Understanding mechanisms of cell-cell and cell-matrix interactions in pancreatic islet cell development and function.
The overall objective of our laboratory is to understand cellular and molecular 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, pancreatic polypeptide, and ghrelin. Special attention in the 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 our research program is to understand the function of highly specialized proteins that regulate cell-cell and cell-matrix interactions in the pancreas. Our 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 β-cells.
In an effort to develop strategies of possible translational value to human diabetes, our team follows a multi-pronged approach: on the one hand we are using gene manipulation techniques to uncover the function of select cell adhesion molecules in β-cell development and function, and on the other hand we are using select cell adhesion molecules produced in our lab as biochemical cues to test whether they elicit the maturation of pluripotent stem cells to become insulin-producing cells, and/or to trigger the proliferation and expansion of donor human β-cells, thus increasing their number for cell-based replacement strategies to cure diabetes.
So far, we have identified several 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 replicate (i.e., proliferate) (Cirulli et al. 1998; Vercollone et al., 2015).
Other molecules that the Cirulli lab has defined as important regulators of islet cell development and function include β1 integrin receptors (Cirulli et al., 2000; Diaferia et al, 2013), and members of the chemoattractant proteins Netrins (Yebra et al., 2003; Cirulli & Yebra 2007; Yebra et al., 2011).
More recently, we discovered that aE-catenin, a key component of adhesion complexes, functions as a positive regulator of pancreatic islet cell lineage differentiation by repressing the sonic hedgehog pathway (SHH). We found that deletion of aE-catenin in multipotent pancreatic progenitors results in the loss of adherens junctions, constitutive activation of SHH, decrease in islet cell lineage differentiation, and accumulation of immature Sox9+ progenitors. Pharmacological blockade of SHH signaling in these aE-catenin null Sox9+ pancreatic progenitors rescues this defect, allowing their differentiation into endocrine cells (Jimenez-Caliani et al., 2017). The results uncover crucial functions of aE-catenin in pancreatic islet development and harbor significant implications for the design of β-cell replacement and/or regeneration therapies in diabetes.
Current and Recent Lab Members
Vincenzo Cirulli MD, PhD
Principal Investigator, Associate Professor of Medicine.Following my MD degree and a board certification in Endocrinology from the University of Rome “La Sapienza” (Rome, Italy), I conducted a postdoctoral training at The University of Geneva, Centre Médical Universitaire (Geneva, Switzerland) under the mentorship of Dr. Philippe A. Halban. There, I was introduced to the inner-world of mechanisms that drive islet cell types recognition, aggregation, architectural organization, and function. Thanks also to productive collaborations with other pioneers in the pancreatic islet field like Drs. Lelio Orci, Paolo Meda, and Claes Wollheim, among others, those early years shaped my future research interests that in 1993 led me to join the Islet Research laboratory at The Whittier Institute for Diabetes, University of California, San Diego (La Jolla, CA) to conduct a Research Doctorate in Endocrine Sciences and Metabolism (PhD) under the mentorship of Dr. Alberto Hayek. Those years furthered cemented the primary focus of my research work that to this day remains centered on the function of cell adhesion molecules as regulators of cellular decisions during the development of the pancreatic islet cell lineage. Hence, in 2009, I was recruited to the University of Washington to integrate and apply my expertise on the developmental biology of the pancreatic islets to pluripotent stem cells, with the ultimate goal of developing cell-based replacement therapies for diabetes.
Antonio Javier Jimenez-Caliani, PhD
Postdoctoral Fellow, Department of MedicineAntonio joined the Cirulli lab in 2009 to work on the role of the junctional protein αE-catenin in the development of the pancreatic islet cell lineage. His work has demonstrated that the deletion of αE-catenin in multipotent pancreatic progenitors results in loss of adherens junctions, constitutive activation of SHH signaling, decrease in islet cell lineage differentiation, and accumulation of immature, Sox9+ putative islet progenitors. Antonio also demonstrated that chemical blockade of SHH signaling in these mutant progenitors rescue this defect and promote massive endocrine differentiation. The results of these studies were published in 2017 and featured in the cover of the August issue of Cell Reports (Jimenez-Caliani et al., 2017).
Lab Manager, Research Scientist IIPatricia is the lab manager of the Cirulli team. She has a keen interest in the biology of pluripotent stem cells, and in animal models of diabetes. Her expertise in cellular and molecular biology has played a pivotal role in helping graduate students and postdoctoral fellows in the lab.
Joseph L. Nadler, MD
Prerana Ranjitkar, PhD
Postdoctoral Fellow, Department of MedicinePrerana joined the Cirulli lab in 2011 to work on the development of novel selection strategies to enrich pancreatic progenitors derived from the in vitro-directed differentiation of pluripotent stem cells, with the goal of using these cells in future cell replacement therapies for diabetes. She also contributed to another project focusing on understanding the role of guidance molecules in the development of the pancreas. Work conducted by Prerana has resulted in one publication. A second manuscript is under completion.
Jeffrey Vercollone, MD
Endocrinology Resident FellowJeff spent two years in the Cirulli Lab, working at a research project that focused on the transgenic over-expression of the cell adhesion molecule EpCAM in pancreatic islet progenitors. His work demonstrated that EpCAM functions as a positive regulator of islet progenitors expansion that can lead to the development of strikingly large pancreatic islets (Vercollone et al., 2015). Following completion of his training, Jeff took an appointment at Tufts Medical Center in Boston where he is an Assistant Professor of Medicine in the Division of Endocrinology, Diabetes and Metabolism.
Wendy Yang, PhD
Graduate Student, Department of PharmacologyWendy conducted her thesis research work in the Cirulli lab, focusing on the role of the Gap Junction protein Connexin 43 in pluripotent stem cell differentiation. Her studies demonstrated that Cx43 is an important regulator of cell-cell communication in stem cells during early steps of differentiation toward the definitive endoderm cell lineage. Wendy co-authored five publications while training in the Cirulli lab, and graduated in the summer of 2016.
UW Diabetes Institute
850 Republican Street, Box 358062
Seattle, WA 98109
Cirulli Office: (206) 685-6638
Laboratory: (206) 616-6090
Vincenzo Cirulli: firstname.lastname@example.org
Patricia Kensel-Hammes (Lab Manager): email@example.com
Careers: To inquire about Postdoctoral and Graduate Student Openings click on: firstname.lastname@example.org