Analysis of Hic1-expressing cells in the murine pancreas and their role in tissue regulation and regeneration
| Autor: | Schreiner, Petra |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Druh dokumentu: | Text |
| Popis: | Mesenchymal stromal cells (MSC) play fundamental roles in tissue development, homeostasis and regeneration and are associated with many pathological conditions. Previous studies analyzing MSCs in skeletal development identified a gene (Hypermethylated in Cancer 1, Hic1) that appears to be solely expressed within embryonic mesenchyme. Analysis of a novel Hic1nLacZ/⁺ mouse line revealed that Hic1 is restricted to interstitial stromal and perivascular cells. In pancreas, Hic1⁺ cells overlap extensively with Pdgfrα and Sca1, which together identify putative MSCs in various tissues. These cells also co-express several markers of Pancreatic Stellate cells (PSC), including vimentin, desmin, nestin and neural/glial antigen 2 (NG2). PSCs are considered effector cells in many pancreatic diseases including fibrosis and cancer, and become activated under these conditions. Using a novel fate-tracking Hic1CreERT² knock-in mouse, we have seen that under homeostatic conditions these cells are capable of some turnover, the labeled cells doubling in number over a 3-month period following induction of the reporter gene in adult 8-week old mice. After caerulein-induced pancreatic damage, the cells become activated, attaining smooth muscle actin α (αSMA) and Collagen-GFP expression, and incorporating EdU, with cells amassing in the damaged areas. Consistent with a potential role for Hic1 in regulating MSC quiescence, conditional deletion of Hic1 in the adult pancreas leads to significantly increased numbers of perilipin⁺ adipocytes in comparison to controls, and an increased number of nLacZ⁺ cells. CD45- CD31- Sca1⁺ cells proliferate at a higher rate after Hic1-deletion. Mouse weight and blood glucose are unaffected. Functional studies into the role of Hic1 have found that Hic1-deletion resulted in a significantly less damage after caerulein-induced damage. This work has identified Hic1 as a novel marker of PSCs and set the stage for a greater understanding of the role of these mesenchymal stromal cells (MSCs) in pancreatic diseases. Medicine, Faculty of Graduate |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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