BINDER Innovation Prize:
Liver organoids for the study of liver biology and disease
1: Gurdon Institute- University of Cambridge, CB2 1QN Cambridge, United Kingdom
2: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
In vitro 3D cultures are emerging as novel systems to study tissue development, organogenesis and stem cell behavior ex-vivo. In the past 10 years, my lab and I, we have developed organoid cultures from healthy and diseased, human and mouse, adult and embryonic tissues for a range of organs including stomach, liver and pancreas [stomach (Barker & Huch et al., Cell Stem Cell 2010); liver (Huch et al., Nature 2013; Huch et al., Cell 2015; Broutier et al Nat Protoc 2016; Broutier et al., Nat Med 2017; Prior et al., Development 2019) and pancreas (Huch et al., EMBO J 2013)]. These have allowed, for the first time, the long-term expansion of adult (stomach, liver and pancreas) and embryonic (liver) tissue into 3D-epithelial structures that we have termed organoids, since these (1) self-assemble and can be clonally expanded, (2) resemble the corresponding tissues-of-origin and (3) allow the study of some aspects of tissue physiology in a dish.
Here, I will present our liver organoid work and summarize our findings on how this culture system is amenable for disease modeling and as well as its applicability for the study of biological principles in a dish. Briefly, our mouse and human liver organoid culture system enables the long-term expansion of liver cells in vitro (for >1 year). The cells can be converted into functional hepatocytes in vitro and upon transplantation in vivo. The expanded cells are highly stable at the chromosome and genomic structure level, while single base changes occur at very low rates. By modifying the system, we recently established the first human liver cancer organoid culture system for modeling both hepatocellular carcinoma as well as cholangiocarcinoma, and demonstrated its applicability for disease modeling and drug testing. Additionally, we have recently found that our organoid culture system enables the study of some aspects of liver regeneration in a dish, specially the activation of adult differentiated liver ductal cells into bi-potent liver progenitors. Using this liver organoid system we have found that the transition from the differentiated state to an active progenitor state involves a global, yet transient, epigenetic reprogramming where global epigenetic changes are required to activate the progenitor program and successfully establish self-renewing liver organoid cultures.
In summary, clonal long-term expansion of primary cells opens up experimental avenues for disease modeling, toxicology studies, regenerative medicine and gene therapy.