Her work incorporated several techniques to test these hypotheses, including the use of pancreas progenitor AR42J cells and transgenic mouse models. The team's data demonstrated that BMP4 signaling is necessary and sufficient for proliferation of AR42J progenitor cells, and that this growth is correlated with an increase in Id expression. The group also did immunohistochemistry staining to show that BMP and Id proteins are found in abundance in the embryonic mouse pancreas, which contains proliferating stem cells.
A possible source of pancreatic progenitor cells is thought to derive from pancreas epithelial duct cells. The pancreas of the mouse model that the Sarvetnick lab used contains an abundance of regenerating stem cells from the ducts. "Importantly, we found that if we inject an antibody that inhibits BMP4 into these mice, this significantly reduced the number of proliferating duct cells. We also found that in these mice inhibition of BMP4 results in an increase in the expression of a bHLH protein-dependent factor PAX6, which is required for the final differentiation of pancreatic islet cells."
The group's results indicate that BMP4 stimulation blocks the differentiation of endocrine progenitor cells through induction of Id, which, in its dual role, promotes their expansion, revealing a novel paradigm of signaling that explains the balance between expansion and differentiation of pancreatic epithelial progenitors.
"The complications of diabetes mellitus impose enormous medical, economic, and social costs to both the patient and the health-care system. These experiments provide novel insights into the signaling pathways that are required for expansion of pancreas stem cells," says Sarvetnick. "Our work may provide
Contact: Keith McKeown
Scripps Research Institute