Derivation of chemically reprogrammed liver progenitors from adult donors at The University of Edinburgh

Deadline: Monday 27th November 2023, 5pm 

1st Supervisor:   Prof Keisuke Kaji 

About the Project

The liver is the major organ that metabolizes the drug, owing to enzymes predominantly expressed in hepatocytes. It is also the most frequent organ with adverse drug reactions (ADRs), a major cause of drug withdrawal from the market. Thus, fully functional hepatocytes are important for the pharmaceutical industry for toxicology tests. Due to species-specific metabolisms, animal studies can predict only about 70% of human hepatotoxicity, and cannot provide a full prediction of human outcomes. Various hepatic cells have been used for hepatotoxicity tests, including hepatoma cell lines (HepG2, HepaRG, etc) and PSC-derived hepatocyte-like cells (HLCs). However, those cell lines do not have robust expression of many of Cytochromes P450 (CYP) enzymes critical for drug metabolisms and specifically expressed in mature hepatocytes. Thus, the gold standard is still the use of cryopreserved primary human hepatocytes (PHHs). Nevertheless, batch-to-batch variation of PHHs is large, likely affected by various factors including genetic variations, donor ages, disease/treatment histories, etc. This makes standardizing the tests and comparisons among the compounds challenging in the pharmaceutical industry. 

Chemically reprogrammed liver progenitors (CLiPs) are a new type of hepatic cells derived from mature hepatocytes that can propagate and re-differentiated into mature hepatocytes. While previously reported human CLiPs could not maintain their re-differentiation capacity over 5 passages, we have recently developed a novel human CLiP culture condition L3. CLiPs generated from neonatal hepatocytes (10¹²-fold expansion) maintaining their re-differentiation capacity. This can allow the generation of a large amount of CLiP-derived hepatocytes (cHeps) with consistent quality for toxicology tests and drug screening in the industry. 

Nevertheless, there is still space to improve in this CLiP technology. CLiP lines from some donors are unstable and lose their re-differentiation capacity easily. We have also not succeeded in producing CLiP lines from adult hepatocytes. This limits the genetic variation of available CLiP lines and makes the derivation of personalized CLiPs from patients impossible. Interestingly, the lab has preliminary data that the conditioned medium of the stable line stabilizes the differentiation capacity of the unstable line. In this project, we aim to further improve the human CLiP culture condition, and enable robust self-renewal and the derivation of CLiP lines from adult donors, generating and comparing secretome and transcriptome data from currently available stable and unstable CLiP lines. 

Funding Notes

This opportunity is open to UK and international students and provides funding covering stipend and UK level tuition fees. The University of Edinburgh covers the difference between home and international fees meaning that the EASTBIO DTP offers fully-funded studentships to all appointees. Please see full advert description for further funding details.

Applications

Please review the full advert description here for details on the application process.