypsin deficiency. Cumulatively, these data provide a reference method to control and screen for i-Hep differentiation, identify Laminin 411 as a key niche protein, and underscore the importance of combining substrates, soluble factors, and HCA when developing iPSC applications.

KEYWORDS:

disease modeling; extracellular niche; iPS hepatocytes; image-based screening; laminin

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