Defining the regenerative capacity of ductular cells from non-transplantable human liver

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Liver disease killed 16,087 people in the UK in 2008, and causes 1 in 50 deaths in Scotland. Although a liver transplant is curative for these patients, a global shortage of donor organs means that many patients die waiting for suitable liver. Development of renewable therapeutic alternatives to whole organ transplants is imperative to alleviate this clinical shortage. Because of this clinical need a cellular treatment strategy would be highly attractive. Hepatocyte transplantation has successfully been used to: help keep patients alive who are waiting for whole liver transplantation; support pediatric patients in acute liver failure and correct metabolic liver disease. However, hepatocytes are not readily obtained and are usually sourced from discarded livers not suitable for transplantation. These livers are either significantly fatty or have undergone prolonged ischaemia (time without blood flow). These liver's cells are damaged and therefore high quality hepatocytes are difficult to obtain from such discarded livers. Furthermore it is not possible to expand the numbers of hepatocytes in the laboratory. An alternative source of transplantable cells for either biliary or hepatocyte regeneration would be a significant healthcare advance.We have previously shown in the mouse that cells in liver called ductal cells or hepatic progenitor cells (HPCs) can act like stem cells and regenerate bile ducts and hepatocytes when the liver is severely damaged. Ductal cells/HPCs can be readily frozen and thawed without damage and then grown in the laboratory increasing the numbers of cells. We now aim to develop human ductal cells/HPCs for cell therapy with the eventual aim of developing a new type of cell therapy for liver patients. We aim to isolate these cells from livers that are too damaged to transplant whole.Potential donor organs are increasingly undergoing normothermic perfusion prior to potential whole organ transplantation. For those livers deemed unsuitable for transplantation or where for logistical reasons the transplantation cannot proceed we will move seemlessly to efficient cell isolation of biliary ductal cells. Putative bipotential HPCs will be purified using the clinical cell sorter. These cells can be expanded and frozen/defrosted prior to use as a clinical cell therapy. Over the course of the grant (48 months) we will: 1. Optimise the isolation and cell culture of ductular cells/HPCs from non-transplantable human livers.2. Test the ability of HPCs to regenerate bile ducts +/- hepatocytes in mouse models. We need to know if the human cells are bipotential (regenerate bile ducts and hepatocytes) like the mouse ductular/HPC cells we described or are limited to bile duct regeneration alone. This result would guide future potential clinical conditions that the cells could be used for.3. Develop protocols to isolate, purify and expand ductular/HPCs in a GMP compatible (suitable for use in man) manner as a potential clinical cell product.4. Assess long term stability and safety of the transplanted ductular/HPCs. 5. If the above components are successful we will apply for MHRA (Medicines and Healthcare products Regulatory Agency) approval. This would pave the way for a fist in human clinical trial of ductular/HPC cell therapy. The above results would guide the clinical target to conditions requiring biliary or hepatocyte regeneration.