Signaling Pathways Required for Expansion of Insulin-Producing Beta Cells

“Our work focused on guiding stem cells, or pancreas progenitors, to differentiate into beta cells.”

IDDM, which used to be referred to as Type 1 diabetes, results from selective destruction of insulin-producing pancreatic islet beta cells by the body’s immune system.

Islet beta cells are spread throughout the pancreas and are made up of two types of cells: alpha cells, which make glucagon, a hormone that raises the level of glucose (sugar) in the blood, and beta cells, which make insulin.

"Our work focused on guiding stem cells, or pancreas progenitors, to differentiate into beta cells. This approach required that we increase the number of pancreas progenitors by finding the signals that cause them to proliferate. It also required that we understand the ‘cues’ that activate stem cells to turn into insulin-producing beta cells," says Nora Sarvetnick, Ph.D., a Scripps Research professor in the Department of Immunology.

The overall goal of this five-year study, was to discover the roles of two proteins-BMP4 and Id-in causing proliferation or expansion of pancreatic progenitors. Hong Hua, a postdoctoral fellow in Sarvetnick’s lab, was the lead author of this study.

The progression of pancreatic stem cells to beta cells is governed by the expression of key proteins, including a class of proteins called bHLH transcription factors that regulate gene expression. Ids (inhibition of differentiation factors) are a family of proteins implicated in a number of cellular processes, including cell proliferation. The major role of Id proteins is to bind to, and inhibit, the function of bHLH proteins, including those that are important in pancreas development. Therefore, Id proteins could bind to bHLH proteins in the developing pancreas and prevent them from differentiating into mature insulin-producing cells and, at the same time, cause them to proliferate.

"Interestingly, the expression of Id proteins is induced by bone morphogenetic proteins (BMPs) targets in another cell type," says Sarvetnick. "We wanted to know whether BMP can cause an increase of Id expression, and if this would result in proliferation of the stem cells."

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.

These experiments provide novel insights into the signaling pathways that are required for expansion of pancreas stem cells," says Sarvetnick. "Our work may provide a starting point toward improving the efficacy of treatments for patients and perhaps the prevention of clinical disease."

" If these cells arise in the pancreatic ducts, as Dr. Sarvetnick’s work has previously shown in animal models developed in her lab, the identification of the proteins (BMPs) described in this research is an important step for the potential application of therapies aimed at increasing a pool of cells that will become insulin-producing."

The Journal of Biological Chemistry. May 2006

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DID YOU KNOW: Drinking Green Tea Can Prevents Type 2 Diabetes: It has repeatedly been shown that drinking coffee reduces the risk of type 2 diabetes. The effect of green, black, and oolong teas is unclear. It has now been shown that not only coffee but also green tea and total caffeine are associated with a reduced risk of type 2 diabetes.
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