Our Research: Faculty/Research Laboratories

Vincenzo Cirulli, MD, PhD

Associate Professor, Department of Medicine, Division of Metabolism, Endocrinology and Nutrition

Email Address: vcirulli@u.washington.edu

Division of Metabolism, Endocrinology and Nutrition Website:  http://depts.washington.edu/metab/

Cirulli

Background:

Vincenzo Cirulli received his MD from the University of Rome in Italy in 1986, and he then moved to the University of Geneva, School of Medicine, Geneva, Switzerland, to train as a postdoctoral fellow in the laboratory of Dr. Philippe Halban. In 1989 he received a Board Certification in Endocrinology and Metabolism, and in 1994 he was recruited as a Senior Research Fellow in the Islet Research Laboratory of Dr. Alberto Hayek at the Whittier Institute for Diabetes, University of California San Diego, La Jolla, California, where in 1996 received a JDRF Career Developmental Award and was appointed as an Assistant Research Scientist. In 1998 he completed a Research Doctorate in Endocrine Sciences and Metabolism through a joint program with the University of Rome (European equivalent of a PhD), and in 2002 was promoted to Associate Research Scientist. In 2009 he was recruited as Associate Professor to the Diabetes and Obesity Center of Excellence and the Institute of Stem cell and Regenerative Medicine, both at the University of Washington.

Dr. Cirulli has been serving on study sections in islet cell biology for the Swiss National Science Foundation, The Netherland Cancer Institute, the Juvenile Diabetes Research Foundation and the NIH.

Focus:

The overall objective of the Dr. Cirulli’s research work is to understand mechanisms of islet cell development and function, with special emphasis on the role of cell-cell and cell-matrix adhesion receptors as instructive cues for developing islet progenitors. In an effort to develop strategies of possible translational value to human diseases, his research makes use of both, animal models and human ES and iPS cells.

The interest of Dr. Cirulli in cell adhesion receptors matured over the years from his former training in islet cell biology. Hence, his earlier work demonstrated that select adhesion receptors are responsible for the highly organized architectural arrangement of the different cell types within pancreatic islets of Langerhans. Building on those observations, his laboratory has uncovered important functions for a number of adhesion molecules expressed in the developing pancreatic epithelium. Some of them involved in pancreatic cell growth and expansion, some regulating basic cell adhesion and migration, others functioning as path-finding cues for the emergence of putative pancreatic progenitors from the pancreatic ductal epithelium. An important corollary of the dynamic expression of some adhesion receptors in distinct pancreatic cell types at select developmental stages is that they can also impart specific developmental decisions. It is from these latter observations that Dr. Cirulli’s current work aims at exploiting the signaling properties of select cell adhesion molecules to foster the development of insulin-producing cells from either ES or iPS cells.

Representative Publications:

Cirulli V, Halban PA, Rouiller DR. Tumor necrosis factor-alpha modifies adhesion properties of rat islet B-cells. J Clin Invest 91:1868-1876, 1993.

Cirulli V, Baetens D, Rutishauser U, Halban PA, Orci L, Rouiller DR. Expression of neural cell adhesion molecule (NCAM) and E-cadherin in rat islets and its role in islet cell type segregation. J Cell Sci 107:1429-1436, 1994.

Cirulli V, Crisa L, Beattie GM, Mally MI, Lopez AD, Fannon A, Ptasznik A, Inverardi L, Ricordi C, Deerinck T, Ellisman M, Reisfeld RA, Hayek A. KSA antigen Ep-CAM mediates cell-cell adhesion of pancreatic epithelial cells: morphoregulatory roles in pancreatic islet development. J Cell Biol 140:1519-1534, 1998.

Cirulli V, Beattie GM, Klier G, Ellisman M, Ricordi C, Quaranta V, Frasier F, Ishii JK, Hayek A, Salomon DR. Expression and function of avb3  and avb5  integrins in the developing pancreas: roles in the adhesion and migration of putative endocrine progenitor cells. J Cell Biol 150:1445-1459, 2000.

Yebra M, Montgomery AM, Diaferia GR, Kaido T, Silletti S, Perez B, Just ML, Hildbrand S, Hurford R, Florkiewicz E, Tessier-Lavigne M, Cirulli V. Recognition of the neural chemoattractant Netrin-1 by integrins a6b4  and a3b1 egulates epithelial cell adhesion and migration. Dev Cell 5:695-707, 2003.

Cirulli V, Yebra M. Netrins: beyond the brain. Nat Rev Mol Cell Biol. 4:296-306, 2007.

  • Rouiller D, Cirulli V, Halban PA. Differences in aggregation properties and levels of the neural cell adhesion molecule (N-CAM) between islet cell types. Exp Cell Res 191:305-312, 1990.

    Giordano E, Bosco D, Cirulli V, Meda P. Repeated glucose stimulation reveals distinct and lasting secretion patterns of individual rat pancreatic b-cells. J Clin Invest 87:2178-2185, 1991.

    Rouiller D, Cirulli V, Halban PA. Uvomorulin mediates Ca++-dependent aggregation of islet cells, whereas Ca++-independent CAMs distinguish between islet cell types. Dev Biol148:233-242, 1991.

    Cirulli V, Halban PA, Rouiller DR. Tumor necrosis factor-a  modifies adhesion properties of rat islet B-cells. J Clinical Invest 91:1868-1876, 1993.

    Giordano E, Cirulli V, Bosco D, Rouiller D, Halban PA, Meda P. B-cell size influences glucose-stimulated insulin secretion. Am J Physiol 265:C358-C364, 1993.

    Chertow BS, Blaner WS, Rajan N, Primerano D, Meda P, Cirulli V, Krozowski Z, Smith R, Cordle MB. Retinoic acid receptor and cytosolic retinol-binding and retinoic acid-binding protein mRNA transcripts and proteins in rat insulin-secreting cells. Diabetes 42:1109-1114, 1993.

    Sekine N, Cirulli V, Regazzi R, Brown L, Gine E, Tamarit-Rodriguez J, Girotti M, Marie S, MacDonald MJ, Wollheim CB, Rutter GA. Glucose metabolism and the control of insulin secretion: low lactate dehydrogenase and high mitocondrial glycerol phosphate dehydrogenase in pancreatic islet B-cells. J Biol Chem 269:4895-4902, 1994.

    Neerman AM, Cirulli V, Halban PA. Levels of the conversion endoproteases PCI and PC2 distinguish between insulin-producing pancreatic islet b-cells and non-b-cells. Biochem J300:57-61, 1994.

    Cirulli V, Baetens D, Rutishauser U, Halban PA, Orci L, Rouiller DR. Expression of neural cell adhesion molecule (NCAM) and E-cadherin in rat islets and its role in islet cell type segregation.  J Cell Sci 107:1429-1436, 1994.

    Hayek A, Beattie G, Cirulli V, Lopez A, Ricordi C, Rubin JS. Growth factor/matrix-induced proliferation of human adult b-cells. Diabetes 44:458-1460, 1995.

    Cirulli V, Ricordi C, Hayek A. E-cadherin, NCAM, and EpCAM expression in human fetal pancreata. Transplant Proc 27:3335, 1995.

    Levine F, Wang S, Beattie GM, Mally MI, Cirulli V, Lopez AD, Hayek A. Development of a cell line from the human fetal pancreas. Transplant Proc 27:3410, 1995.

    Mally MI, Cirulli V, Otonkoski T, Soto G, Hayek A. Ontogeny and tissue distribution of human GAD expression. Diabetes 45:496-501, 1996.

    Mally MI, Cirulli V, Hayek A, Otonkoski T. ICA69 is equally expressed in the human endocrine and exocrine pancreas.  Diabetologia 39:474-480, 1996.

    Crisa L, Cirulli V, Ellisman MH, Ishii JR, Elices MJ, Salomon DR. Cell adhesion and migration are regulated at distinct stages of thymic T cell development: the roles of fibronectin, VLA4 and VLA5. J Exp Med 184:215-228, 1996.

    Otonkoski T, Cirulli V, Beattie G, Mally MI, Soto G, Rubin JS, Hayek A. A role for HGF/SC factor/scatter factor in fetal mesenchyme-induced pancreatic B-cell growth. Endocrinology 137:3131-3139, 1996.

    Wang S, Beattie GM, Mally M, Cirulli V, Itkin-Ansari P, Lopez AD, Hayek A, Levine F. Isolation and characterization of a cell line from epithelial cells of the human fetal pancreas.   Cell Transplant 6:59-67, 1997.

    Beattie GM, Crowe JH, Lopez AD, Cirulli V, Ricordi C, Hayek A. Trehalose: a  cryoprotectant that enhances recovery and preserves function of human pancreatic islets after long-term storage. Diabetes 46: 519-523, 1997.

    Beattie GM, Cirulli V, Lopez AD, Hayek A. Ex vivo expansion of human pancreatic endocrine cells. J Clin Endocrinol Metab 82:1852-1856, 1997.

    Ptasznik A, Beattie GM, Mally MI, Cirulli V, Lopez A, Hayek A. Phosphatidylinositol 3-kinase is a negative regulator of cellular differentiation. J Cell Biol 137:1127-1136, 1997.

    Cirulli V, Crisa L, Beattie GM, Mally MI, Lopez AD, Fannon A, Ptasznik A, Inverardi L, Ricordi C, Deerinck T, Ellisman M, Reisfeld RA, Hayek A. KSA antigen Ep-CAM mediates cell-cell adhesion of pancreatic epithelial cells: morphoregulatory roles in pancreatic islet development. J Cell Biol 140:1519-1534, 1998.

    Beger C, Cirulli V, Vajkoczy P, Halban PA, Menger MD. Vascularization of purified pancreatic islet-like cell aggregates (pseudoislets) after syngeneic transplantation. Diabetes47:559-565, 1998.

    Plopper GE, Domanico S, Cirulli V, Kiosses WB, Quaranta V. Migration of breast epithelial cells on Laminin-5: differential role of integrins in normal and transformed cell types.  Breast Cancer Res Treat 51:57-69, 1998.

    Leibowitz G, Beattie GM, Kafri T, Cirulli V, Lopez AD, Hayek A, Levine F. Gene transfer to human pancreatic endocrine cells using viral vectors. Diabetes 48:745-753, 1999.

    Beattie GM, Itkin-Ansari P, Cirulli V, Leibowitz G, Lopez AD, Bossie S, Mally MI, Levine F, Hayek A. Sustained proliferation of PDX-1+ cells derived from human islets. Diabetes48:1013-1019, 1999.

    Crisa L, Cirulli V, Smith KA, Ellisman M, Torbett BE, Salomon DR. Human Cord blood progenitors sustain thymic T cell development and a novel form of angiogenesis. Blood94:3928-3940, 1999.

    Koshikawa N, Giannelli G, Cirulli V, Miyazaki K, Quaranta V. Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5. J Cell Biol 148:615-624, 2000.

    Cirulli V, Beattie GM, Klier G, Ellisman M, Ricordi C, Quaranta V, Frasier F, Ishii JK, Hayek A, Salomon DR. Expression and function of avb3  and avb5  integrins in the developing pancreas: roles in the adhesion and migration of putative endocrine progenitor cells. J Cell Biol 150:1445-1459, 2000.

    Humphrey RK, Bucay N, Beattie GM, Lopez A, Messam CA, Cirulli V, Hayek A. Characterization and isolation of promoter-defined nestin-positive cells from the human fetal pancreas. Diabetes 52:2519-2555, 2003.

    Yebra M, Montgomery AM, Diaferia GR, Kaido T, Silletti S, Perez B, Just ML, Hildbrand S, Hurford R, Florkiewicz E, Tessier-Lavigne M, Cirulli V. Recognition of the neural chemoattractant Netrin-1 by integrins a6b4 and  a3b1 regulates epithelial cell adhesion and migration. Dev Cell 5:695-707, 2003.

    Kaido T, Perez B, Yebra M, Hill J, Cirulli V, Hayek A, Montgomery AM. Alpha-v-integrin utilization in human b cell adhesion, spreading and motility.  J Biol Chem 279:17731-17737, 2004.

    Silletti S, Yebra M, Perez B, Cirulli V., McMahon M, Montgomery AM. Extracellular Signal-regulated Kinase (ERK)-dependent Gene Expression Contributes to L1 Cell Adhesion Molecule-dependent Motility and Invasion. J Biol Chem 279:28880-28888 2004, (Epub 2004 May 05).

    Hildbrand P, Cirulli V, Robyn PC, Smith KA, Torbett BE, Salomon DR, Crisa L. The role of angiopoietins in the development of endothelial cells from cord blood CD34+ progenitors.Blood 104:2010-2019, 2004.

    Varadi A, Johnson-Cadwell LI, Cirulli V, Yoon Y, Allan VJ, Rutter GA. Cytoplasmic dynein regulates the subcellular distribution of mitochondria by controlling the recruitment of the dynamin-related protein-1. J Cell Sci 117:4389-4400, 2004.

    Kaido T, Yebra M, Cirulli V, Montgomery AM. Regulation of human beta-cell adhesion, motility, and insulin secretion by collagen IV and its receptor alpha1beta1. J Biol Chem279:53762-53769, 2004.

    Varadi A, Cirulli V, Rutter GA.  Mitochondrial localization as a determinant of capacitative Ca2+ entry in HeLa cells. Cell Calcium 36:499-508, 2004.

    Cirulli V, Zalatan J, McMaster M, Prinsen R, Salomon DR, Ricordi C, Torbett BE, Meda P, Crisa L. The class I HLA repertoire of pancreatic islets comprises the non-classical class Ib antigen HLA-G. Diabetes 55:1214-1222, 2006.

    Kaido T, Yebra M, Cirulli V, Rhodes CJ, Diaferia G, Montgomery AM. Impact of Defined Matrix Interactions on Insulin Production by Cultured Human β-cells: Effect on Insulin Content, Secretion, and Gene Transcription.   Diabetes 55:2723-2729, 2006.

    Winter M, Cirulli V, Briaire-De Bruijn IH, Litvinov SV. Cadherins are regulated by Ep-CAM via phosphaditylinositol-3 kinase. Mol Cell Biochem 302:19-26, 2007.

    Miller R, Cirulli V, Diaferia GR, Ninniri S, Hardiman G Torbett BE, Benezra R, Crisa L. Switching-on survival and repair esponse programs by bone marrow-derived vasculogenic cells.   Diabetes 57:2402-2412, 2008.

    Serre-Beinier V, Bosco D, Zulianello L, Charollais A, Caille D, Charpantier E, Gauthier BR, Diaferia GR, Giepmans BN, Lupi R, Marchetti P, Deng S, Buhler L, Berney T, Cirulli V, Meda P. Cx36 makes channels coupling human pancreatic beta-cells, and correlates with insulin expression. Hum Mol Genet 18:428-439, 2009.

    Bucay N, Yebra M, Cirulli V, Afrikanova I, Kaido T, Hayek A, Montgomery AM. A novel approach for the derivation of putative primordial germ cells and sertoli cells from human embryonic stem cells. Stem Cells 27:68-77, 2009.

    Schwartz MW, Guyenet SJ,  Cirulli V.   The Hypothalamus-Beta Cell Connection in Gene-Targeting Era. Diabetes 2010. In Press.

    Reviews and Book Chapters:
    Cirulli V, Hayek A. Developmental roles of cell adhesion molecules: Implications for pancreatic islet morphogenesis. Pancreatic Growth and Regeneration Sarvetnick N., Editor. Austin, TX: RG Landes Press, 1997. (pp. 154-169).

    Otonkoski T, Beattie GM, Cirulli V, Mally MI, Hayek A. Human pancreatic P-cell differentiation and growth in vitro and after transplantation. Pancreatic Growth and Regeneration Sarvetnick N., Editor. Austin, TX: RG Landes Press, 1997. (pp 231-245).

    Serre-Beinier V, Mas C, Calabrese A, Caton D, Bauquis J, Caille D, Charollais A, Cirulli V, Meda P. Connexins and secretion. Biol Cell 94:477-492, 2002.

    Cirulli V, Yebra M. Netrins: beyond the brain. Nat Rev Mol Cell Biol 4:296-306, 2007

Current Collaborations:

Within the Diabetes and Obesity Center of Excellence and its Affiliated Members
Laura Crisa, MD, PhD
Alan Chait, MD
Mike Schwartz, MD
Ian Sweet, PhD

 

Outside of the Diabetes and Obesity Center of Excellence
Anthony Blau, MD, Institute for Stem Cell and Regenerative Medicine (ISCRM), University of Washington, Seattle, WA
Carol Ware, PhD, ISCRM, University of Washington, Seattle, WA
Marshall Horwitz, PhD, ISCRM, University of Washington, Seattle, WA
Randall Moon, PhD, ISCRM, University of Washington, Seattle, WA
Jerry Nepom, MD, PhD, Benaroya Research Institute, Seattle, WA
Valera Vasioukhin, PhD, Fred Hutchinson Cancer Research Center, Seattle, WA
Alberto Hayek, MD, UCSD, La Jolla, CA
Maike Sander, MD, UCSD, La Jolla CA
Christopher Rhodes, PhD, University of Chicago, IL

Lab Members:

Robert Florkiewicz, Laboratory Manager
Antonio Jimenez-Caliani, Post Doctoral Fellow