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We previously showed that human pluripotent stem cells (hiPSCs) provide a suitable model to study
metabolic diseases upon hepatocyte-like cell (HLC) differentiation. With a non-invasive approach, hiPSCs can be generated from urine samples of patients and HLCs have been used to model cholesterol metabolism regulation, by the study of LDLR- and PCSK9-mediated autosomal dominant hypercholesterolemia (ADH) as well as PCSK9-mediated familial hypobetalipoproteinemia (FHBL). This model provides promising advantages with a direct link to the patient and with an unlimited source of HLCs. But like all models, there are limitations, mainly by the neonatal characteristic of HLCs lead to difficulties for pharmacological investigations.

Therefore, to overcome these burdens, we chose to 1. Differentiate hiPSCs into HLCs in an innovative
3D hyaluronic acid-based hydroscaffold, BIOMIMESYS® produces by HCS Pharma to enhance their maturation. 2. Adapt our 3D differentiation process to a 96-well format to make it compatible for drug screening. 3. Characterization of the 3D HLCs model by metabolism tests and compare to primary human hepatocyte (PHH).

We gathered 3’ SRP data all along the differentiation process and RNAseq has been performed by comparing 2D and 3D differentiation conditions to characterize hiPSCs differentiation into liver organoids. We observed an enhanced expression of most hepatic genes and genes expressed by non-parenchymal cells such as stellate cells. Immunofluorescence data confirmed the co-localization of albumin-positive
hepatocytes, desmin-positive stellate cells and LYVE1-positive endothelial cells in liver organoids. Finally, at a functional level, several CYP activities including CYP3A4 were detected at the basal level and successfully induced. Liver organoids responded to pharmacological treatments as shown by their ability to accumulate lipids upon amiodarone treatment or uptake LDL-bodipy upon statin treatment.

Altogether, our development gave rise to functional liver organoids generated with a unique and common procedure, in a process of automating for future high throughput screening.


Grégory MAUBON

Grégory MAUBON is Chief Data Officer and digital coordinator at HCS Pharma, a biotech startup focused in high content screening and complex diseases. He manages IT missions and leads digital usages linked to company needs. He is also a Augmented Reality Evangelist (presenter and lecturer) since 2008, where he created www.augmented-reality.fr and founded in 2010 RA'pro (the augmented reality promotion association). He helped many companies (in several domains) to define precisely their augmented reality needs and supported them in the implementation.

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