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

Stem Cell Reports
John OngS Tamir Rashid

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.

Citations

Mar 7, 2020·Journal of Cellular and Molecular Medicine·Francesca PassarettaRoberta Di Pietro
Jan 27, 2019·SLAS Discovery·Erika WisemanLorenzo Veschini
May 27, 2021·Scientific Reports·Andrea Antonio ElleroTracey Hurrell

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Methods Mentioned

BETA
ELISA
flow cytometry
PCR
HT-Seq
PCA

Software Mentioned

GraphPad Prism
Prism
HT
PhenoLOGIC
Seq
Bowtie2
Random Forest
DESEq2
GraphPad
XLSTAT

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