Three-dimensional bioprinted liver tissue for transplantation: hope or hype?

HepatoBiliary Surg Nutr 2020;9(6):788-790 | http://dx.doi. org/10.21037/hbsn-20-549 Liver transplantation is one of the best available choices for those with end-stage liver diseases and liver cancer who meet Milan criteria (1,2). However, a critical shortage of available liver donors is the main problem associated with transplantation, which presumably cannot be solved in the foreseeable future. Various effects have been made in the last few decades to compensate for this shortage, including developing different kinds of artificial liver support systems (3). Unfortunately, it is still far away from meeting the demand. Recently, there are achievements in three-dimensional (3D) bioprinting of organs with multiple functions in vitro that might lighten up the hope of future implantable artificial organs, including the liver. We believe the closest try could be a recent fascinating work by Yang et al. published in the journal “Gut” with the title of “three-dimensional bioprinted hepatorganoids prolong survival of mice with liver failure” (4). The authors described a new liver tissue model constructed by 3D bioprinting of HepaRG cells. They give this 3D printed liver a special name of “Hepatorganoids” ( 3 D P H O s ) . F u r t h e r, 3 D P H O s w a s a c t u a l l y transplanted into animal models with liver failure (5), which significantly prolonged the survival. This study is, to the best of our knowledge, the current most interesting and far front research in this field. There are at least several intriguing establishments and findings on this 3DPHOs. First, HepaRG cells were managed to differentiate into hepatocytes with the full ability of regeneration in the study. After 7 days of dimethyl sulfoxide (DMSO) induction, HepaRG cells in the 3DP-HOs frame could stably differentiate into hepatocytes, and in the mean time, carried out almost all the liver functions. The liver function-related proteins, such as albumin, multidrugresistance-associated protein 2, and CYP3A4, are markedly higher in 3DP-HOs than that in 2D cultures. The cells with 3D structure showed the capability of accumulating glycogen, uptaking and releasing indocyanine green, which are unique features of the normal liver cells. Though the inherent mechanism is not clear at the moment, it surely deserves further in-depth investigations in this field. Second, as the most important implication of the study, 3DP-HOs manifests as human liver functional units inside the abdomen of mice. After the transplantation of 3DPHOs into the abdominal cavities of F/R mice, which represent a well-established liver failure model (5), the mice acquired human-specific drug metabolism activities and can respond to certain inducers, such as sodium phenobarbital, and showed increased activities of CYP1A2 or CYP3A4 at the levels that are comparable to those of primary human hepatocytes. Exposing F/R mice transplanted with 3DP-HOs to debrisoquine, the production of humanspecific metabolite 4-hydroxydebrisoquine (4-OH-DEB) is significantly elevated. This is a clear message that 3DPHOs manifested as human liver functional units after being transplanted into mice. Third, a very interesting finding of this study is the vascularization growing into 3DP-HOs after transplantation. 3DP-HOs transplants started becoming neovascularized at day 14 after the transplantation, which can be clearly visualized 4 weeks after the transplantation. Last but not least, 3DP-HOs transplants prolonged the survival duration of the liver Editorial