Generation of Functional Hepatocyte-Like Cells (HLCs) from Human Adipose-Derived Stem Cells (ADSCs) in 2D and 3D

Abstract

Mortality and morbidity rates caused by acute liver failure (ALF), acute-on-chronic liver failure (ACLF) and chronic liver disease continue to rise because of drug induced failure or viral hepatitis, currently with 2,000 cases annually in the United States. Liver transplantation is the only intervention that has shown the most promising patient outcomes, but this approach has major shortcomings like shortage of donor livers, lifelong immunosuppression and a risk of organ rejection after transplantation. Additionally, with rapid liver deterioration and subsequent multi-organ failure characterized by ALF and ACLF conditions, there are high mortality rates as patients await a liver transplant or wait for their livers to regenerate. As such, bioartificial liver support devices provide an alternative to improve patient survival through either offloading liver functions to allow for liver regeneration or by allowing the patient time to receive a liver transplant. These bioartificial liver support devices are designed to perform essential liver functions through incorporation of an active cellular component that performs the liver functions and their success is therefore heavily reliant on the performance of the incorporated cell lines. Because of this, limited sources of these characteristic cell lines with hepatic function is a great challenge being faced in the research and development of the devices. Adipose-derived stem cells (ADSCs) are a great candidate as a stem cell source for differentiation of hepatocyte-like cells because they can be easily obtained in large quantities with little donor site morbidity or discomfort and have been successfully differentiated into multiple cell lineages. In this study, we investigate the possibility of differentiating human ADSCs into functional hepatocyte-like cells. Furthermore, we investigated the ability to differentiate ADSCs into hepatocyte-like cells in both 2D and 3D environments. We found that induced ADSCs can produce high levels of some hepatocyte functions, like albumin secretion. However, other functions, like urea secretion and cytochrome P450 metabolic activity, while present, are not yet at sufficient levels to be comparable to primary hepatocytes.