Could a Bioartificial Liver System Help To Treat Acute Liver Failure?
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Researchers recently reported in Science Translational Medicine the development of a cell-based extracorporeal bioartificial liver system. Findings from the study showed that three hours of treatment with the system helped to reduce inflammation and stimulate hepatocyte regeneration in pigs with acute liver failure.
Technology Networks spoke with one of the study’s authors, Professor Hexin Yan, to find out more about the bioartificial liver and its development, as well as learn about the potential future role the system could play in the treatment of acute liver failure in humans.
Anna MacDonald (AM): What was the motive behind this research?
Hexin Yan (HY): Acute liver failure (ALF) causes severe injury and massive necrosis of hepatocytes, resulting in a mortality rate of up to 80%. Liver transplantation is the only definitive treatment option for patients with ALF, which is limited by donor organ shortage and a lifelong immunosuppressive therapy. Bioartificial liver devices have been developed to bridge patients to liver transplantation or to facilitate liver self-regeneration. The major hindrance in the development of bioartificial liver devices is the lack of expandable human hepatocytes and appropriate bioreactor configuration. To overcome these problems, we developed a novel extracorporeal bioartificial liver embedded with 3D-layered human liver progenitor-like cells derived from human primary hepatocytes.
AM: How were the cells for the bioartificial liver created? How does this differ to other bioartificial livers, and what advantages does this offer?
HY: Prior to our publication, many types of cells are being used in bioartificial livers. Human hepatocytes are the preferred cells for BAL devices, but to obtain sufficient human hepatocytes is impractical due to organ shortage. The hepatoblastoma cells are capable of in vitro expansion and secretion of albumin (ALB), but they lack key hepatic functions like urea production. Reprogrammed hepatocytes derived from human iPS or fibroblasts may have metabolic activity, however, to prepare sufficient and homogenous cells is difficult to achieve. Porcine hepatocytes raise many medical and ethical issues due to the high risk of cross species transmission of infection to humans. It is therefore imperative to seek alternative human cell sources for BAL applications. Here we generated immortalized and functionally enhanced human HepLPCs with both growth potential and physiologic function. These cells provide a novel and optimal cell source for a bioartificial liver.
AM: Why was the bioreactor configuration so important? What challenges did you face in reaching the optimal configuration?
HY: An appropriate bioreactor configuration should allow for mass production of functional hepatocytes. On the other hand, mass and oxygen transfer determine the effectiveness of plasma-perfused devices. For example, the failure of the Vital Therapies device appears to have coincided with a switch from blood perfusion with high oxygen supply to plasma perfusion with very low oxygen supply. To address these issues, we developed an air-liquid interactive bioreactor (Ali-BAL) that provides alternating air-liquid exposure of the cells on macroporous carriers. The expanded hepatocytes organized into 3D clusters and demonstrated the metabolic function. Our cell chamber design overcomes the problems of mass/oxygen transfer that diminish the effectiveness of other BALs.
AM: Can you give us an overview of the main findings from the study?
HY: We developed the techniques to expand liver progenitor-like cells from human hepatocytes with functional properties (protein synthesis and toxin clearance). We then seeded a bioreactor with an air-liquid interface where these liver progenitor-like cells grew into 3D clusters and maintained the metabolic function. The ability of this bioreactor to function as an artificial liver support was tested in a D-gal-induced acute liver failure model. Three-hour plasma perfusion of pigs through the bioreactor prevented hepatic encephalopathy and led to markedly improved survival compared to two control groups that received no treatment or plasma perfusion through an empty bioreactor. The survival and inflammatory markers in the treatment group were also significantly improved compared to the control groups.
AM: In the study, native hepatocyte regeneration was stimulated. What are the implications of this?
HY: It is of note that liver regeneration factors and markers such as HGF and AFP were found to be significantly upregulated with respect to controls, suggesting the importance of early and sustained liver regeneration for survival. As the Ali-BAL bioreactor perfusion not only removed ammonia but supplemented numerous cytokines and growth factors for liver regeneration, we believe that both the timely clearance of detrimental toxins (e.g. ammonia and lactate) and, more importantly, the early liver recovery was responsible for the improved survival. These data together indicate a remarkable therapeutic effect of the Ali-BAL treatment on the ALF porcine model.
AM: What further work needs to be done before the Ali-BAL could become available to liver failure patients?
HY: ALF in humans is more complicated because patients present later and with conditions that are not as readily reversible as toxic injury. Therefore, it is necessary to demonstrate the survival advantage of Ali-BAL treatment in ALF models of other complications such as that induced by surgical procedures. A dose-response relationship study should also be performed to determine the efficacy and safety of Ali-BAL treatment in animal models before moving to clinical studies in humans. That is what we need to do next!
Hexin Yan was speaking to Anna MacDonald, Science Writer for Technology Networks.