Clonal Development, Age-Dependent Polyploidization and Thyroid Hormone-Induced Metaplasia in Pancreatic Acinar Cells.

摘要

My current studies examined three important topics related to the growth and maturation of the pancreatic acinar cell. In the first study, I utilized male/female chimeric mice combined with fluorescence in situ hybridization for the Y chromosome (Y-FISH) to reveal the clonal patterning of pancreatic acini and islets. I established that all of the acinar cells in a single acinus are clonal descendants of single progenitor/stem cells, while multiple progenitor/stem cells pattern each endocrine subtype at the level of the islet. These findings will inform future lineage tracing studies designed to locate these progenitor cells. In the subsequent study, I utilized Y-FISH as a marker of genome number in male mice, allowing me to calculate the extent of polyploidization during normal aging, as well as in response to a mitogenic stimulus. Polyploidy increased with age and trypsin inhibitor feeding. These dramatic changes in DNA content may include the generation of aneuploid cells that are often found in cancer. In the final study, I characterized the response of pancreatic acinar cells to increased circulating levels of thyroid hormone. I observed a dramatic increase in acinar cell proliferation, a substantial loss of acinar cell digestive enzyme content and saw phenotypic changes suggestive of acinar-ductal transdifferentiation. Loss of digestive enzymes, increased acinar proliferation and ductal metaplasia due to excess thyroid hormone may promote malabsorption and neoplastic transformation. In summary, these studies provide important insights into pancreatic acinar cell stem cell biology, aging and response to thyroid hormone and considers how each of these findings relate to our understanding of normal pancreatic physiology and disease.