Senior Vice Chancellor's Research Seminar

Topic Overview:

During liver regeneration, regenerated hepatocytes can be derived from preexisting hepatocytes or biliary epithelial cells (BECs). BEC-driven liver regeneration occurs when hepatocyte-driven liver regeneration is not sufficient or is compromised, which is the case in chronic liver diseases. Rodent oval cell activation models have significantly contri buted to the current understanding of BEC-driven liver regeneration: A subset of BECs are activated and become oval cells that actively proliferate and differentiate into hepatocytes or BECs, thereby leading to liver recovery. However, recent Cre/loxP-mediated lineage tracing studies in mice imply that only a small subset of regenerated hepatocytes are derived from BECs or oval cells in the current oval cell activation models, suggesting that BEC contribution to liver regeneration is minor in these models. Thus, to study BEC-driven liver regeneration, it would be ideal to develop a new model in which regenerated hepatocytes are mainly derived from BECs and thereby lead to liver recovery because, in such a model, liver regeneration and recovery are due to BECs, not preexisting hepatocytes. Shin and colleagues developed the model by generating a transgenic zebrafish line that expresses bacterial nitroreductase (NTR), fused with cyan fluorescent protein (CFP), under the hepatocyte-specific fabp10a promoter Tg(fabp10a:CFP-NTR). Because NTR converts the nontoxic prodrug metronidazole (Mtz) into a cytotoxic drug, it ablates only the intended NTR-expressing cells, the hepatocytes, but not BECs. By manipulating the duration of Mtz treatment, the extent of hepatocyte ablation can be controlled. By tracing the lineage of BECs and hepatocytes, Shin’s lab found that severe hepatocyte loss resulted in the extensive BEC contribution to regenerated hepatocytes in larval and adult zebrafish. Upon severe hepatocyte loss, BECs proliferate and dedifferentiate into hepatoblast-like cells (HB-LCs), and HB-LCs subsequently differentiate into newborn, highly proliferative hepatocytes that can restore liver mass. Using this new model, Shin analyzed gene expression profiles in the liver during liver regeneration and performed a targeted chemical screen to identify pathways or genes that regulate BEC-driven liver regeneration.

Shin found that Wnt and Fgf signaling, which are implicated in this process in rodents, are also important for BEC-driven liver regeneration in zebrafish, indicating that this zebrafish liver injury model is useful for elucidating mechanisms underlying BEC-driven liver regeneration. Importantly, Shin and colleagues found that additional signaling pathways and genes, which have not been implicated in BEC-driven liver regeneration, are important for this process in zebrafish. This new zebrafish liver injury model will greatly contribute to a better understanding of BEC-driven liver regeneration, which will provide insight into how to augment liver regeneration as therapeutics in patients with chronic liver diseases.









		Topic Overview: During liver regeneration, regenerated hepatocytes can be derived from preexisting hepatocytes or biliary epithelial cells (BECs). BEC-driven liver regeneration occurs when hepatocyte-driven liver regeneration is not sufficient or is compromised, which is the case in chronic liver diseases. Rodent oval cell activation models have significantly contri buted to the current understanding of BEC-driven liver regeneration: A subset of BECs are activated and become oval cells that actively proliferate and differentiate into hepatocytes or BECs, thereby leading to liver recovery. However, recent Cre/loxP-mediated lineage tracing studies in mice imply that only a small subset of regenerated hepatocytes are derived from BECs or oval cells in the current oval cell activation models, suggesting that BEC contribution to liver regeneration is minor in these models. Thus, to study BEC-driven liver regeneration, it would be ideal to develop a new model in which regenerated hepatocytes are mainly derived from BECs and thereby lead to liver recovery because, in such a model, liver regeneration and recovery are due to BECs, not preexisting hepatocytes. Shin and colleagues developed the model by generating a transgenic zebrafish line that expresses bacterial nitroreductase (NTR), fused with cyan fluorescent protein (CFP), under the hepatocyte-specific fabp10a promoter Tg(fabp10a:CFP-NTR). Because NTR converts the nontoxic prodrug metronidazole (Mtz) into a cytotoxic drug, it ablates only the intended NTR-expressing cells, the hepatocytes, but not BECs. By manipulating the duration of Mtz treatment, the extent of hepatocyte ablation can be controlled. By tracing the lineage of BECs and hepatocytes, Shin’s lab found that severe hepatocyte loss resulted in the extensive BEC contribution to regenerated hepatocytes in larval and adult zebrafish. Upon severe hepatocyte loss, BECs proliferate and dedifferentiate into hepatoblast-like cells (HB-LCs), and HB-LCs subsequently differentiate into newborn, highly proliferative hepatocytes that can restore liver mass. Using this new model, Shin analyzed gene expression profiles in the liver during liver regeneration and performed a targeted chemical screen to identify pathways or genes that regulate BEC-driven liver regeneration. Shin found that Wnt and Fgf signaling, which are implicated in this process in rodents, are also important for BEC-driven liver regeneration in zebrafish, indicating that this zebrafish liver injury model is useful for elucidating mechanisms underlying BEC-driven liver regeneration. Importantly, Shin and colleagues found that additional signaling pathways and genes, which have not been implicated in BEC-driven liver regeneration, are important for this process in zebrafish. This new zebrafish liver injury model will greatly contribute to a better understanding of BEC-driven liver regeneration, which will provide insight into how to augment liver regeneration as therapeutics in patients with chronic liver diseases.