Regenerative medicine applications of cholangiocyte organoids

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Transplantation remains the only treatment for all end-stage diseases; but it is limited by organ availability. Regenerative medicine could provide a therapeutic alternative, using cells or lab-grown artificial tissue to regenerate or replace damaged organs. This approach is particularly relevant in bile duct diseases, which are a leading cause for liver transplantation in children and adults with no other treatment. The bile ducts are tubes transferring a toxic digestive fluid, called bile, from the liver to the intestine. In disease, bile ducts break down and bile damages surrounding tissue causing liver failure. To repair this damage, I grew human duct cells in the lab, in 3D structures called organoids. I then made artificial ducts from my organoids, transplanted them in mice and showed their therapeutic potential. My goal is to progress regenerative medicine using organoids to first-in-man studies. I will first focus on biliary disease, but the technology and know-how developed will be highly transferable to other organs. To achieve this, I will address three main challenges. 1. Optimise organoids grown in the lab for human transplantationTransplanted cells should match the tissue they are replacing and meet regulatory standards. I will collaborate with Bilitech LTD and the UK Cell and Gene Therapy Catapult (CGTC) to generate organoids complying with requirements for human transplantation. I will compare these organoids to human bile ducts with a high-resolution method called Single Cell RNA sequencing and use this information to further improve my cells and minimize differences. 2. Develop organoid transplantation techniques tailored to different disease indicationsCertain diseases may affect too many and too small bile ducts to be amenable to surgical correction with artificial tissue. However, these small branches may be reached and regenerated by organoids injected directly in the ducts, providing a valuable therapeutic alternative to lab-grown tissue. To establish the safety and efficacy of this approach, I will attempt to rescue small animal models of widespread duct damage using organoid injection.3. Validate the safety and efficacy of my organoids in large animal models and ex-vivo human organsOrganoids can't be transplanted in human organs outside clinical trials, and large animal experiments are a pre-requisite for such studies. In the context of a UKRI feasibility award with Bilitech LTD and CGTC, I have upscaled my artificial bile ducts from mouse to human size. I will transplant these artificial ducts in adult pigs and follow up the animals for 6 months to demonstrate safety and efficacy. In parallel, I will explore the cells' capacity to engraft in human organs using a new system I developed. I will capture liver grafts not used for transplantation, maintain them outside the body (ex-vivo) by circulating oxygenated blood through the liver, and inject my organoids in these organs to repair their bile ducts. This work will advance regenerative medicine using organoids from proof-of-principle to first-in-human studies, which is in direct alignment with the UK strategy on Regenerative Medicine (Regenerative Medicine Expert Group report). It will address a pressing clinical need; provide an alternative to liver transplantation, which is the only treatment for bile ducts disorders; and reduce pressure on the transplantation program benefiting all other liver diseases. It will generate transferrable outputs impacting on broader fields, such as tissue engineering, organoid biology and bioinformatics, which can instruct my future research. The collaboration with Bilitech LTD and CGTC will forge ties between academia and industry. The expertise and technology developed will be applicable to other tissues and organs and will make a significant contribution to UK regenerative and medicines manufacturing know-how.