The overall objective of Dr. Cirulli's research work is to understand mechanisms that foster the development and function of pancreatic islets of Langerhans, small clusters of 2,000-3,000 cells scattered throughout the pancreas, that are responsible for the production of such hormones as insulin, glucagon, somatostatin, and pancreatic polypeptide. Special attention in his laboratory is devoted to insulin-producing cells (also known as β-cells) whose function is lost in both type 1 and type 2 diabetes. The specific focus of Dr. Cirulli's research program is to understand the function of highly specialized proteins that regulate cell-cell and cell-matrix interactions in the pancreas. His previous work has established that these proteins, also referred to as "cell adhesion molecules," are used by cells not only to aggregate with each other, but also to let cells talk to one another through the exchange of biochemical signals, thereby helping developing cells to decide whether to grow (i.e. increase in numbers) or to differentiate (i.e. mature) into functional adult cells.
In an effort to develop strategies of possible translational value to human diabetes, Dr. Cirulli's team is using a multi-pronged approach: On the one hand, his team is trying to understand if it is possible to coax immature pancreatic ductal cells (regarded in the field as a reservoir of islet cell progenitors) to produce insulin. On the other end, some cell adhesion molecules are used as biochemical signals to test whether they can be exploited to trigger the maturation of stem cells, both EC and iPS cells, to become insulin-producing cells, and/or to trigger the proliferation of donor human insulin-producing cells and thus increase their number before transplantation in diabetics.
So far, his team has identified several types of cell adhesion molecules that appear to influence cell communication and development in the pancreas. One of such molecules, named Ep-CAM (Epithelial Cell Adhesion Molecule), appears to be used by cells preferentially when they need to increase in numbers (i.e., proliferate) (Cirulli et al. 1998). An example of this molecule production by a developing pancreatic islet cluster is shown in the figure at left by the green fluorescent signal that highlights cell-cell contacts. Numerous proliferating cells are marked by the nuclear proliferation antigen Ki76 (in blue), whereas developing insulin-producing cells are stained in red.
Other molecules whose function has been identified in the pancreas by his laboratory include Netrin-1 and select Integrin receptors. As shown in the figure at right, Netrin-1 (in red) is produced by a small number of cells (white arrowheads) that appear as budding (delaminating) from pancreatic ducts, marked in green by integrin adhesion receptors subunits Alpha3 and Beta1. From these studies it was concluded that Netrin-1 functions as a path-finding cue for pancreatic cell migration that use Integrin adhesion receptors to migrate during pancreas development (Yebra et al. 2003; Cirulli et al, 2000).
Building on these discoveries, Dr. Cirulli's hypothesis is that through the purposeful manipulation of select cell adhesion molecules it will be possible to coax immature pancreatic progenitors, and/or stem cell populations derived from ES or iPS cells, to develop into insulin-producing cells. Ultimately, understanding the function that these proteins play in pancreatic development may also help design strategies to induce the regeneration of insulin-producing cells in vivo in diabetic patients.