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UBC Theses and Dissertations

Analysis of Hic1-expressing cells in the murine pancreas and their role in tissue regulation and regeneration Schreiner, Petra


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.

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