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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Ong, John 
Serra, Maria Paola 
Segal, Joe 
Cujba, Ana-Maria 
Ng, Soon Seng 

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.

Description

Keywords

disease modeling, extracellular niche, iPS hepatocytes, image-based screening, laminin, Adolescent, Adult, Cell Differentiation, Female, Hepatocytes, Humans, Induced Pluripotent Stem Cells, Laminin, Liver, Male, alpha 1-Antitrypsin

Journal Title

Stem Cell Reports

Conference Name

Journal ISSN

2213-6711
2213-6711

Volume Title

10

Publisher

Elsevier BV