We identify genes that control development of liver and pancreatic cells in the embryo. We then unravel how dysfunction of these genes in adults causes disease and how disease can be treated by restoring cell and gene function.
The form and function of cells differ from one organ to the other. The acquisition of organ-specific properties of cells is called "cell differentiation" and this process mainly occurs during embryonic development. Using transgenic mouse models and human tissue samples we have identified genes that are essential for normal differentiation of liver and pancreatic cells. In parallel, we found that dysfunction of these genes in adults is associated with diseases such as liver or pancreas malformation, metabolic anomalies and cancer.
The cells that initially constitute the fetal liver are called hepatoblasts, and these cells progressively give rise to hepatocytes which exert the metabolic functions of adult liver, or to cholangiocytes which form the bile ducts. We have identified genes that determine how a hepatoblast becomes either a hepatocyte or a cholangiocyte, and now investigate how dysfunction of these genes impacts on disease. First, we determine how genes influence polycystic liver disease, an anomaly characterized by dilated bile ducts and excessive number of cholangiocytes. Second, in liver cancer, cells change their differentiation status while converting to malignant cells, and we investigate how genes involved in cell differentiation regulate this conversion. Third, a number of metabolic anomalies of the liver are expected to be cured by cell therapy which consists in administering in vitro-produced hepatocytes. We collaborate with scientists to optimize in vitro production of hepatocytes by contributing our knowledge on liver cell differentiation.
We have also identified genes that are critical for normal differentiation of pancreatic progenitor cells to the main cell types of the pancreas, namely endocrine cells which include insulin-producing cells, acinar cells which secrete digestive enzymes, and ductal cells which delineate the pancreatic ducts. Similar to liver cancer, pancreatic cancer can be initiated by conversion of exocrine acinar cells to duct-like cells, a process called acinar-to-ductal metaplasia. Using cell and molecular biology technology and mathematical modeling we now investigate how genes control such metaplasia and how they modulate progression toward pancreatic cancer.
Hepatic cell differentiation
In the embryo, liver progenitor cells (hepatoblasts) derive from the endoderm, the cell layer that delineates the primitive gut. The classical model of liver development predicts that hepatoblasts give rise to hepatocyte precursors, which mature to hepatocytes, and to "ductal plate cells", which generate the cholangiocytes and form bile ducts. Using trangenic mouse models, we have updated the fate map of the hepatic cells in the embryo: the ductal plate cells generate cholangiocytes and bile ducts, but also a subset of hepatocytes, as well as the adult liver stem cells. We now investigate the mechanisms that control acquisition and maintenance of liver cell differentiation in health and disease.
During development, liver progenitor cells called hepatoblasts give rise to hepatocyte and cholangiocyte precursors. These cells then mature to generate adult hepatocytes forming cords and cholangiocytes delineating bile ducts. Part of the cholangiocyte precursors revert to a hepatocyte phenotype or give rise to adult liver progenitor cells.
Our discovery of the Onecut transcription factors Onecut-1 (OC-1/HNF-6), OC-2 and OC-3, and the subsequent phenotypic characterization of HNF-6 and OC-2 knockout mice led to the identification of transcriptional and signaling networks regulating liver development. Current efforts are devoted to the characterization of the transcription factor–microRNA networks that control hepatocyte differentiation.
Cholangiocytes delineate the lumen of the bile ducts and modify the composition of the bile. We investigate transcription factors and microRNAs that control cholangiocyte differentiation and bile duct morphogenesis. In this context, we found that biliary development proceeds according to a unique process characterized by transient asymmetry. In collaboration with clinical centers, we investigate how the knowledge gained from our fundamental studies can be translated in the understanding of the pathophysiology of human biliary diseases. The latter include polycystic liver disease and cholangiocarcinoma.
Pancreatic cell differentiation
Like the liver, the pancreas develops as an outgrowth of the endoderm. Pancreatic progenitors derived from the endoderm form two buds (dorsal and ventral) which later fuse to form a single organ. Within these buds the progenitor cells give rise, through a stepwise process, to endocrine, acinar and duct cells. Our group investigates the molecular mechanisms that control development of the various pancreatic cell types, and the maintenance of the differentiated phenotype in adults.
Our research on the role of the Onecut transcription factor OC-1/HNF-6 uncovered that this protein is required for development of endocrine cells and pancreatic ducts. In the absence of HNF6, endocrine cells fail to develop in the embryo and ducts form cysts. Subsequent research identified transcription-factor microRNA networks in pancreatic cell differentiation. Current work is focused on the role of gene regulatory networks, oncogenes and signaling pathways in development of pancreatic adenocarcinoma from acinar or ductal cells.
Alcian Blue staining of section of a pancreas expressing the oncogene Kras (left) and of a pancreas expressing the oncogene Kras in the absence of the transcription factor Sox9 (right). Dark blue staining identifies preneoplastic lesions whereas no such lesions are seen in the absence of Sox9. This result reveals that Sox9 is essential for the initiation of pancreatic ductal adenocarcinoma.
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HEPATIC AND PANCREATIC CELL DIFFERENTIATION IN HEALTH AND DISEASE