We are very pleased to announce that Meryl, our first CIFRE PhD student, defended his doctoral thesis last week!
His PhD work was dealing with the use of pluripotent stem cells to study liver diseases. He has also developed an innovative model to obtain liver organoïds in our BIOMIMESYS® product.
Now Meryl is a now a full time study director in HCS Pharma and available to answer your questions.
(1) Shihavuddin, A., Basu, S., Rexhepaj, E. et al. Smooth 2D manifold extraction from 3D image stack. Nat Commun 8, 15554 (2017). https://doi.org/10.1038/ncomms15554
Title : Human induced pluripotent stem cells: an innovative model for the discovery of a new function of PCSK9 and the setup of liver organoids.
Human induced pluripotent stem cell (hiPSC) offer an attractive alternative to study novel functions linked to diseases and to setup innovative models. In this context, we studied a key player of the hepatic cholesterol metabolism regulation, PCSK9. Upon hiPSC differentiation into hepatocyte-like cells, we found an unexpected role of PCSK9 in undifferentiated cells. Using tools such as overexpression, CRISPR/Cas9-mediated gene invalidation, and hiPSC derived from a patient carrying PCSK9 loss of functions mutations, we found a regulatory effect of PCSK9 on the TGFß pathway. This effect is mediated by DACT2, a negative regulator of the TGFßR subunit R1. Through DACT2 modulation by PCSK9, the SMAD2 phosphorylation is impacted, thus hiPSC proliferation.
In parallel, to enhance hepatic cells functions generated from hiPSC, we setup a new simplified procedure to obtain liver organoïdes. hiPSC are cultured in a modified hydroscaffold, BIOMIMESYS®, produced by HCS Pharma in a 96-well format suitable for molecular screening. Our procedure, recapitulating key steps of liver development, allowed us to generate liver organoids including not only hepatocytes but also, biliary-, stellate- and endothelial-cells. Functional characterizations showed enhanced cytochrome activities compared to HLC and excellent pharmacological responses with lipid accumulation upon amiodarone or ethanol treatments and LDL-bodipy uptake upon statin treatments. As our model can be personalized and automatized, if offers a new perspective for high content molecular screening.