Bioartificial livers in vitro and in vivo: tailoring biocomponents to the expanding variety of applications.

INTRODUCTION: Bioartificial livers (BALs) were originally developed to treat patients suffering from severe liver failure and relied on primary hepatocytes or on hepatoblastoma-derived cell lines. Currently, new in vitro BAL applications are emerging, including drug toxicity testing, disease modeling and basic clinical research, and in recent years, advances in the field of stem cell biology have resulted in potential alternative cell sources. AREAS COVERED: This review identifies the demands of clinical and in vitro BAL applications to their biocomponent and summarizes the functionality and developmental state of BAL technology and cell types currently available. Relevant studies identified by searching the MEDLINE database until April 2014 were reviewed, supplemented with some of our own unpublished data. EXPERT OPINION: BALs have the potential to meet demands currently left unmet in both clinical and in vitro applications. All the reviewed biocomponents show limitations towards one or more BAL applications. However, the generation of stem cell-derived hepatocyte-like cells is progressing rapidly, so the criteria for patient-specific drug toxicity screening and disease modeling are probably met in the near future. HepaRG cells are the most promising biocomponent for clinical BAL application, based on their proliferative and differentiation capacity.

Incorporating dynamics for predicting poor outcome in acute liver failure patients.

Acute liver failure (ALF), also known as fulminant hepatic failure (FHF), is a devastating clinical syndrome with a high mortality of 60%-90%. An early and exact assessment of the severity of ALF together with prediction of its further development is critical in order to determine the further management of the patient. A number of prognostic models have been used for outcome prediction in ALF patients but they are mostly based on the variables measured at one time point, mostly at admission. ALF patients rarely show a static state: rapid progress to a life threatening situation occurs in many patients. Since ALF is a dynamic process, admission values of prognostic variables change over time during the clinical course of the patient. Kumar et al developed a prognostic model [ALF early dynamic (ALFED)] based on early changes in values of variables which predicted outcome. ALFED is a model which seems to be worthwhile to test in ALF patients in other parts of the world with different aetiologies. Since the exact pathophysiology of ALF is not fully known and is certainly complex, we believe that adding promising variables involved in the pathophysiology of ALF to the dynamic approach might even further improve prognostic performance. We agree with Kumar et al that an improved dynamic prognostic model should be based on simplicity (easily to be performed at the bedside) and accuracy. Our comments presented in this paper may be considered as recommendations for future optimization of ALF prediction models.

Novel immortalized human fetal liver cell line, cBAL111, has the potential to differentiate into functional hepatocytes.

BACKGROUND: A clonal cell line that combines both stable hepatic function and proliferation capacity is desirable for in vitro applications that depend on hepatic function, such as pharmacological or toxicological assays and bioartificial liver systems. Here we describe the generation and characterization of a clonal human cell line for in vitro hepatocyte applications. RESULTS: Cell clones derived from human fetal liver cells were immortalized by over-expression of telomerase reverse transcriptase. The resulting cell line, cBAL111, displayed hepatic functionality similar to the parental cells prior to immortalization, and did not grow in soft agar. Cell line cBAL111 expressed markers of immature hepatocytes, like glutathione S transferase and cytokeratin 19, as well as progenitor cell marker CD146 and was negative for lidocaine elimination. On the other hand, the cBAL111 cells produced urea, albumin and cytokeratin 18 and eliminated galactose. In contrast to hepatic cell lines NKNT-3 and HepG2, all hepatic functions were expressed in cBAL111, although there was considerable variation in their levels compared with primary mature hepatocytes. When transplanted in the spleen of immunodeficient mice, cBAL111 engrafted into the liver and partly differentiated into hepatocytes showing expression of human albumin and carbamoylphosphate synthetase without signs of cell fusion. CONCLUSION: This novel liver cell line has the potential to differentiate into mature hepatocytes to be used for in vitro hepatocyte applications.

Future of bioartificial liver support.

Many different artificial liver support systems (biological and non-biological) have been developed, tested pre-clinically and some have been applied in clinical trials. Based on theoretical considerations a biological artificial liver (BAL) should be preferred above the non-biological ones. However, clinical application of the BAL is still experimental. Here we try to analyze which hurdles have to be taken before the BAL will become standard equipment in the intensive care unit for patients with acute liver failure or acute deterioration of chronic liver disease.