The study of hepatocytes may provide insight into the overall process by which stem cells commit to their cellular fates of either proliferation or differentiation. This is because the liver, unlike most other human organs shows the ability to regenerate itself even when two-thirds of the liver has been excised. The interesting aspect about this regenerative ability is that the liver is able to sense self-injury in which the cells change from a differentiated state into a proliferative state vs. systemic injury in which metabolic changes occur in order to satisfy the different energetics required by the organism. We wish to investigate the ability of the liver to sense self-injury vs. severe systemic injury in other locations to better understand which injury signals cause the shift in cellular fates. We hypothesize that paracine signaling between the hepatocytes and non-parachymal cells plays a key role in this phenomenon.
The specific aims of this project are as follows: (1) adapt the Living Cell Array (LCA) for primary liver cell cultures;(2) characterize the transcriptional dynamics of the system given the different cell fates;and (3) identify external cell types which affect the response to inflammation. This research program aims to characterize the transcriptional response of the cells in response to inflammatory cytokines such as IL1, IL6 and identify what differences are caused by the presence of non-parenchymal cells, and specifically which cells are most responsible for the changes observed. Once these interactions have been identified, it may be possible to isolate the signals that are necessary of the alteration of cellular fates. The LCA was selected as the primary tool for these studies due to its capability for obtaining data of high temporal resolution which greatly simplifies the underlying modeling and data processing aspect. We feel that this research would greatly improve our understanding as to the mechanisms that govern cellular commitment. In the short term, such research would allow us to expand a population of hepatic cells for use in devices such as the bio-artificial liver. In the long term, such work may allow us to identify the factors that govern stem cell differentiation/proliferation thereby enhancing our ability to use stem cells for therapeutic purposes.
