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

Here, the authors show that extracellular niche factors likely play a critical role in bridging this gap in functional differences between hepatocytes derived from induced pluripotent stem cells (i-Heps) and primary cells. They defined a profile of healthy, freshly isolated primary hepatocytes (Hepatocyte Likeness Index; HLI) that cells of interest can be compared against for high-throughput screening. They applied this platform to screen hepatocyte niche factors for their ability to drive i-Heps closer to that target and validated their findings in a pharma-like screening environment. The HLI was applied in a targeted screen of extracellular niche factors to identify substrates driving i-Heps closer to the standard. Results from the screen performed highlighted the important role played by laminins where laminin 411 was identified as a key niche protein. Laminin 411 is a component of the hepatic niche. Laminin 411 advanced i-Heps toward functional significance and prolonged survival of hepatic progenitor cells, contributing to better i-Hep-based drug-screening applications. This paper underscores the importance of combining substrates, soluble factors, and HCA when developing iPSC applications.