Enhancing Drug Responsiveness with Synthetic Liver Microenvironments
Identification of small molecules for human hepatocyte expansion and iPS differentiation
Modeling human liver disease and cell-based liver therapies both require human liver cells, called hepatocytes. When in a normal liver environment, the adult hepatocyte is capable of dividing many times to generate more liver cells; however, this special talent is lost when hepatocytes are grown in the lab - and thus finding a source of human hepatocytes has been an important goal for the field for decades. Testing large numbers of compounds or genes for their capacity to make liver cells grow has not been possible due to the rapid loss of cell function in culture outside of a person / animal. We hypothesized that if human hepatocytes could be maintained by providing cues from a normal liver environment in a high-throughput format, they might become susceptible to expansion signals delivered by test drugs. We developed a co-culture platform using supporting cells that stabilized the hepatocytes in a state closer to their behavior in a normal liver. We screened 12,500 compounds and identified two classes of small molecule drugs that hold exciting potential. (Shan et al., 2013)
The first class caused up to 10-fold growth of human hepatocytes over just two days. Another possible source of human hepatocytes is to generate them from stem cells, such as induced pluripotent stem cells, or 'iPS' cells. However, to date the liver cells that can be made from stem cells ('iHeps') behave more like fetal hepatocytes than cells from an adult. Our second identified class of small molecule drugs causes iHeps to become more mature, and closer to adult cell function, than ever before. The molecular targets of these compounds are the subject of ongoing investigation.