Odorico Lab - Introduction

Laboratory of Dr. Jon Odorico

Major Research Interests

Our laboratory is interested in using embryonic stem (ES) cells to study pancreatic islet development. Despite advances in our understanding of islet ontogeny, there are still significant gaps in our knowledge. Specifically, we do not yet understand precisely how insulin secreting beta cells and other endocrine cell types within mammalian pancreatic Islets of Langerhans are specified from embryonic foregut endoderm, or what complement of transcription factors direct this fate choice. Furthermore, the phenotype of islet progenitor cells and the nature of critical epithelial - mesenchymal interactions that guide their development are still poorly understood. We have recently described the derivation of pancreatic progenitor cells characterized by the expression of a homeodomain transcription factor called pancreatic and duodenal homeobox 1 (PDX1) from murine and human ES cells. Within focal clusters of these cells in ES cell cultures, mature islet cell types expressing insulin, glucagon, somatostatin, and pancreatic polypeptide emerge. In this in vitro differentiation system many aspects of normal islet development are reproduced, thus offering a simple, controllable culture model in which to study islet ontogeny and the formation of insulin-producing beta cells.

Immediate goals of the lab include: 1) inducing and studying neurogenin3-expressing islet progenitor cells from murine ES cells, 2) testing genetic selection transgene constructs as a means for selecting relatively homogeneous populations of pancreatic lineage cells from mouse and human ES cells, 3) selecting and testing the physiologic function of insulin -secreting ES cell progeny in vitro and in vivo, 4) investigating varieties of growth factors and culture conditions that increase the yield of mature and precursor islet progeny, 5) testing the effect of over-expression of key pancreatic transcription factor genes such as ptf1a and pax4 on differentiation of ES cells, 6) developing an in vitro clonogenic assay for insulin positive cell progeny, 7) testing in vivo conditions that promote terminal differentiation of ES cell - derived PDX1+ pancreatic precursors, and 8) studying the developmental potential of magnetic bead sorted Ep-CAM+ ESC-derived endoderm progenitors.

In the future, we intend to expand studies to focus on the major histocompatibility complex antigen expression of human ES cells and their differentiated progeny, particularly islet derivatives, and to investigate the immunogenicity in transplant models of specific ES cell - derived lineages. Another line of investigation will focus on combining this ES cell differentiation system and gene trap technology to discover novel genes that are critical for islet development. Furthermore, in the mouse system we will investigate the ability of transcription factor, signaling molecule, etc. "knockout" or transgenic murine ES cells to differentiate into islet lineages and islet progenitor cells and for islet progenitors to differentiate into fully mature endocrine cells.

The long-term goal of this research is to bring these ES cell derivatives to the clinic as a transplant therapy for patients with diabetes. This will require the definitive derivation of a pure population of functional beta cells from human ES cells applying the concepts learned in basic experiments using mouse and primate ES cells and on future insights into the mechanisms regulating islet growth and development. Subsequently, a primate transplant model will be used for preclinical safety and efficacy testing, ultimately leading to Phase I human trials.

The lab encompasses an active and vibrant group of scientists working in the exciting and growing fields of stem cell biology and islet development. There is ample opportunity for scientists in the lab to present research at national and international meetings, including those of the Society of Developmental Biology, Cold Spring Harbor Laboratory, Keystone Symposia, American Diabetes Association and Transplantation Society, among others. We are fortunate to have state of the art equipment and facilities, including a quantitative PCR system, laser confocal immunofluorescence microscope, computerized digital imaging systems, and animal surgery facilities.

Additional Research Interests:

In addition to his active laboratory effort, Dr. Odorico has several clinical studies involving patients receiving pancreas or islet transplantation. Some of these studies in pancreas transplant recipients involve understanding the molecular fingerprint of pancreas allograft rejection by microarray analysis, understanding the expression of chemokines and their receptors during pancreas rejection, and developing better non-invasive methods of diagnosing rejection without need for a biopsy. Dr. Odorico is also principal investigator for the UW Islet Transplant Program clinical trial, which is studying the effects of insulin sensitizers, such as pioglitazone, on blood sugar control after islet transplantation. There are also many opportunities to initiate retrospective clinical chart-review studies on these two patient populations in order to address a pertinent transplant related-study question.

Dr. James Thomson (center), Nick Seay (right) and Dr. Jon Odorico attend the 3rd annual scientific meeting of the ISSCR in San Francisco.