Leadership In Controlled Gene Expression

Diabetes, Pancreas & Liver

The DTA mouse line described above was subsequently used by Stanger and colleagues (Stanger et al., 2007) to study determinants of pancreatic development. In their study, double transgenic mice were raised which expressed DTA specifically in pancreatic progenitor cells. Using this animal model, they selectively destroyed pancreatic progenitor cells at distinct time points during embryogenesis. Newborn mice with progenitor cell ablation during the critical embryonic period showed nearly a complete absence of the pancreas. When the progenitor cell number was reduced during a brief period early in development, prenatal embryos reproducibly had significantly smaller organs, suggesting that the remaining progenitor cells were insufficient to restore normal organ size and function. In a second set of studies having Tet regulated DTA expression directed against hepatic progenitor cells, liver growth was normal even after severe reduction of progenitor cell numbers. These studies demonstrated that progenitor cell number is a critical determinant of pancreas size, whereas liver size is independent of the progenitor cell pool size and depends on extrinsic growth factors.

Insulin-producing pancreatic beta-cells are either destroyed (type-1) or dysfunctional (type-2) and the resulting unregulated elevated blood glucose levels eventually lead to diabetes and its underlying pathology including severe organ damage. New ways to find more effective treatments for diabetes like generation of beta-cells from stem cells, expansion of existing beta-cells or conversion of other cells into functional beta-cells are under investigation.

Thorel et al. (Thorel et al., 2010) also used the DTA ablation technology in a very elegant series of studies to investigate pancreatic regeneration. Following DTA induction, 99% of the beta-cells in adult mice were destroyed. However, functional beta-cells slowly repopulated pancreatic islets in the following months. To determine the origin of these new insulin producing cells they carried out very detailed cell lineage tracing studies. Using an elaborate system of transgenic mice carrying cells that were labeled before beta-cell ablation, they could demonstrate that the beta-cell increase results from regeneration of non-beta cells and not from beta-cell proliferation. The Tet-On Advanced System was instrumental in a series of sophisticated experiments to demonstrate that the regenerated beta-cells where actually derived from glucagon-producing alpha-cells. From these studies it is obvious that, at least in mice, functional beta-cells can be replaced through trans-differentiation of alpha-cells when almost all beta-cells are destroyed. These insights may lead to new diabetes treatment modalities.