Jon S. Odorico, MD
Position title: Professor, Surgery
Our lab studies pancreatic lineage differentiation, including the differentiation of insulin-producing islet endocrine cells, from embryonic stem cells (ESCs). The work is designed to address two critical needs. First is the need to generate an unlimited supply of functional insulin-secreting beta cells to be used to replace damaged beta cells in patients with diabetes. Second is the need for a cell culture model to study, specifically, human pancreas and islet development, given known differences in pancreas and islet organ formation between humans and lower organisms and the inability to study human organ development in vivo.
The first step in achieving these two goals was to simply test whether ESCs from various species can become pancreatic cell types. We and others have now demonstrated that murine, rhesus, and human ESCs are in fact capable of committing to a pancreatic progenitor cell fate defined by cells expressing pancreatic duodenal homeobox 1 (PDX1) via an endoderm pathway. Ultimately, progenitor cells can give rise to islet endocrine cells expressing insulin, glucagon, and somatostatin. (Kahan et al. Diabetes 2003, Jacobson et al. Transplant Proc 2001, Xu et al. Stem Cells and Development 2006).
Current work in the lab focuses on identifying key extrinsic signals regulating early endoderm fate of human ESCs in order to develop culture protocols that selectively enrich for pancreatic lineage cells (Xu et al. Mech of Development 2011). Ongoing studies in the lab are refining these differentiation protocols to enhance endocrine specification from these pancreatic progenitor cells. In addition, pluripotent stem cell-derived insulin-expressing cells are being studied using functional assays that are established in the lab comparing them to adult human islets in their ability to respond to secretagogues and reverse diabetes in animal models. We are also interested in exploring whether such cells might be less immunogenic than adult islets, which would have significant clinical implications. Other projects in the lab are evaluating the roles of key pancreatic transcription factors, such as Ngn3, Ptf1a, HNF6 and others in directing pancreatic differentiation from ESCs.
- Kahan B, Magliocca J, Merriam F, Treff N, Budde M, Nelson J, Browning V, Ziehr B, Odorico J: Elimination of tumorigenic stem cells from differentiated progeny and selection of definitive endoderm reveals a Pdx1+ foregut endoderm stem cell lineage. Stem Cell Res. 2011 Mar;6(2):143-57.
- MacDonald MJ, Longacre MJ, Stoker SW, Kendrick M, Thonpho A, Brown LJ, Hasan NM, Jitrapakdee S, Fukao T, Hanson MS, Fernandez LA, Odorico J: Differences between human and rodent pancreatic islets: low pyruvate carboxylase, atp citrate lyase, and pyruvate carboxylation and high glucose-stimulated acetoacetate in human pancreatic islets. J Biol Chem. May 27;286(21):18383-96, 2011.
- Xu X, Browning VL, Odorico JS. Activin, BMP and FGF pathways cooperate to promote endoderm and pancreatic lineage cell differentiation from human embryonic stem cells. Mech Dev. Sep; 128(7-10): 412-27, 2011.
- Baiu D, Merriam F, Odorico JS: Potential Pathways to Restore β-Cell Mass: Pluripotent Stem Cells, Reprogramming, and Endogenous Regeneration. Curr Diab Rep Oct;11(5):392-401, 2011.
- Xu X, Browning V, Odorico J. Culture protocols for producing definitive endoderm and pancreatic lineage cells from human ES or iPS cells. Methods in Bioengineering, eds. M. Yarmush, R. Langer, Artech House, Boston, 2011.