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RGD density along with substrate stiffness regulate hPSC hepatocyte functionality through YAP signalling by Samuel J.I. Blackford; Tracy T.L. Yu; Michael D.A. Norman; Adam M. Syanda; Michail Manolakakis; Dariusz Lachowski; Ziqian Yan; Yunzhe Guo; Elena Garitta; Federica Riccio; Geraldine M. Jowett; Soon Seng Ng; Santiago Vernia; Armando E. del Río Hernández; Eileen Gentleman; S. Tamir Rashid is a Engineering article available to read on EtoBox.

What is RGD density along with substrate stiffness regulate hPSC hepatocyte functionality through YAP signalling about?

Human pluripotent stem cell-derived hepatocytes (hPSC-Heps) may be suitable for treating liver diseases, but differentiation protocols often fail to yield adult-like cells. We hypothesised that replicating healthy liver niche biochemical and biophysical cues would produce hepatocytes with desired metabolic functionality. Using 2D synthetic hydrogels which independently control mechanical properties and biochemical cues, we found that culturing hPSC-Heps on surfaces matching the stiffness of fibrotic liver tissue upregulated expression of genes for RGD-binding integrins, and increased expression of YAP/TAZ and their transcriptional targets. Alternatively, culture on soft, healthy liver-like substrates drove increases in cytochrome p450 activity and ureagenesis. Knockdown of ITGB1 or reducing RGD-motif-containing peptide concentration in stiff hydrogels reduced YAP activity and improved metabolic functionality; however, on soft substrates, reducing RGD concentration had the opposite effect. Furthermore, targeting YAP activity with verteporfin or forskolin increased cytochrome p450 activity, with forskolin dramatically enhancing urea synthesis. hPSC-Heps could also be successfully enc

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Author

Samuel J.I. Blackford; Tracy T.L. Yu; Michael D.A. Norman; Adam M. Syanda; Michail Manolakakis; Dariusz Lachowski; Ziqian Yan; Yunzhe Guo; Elena Garitta; Federica Riccio; Geraldine M. Jowett; Soon Seng Ng; Santiago Vernia; Armando E. del Río Hernández; Eileen Gentleman; S. Tamir Rashid

Publisher

Elsevier BV

Published

2023

Language

EN

Field

Engineering (Physical Sciences)