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RGD density along with substrate stiffness regulate hPSC hepatocyte functionality through YAP signalling.

Samuel J I Blackford1, Tracy T L Yu2, Michael D A Norman2

  • 1Department of Metabolism, Digestion and Reproduction, Imperial College London, UK; Centre for Craniofacial & Regenerative Biology, King's College London, UK; Centre for Gene Therapy & Regenerative Medicine, King's College London, UK; NIHR Imperial BRC iPSC and Organoid Core Facility, Imperial College London, UK.

Biomaterials
|January 14, 2023
PubMed
Summary
This summary is machine-generated.

Replicating liver niche cues with synthetic hydrogels improved human pluripotent stem cell-derived hepatocyte (hPSC-Hep) functionality. Controlling substrate stiffness and RGD peptide concentration optimized metabolic activity and differentiation, revealing YAP/TAZ mechanosensing

Keywords:
HepatocyteHydrogelInduced pluripotent stem cellMechano sensingYAP

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Area of Science:

  • Hepatology
  • Stem Cell Biology
  • Biomaterials Science

Background:

  • Human pluripotent stem cell-derived hepatocytes (hPSC-Heps) show promise for liver disease treatment but often lack adult-like functionality.
  • Current differentiation protocols struggle to replicate the complex liver niche environment, hindering the development of metabolically functional hPSC-Heps.

Purpose of the Study:

  • To investigate how biochemical and biophysical cues of the liver niche influence hPSC-Hep differentiation and function.
  • To develop a synthetic hydrogel platform for precisely controlling niche properties and optimizing hPSC-Hep maturation.

Main Methods:

  • Utilized 2D and 3D synthetic hydrogels to independently control mechanical stiffness and RGD peptide concentration.
  • Cultured hPSC-Heps on substrates mimicking healthy and fibrotic liver stiffness.
  • Manipulated YAP/TAZ activity using small molecules (verteporfin, forskolin) and genetic knockdown (ITGB1).
  • Assessed hepatic functionality through gene expression (integrins, YAP/TAZ targets), cytochrome P450 activity, ureagenesis, and alpha-fetoprotein secretion.

Main Results:

  • Culturing hPSC-Heps on stiff, fibrotic-like hydrogels upregulated integrin and YAP/TAZ signaling.
  • Soft, healthy liver-like substrates enhanced cytochrome P450 activity and ureagenesis.
  • Modulating RGD concentration and YAP/TAZ activity differentially impacted metabolic function based on substrate stiffness.
  • 3D encapsulation in hydrogels reduced fetal alpha-fetoprotein secretion, indicating improved differentiation compared to 2D cultures.

Conclusions:

  • Synthetic hydrogels can effectively replicate liver niche cues to enhance hPSC-Hep differentiation and metabolic function.
  • YAP/TAZ-mediated mechanosensing plays a critical role in hPSC-Hep response to substrate stiffness.
  • This platform offers a powerful tool for studying liver development and optimizing cell-based therapies for liver diseases.