Our goal is to realize new strategies of regenerative medicine for untreatable liver diseases based on transplantation of human biliary tree stem cells (hBTSCs). The central part of the project is a controlled, randomized clinical trial (RCT) in which we will evaluate feasibility, safety and efficacy of a protocol of cell therapy based on transplantation, via hepatic artery infusion, of freshly isolated hBTSCs into patients with advanced liver cirrhosis. In parallel with the RCT, and to improve the benefits of hBTSC transplantation, we propose preclinical studies aimed to: i) assess if cryopreserved hBTSCs are also effective; ii)improve liver engraftment of transplanted cells; iv) identify additional subpopulations of biliary tree stem cells suitable for clinical programs. The project, presented at the call H2020-PHC-2015-single-stage_RTD (Funding scheme: Research and Innovation action, Proposal number: 681011, Activity: PHC-15-2015) received an evaluation of excellence (Total score: 12.00 (Threshold: 12). As part of the project presented at H2020-PHC-2015, the specific objectives of this application are: Clinical studies: to start the clinical trial aimed to demonstrate that administration via hepatic artery of hBTSCs in patients with advanced cirrhosis is feasible, safe and determines a clinically relevant improvement of liver function. Pre-clinical studies: specific objectives: 1. to assess serum-free, defined cryopreservation conditions for fetal hBTSCs with the final purpose to generate a cell bank helping the treatment of patients, the distribution and commercialization of the cell product. 2. to identify new human tissues as sources of cells similar to hBTSCs. To this purpose we have preliminary data showing how Brunner glands in the duodenal wall (peri-ampullar region) contain cells with similar phenopypic and genotypic traits with respect to hBTSCs. Positive results could give us an additional cell source to be used for the cell therapy of liver diseases.