Human induced pluripotent stem cells ‐derived liver organoids grown on a Biomimesys® hyaluronic acid‐based hydroscaffold as a new model for studying human lipoprotein metabolism

Meryl Roudaut (1, 2) , Amandine Caillaud (1) , Zied Souguir (2) , Lise Bray (1) , Aurore Girardeau (1) , Antoine Rimbert (1) , Mikaël Croyal (1, 3) , Gilles Lambert (4) , Murielle Patitucci (1) , Gaspard Delpouve (2) , Élodie Vandenhaute (2) , Cédric Le May (1) , Nathalie Maubon (2) , Bertrand Cariou (1) , Karim Si-Tayeb (1)

1 Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, 44000 Nantes, France.
2 HCS Pharma, Lille, France
3 CRNH-Ouest Mass Spectrometry Core Facility, Nantes, France
4 DéTROI - Diabète athérothrombose et thérapies Réunion Océan Indien

Abstract The liver plays a key role in the metabolism of lipoproteins, controlling both production and catabolism. To accelerate the development of new lipid‐lowering therapies in humans, it is essential to have a relevant in vitro study model available. The current hepatocyte‐like cells (HLCs) models derived from hiPSC can be used to model many genetically driven diseases but require further improvement to better recapitulate the complexity of liver functions. Here, we aimed to improve the maturation of HLCs using a three‐dimensional (3D) approach using Biomimesys®, a hyaluronic acid‐based hydroscaffold in which hiPSCs may directly form aggregates and differentiate toward a functional liver organoid model. After a 28‐day differentiation 3D protocol, we showed that many hepatic genes were upregulated in the 3D model (liver organoids) in comparison with the 2D model (HLCs). Liver organoids, grown on Biomimesys®, exhibited an autonomous cell organization, were composed of different cell types and displayed enhanced cytochromes P450 activities compared to HLCs. Regarding the functional capacities of these organoids, we showed that they were able to accumulate lipids (hepatic steatosis), internalize low‐density lipoprotein and secrete apolipoprotein B. Interestingly, we showed for the first time that this model was also able to produce apolipoprotein (a), the apolipoprotein (a) specific of Lp(a). This innovative hiPSC‐derived liver organoid model may serve as a relevant model for studying human lipopoprotein metabolism, including Lp(a).

Mots clés: cytochrome activities hiPSC-derived liver organoids hyaluronic-acid based hydroscaffold lipid metabolism liver steatosis Lp; cytochrome activities; hiPSC-derived liver organoids; hyaluronic-acid based hydroscaffold; lipid metabolism; liver steatosis; Lp

Domaines: Sciences du Vivant [q-bio]

Meryl Roudaut, Amandine Caillaud, Zied Souguir, Lise Bray, Aurore Girardeau, et al.. Human induced pluripotent stem cells ‐derived liver organoids grown on a Biomimesys® hyaluronic acid‐based hydroscaffold as a new model for studying human lipoprotein metabolism. Bioengineering & Translational Medicine, 2024, ⟨10.1002/btm2.10659⟩. ⟨hal-04509118⟩