Project Details
Projekt
NASH livers as a source for hepatic organoids for a bioartificial liver device
Applicant
Dr. Silvana Wilken
Subject Area
General and Visceral Surgery
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 543017646
Treatment of acute liver failure (ALF) remains an interdisciplinary challenge with high mortality. Extracorporeal liver support devices are a promising approach alternative to liver transplantation (LTx). The spheroid reservoir bioartificial liver (SRBAL) is a novel device incorporating hepatic organoids, substituting broader parts of hepatic functions compared to artificial liver devices and showing remarkable results in preclinical trials. To avoid concerns related to xenogeneic cells or cell lines, organoids generated from human hepatocytes represent the most appropriate option considering safety and metabolic aspects. One potential source for human hepatocytes are liver grafts rejected for LTx due to pathologies, a common reason being non-alcoholic steatohepatitis (NASH). In preparation for implementing human NASH hepatocytes in the SRBAL treatment, extended preclinical investigations in an appropriate large animal model are imperative. The objective of the planned project is the functional evaluation of NASH organoids as an appropriate cell source for the SRBAL treatment. This evaluation will be carried out on a porcine model and will take place in three work packages (WPs). In WP1 the progress of NASH based on histological characteristics will be correlated with the duration of NASH-inducing diet. The aim is to define the feeding period needed to generate moderate (30-60%) and severe macrovesicular steatosis (>60%). In WP2 organoids in mono- and coculture conditions (with mesenchymal stem cells (MSCs)) generated from NASH livers will be examined for their functionality (synthetic, metabolic and detoxifying) in in vitro experiments also taking cold ischemia time into account. The aim is to evaluate whether they can reach a comparable hepatic functional capacity to healthy organoids and if the coculture conditions have a functional benefit. In WP3 the suitability and functionality of NASH organoids for SRBAL treatment of ALF will be examined in an in vivo setting in the form of a proof of concept study. In this study a SRBAL loaded with NASH organoids will be used as a treatment in a drug-induced porcine model for ALF. The survival benefit, as well as various blood parameters representing liver function will be evaluated. The findings of the proposed project could potentially pave the way for the implementation of SRBAL treatment in patients with ALF as an alternative to LTx and as a beneficial supplement to standard medical care. This approach could revolutionize the ALF therapy as patients who cannot receive LTx due to organ shortage or contraindications could still be provided with a life-saving therapy and risks of surgery and lifelong immunosuppression would be avoided.
DFG Programme
WBP Fellowship
International Connection
USA
