Abstract
Liver disease is an escalating global health issue. While liver transplantation is an effective mode of therapy, patient mortality has increased due to the shortage of donor organs. Developing renewable sources of human liver tissue is therefore attractive. Pluripotent stem cell-derived liver tissue represents a potential alternative to cadaver derived hepatocytes and whole organ transplant. At present, two-dimensional differentiation procedures deliver tissue lacking certain functions and long-term stability. Efforts to overcome these limiting factors have led to the building of three-dimensional (3D) cellular aggregates. Although enabling for the field, their widespread application is limited due to their reliance on variable biological components. Our studies focused on the development of 3D liver tissue under defined conditions. In vitro generated 3D tissues exhibited stable phenotype for over 1 year in culture, providing an attractive resource for long-term in vitro studies. Moreover, 3D derived tissue provided critical liver support in two animal models, including immunocompetent recipients. Therefore, we believe that our study provides stable human tissue to better model liver biology ‘in the dish’, and in the future may permit the support of compromised liver function in humans.
Highlights
The liver performs a wide range of functions essential for body function
Haematoxylin and Eosin staining indicated that the outer layer was 2–3 cells in depth with a dense core that was expelled in most spheroids between days 8 and 10 to form cystic 3D Heps which could be harvested (Day 8a; Fig. 1c)
Mortality associated with end-stage liver disease has increased dramatically over the last 20 years
Summary
The liver performs a wide range of functions essential for body function. Significant loss of liver function has serious consequences for human health (Ebrahimkhani et al 2014). Three-dimensional (3D) approaches have been explored to generate human liver tissue (Szkolnicka and Hay 2016) Those processes employ matrix or scaffold-driven formation of 3D aggregates with or without inclusion of other cell types (Gieseck et al 2014; Takebe et al 2014; Camp et al 2017). Our study demonstrates that functional human liver tissue, derived from pluripotent stem cells, can be stably cultured in vitro for long periods of time and provide liver support in vivo. We believe this resource provides promise for in vitro applications, such as repeated dosing and disease modelling, and in the future may serve as a source of tissue for the clinic
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