Jon S. Odorico, MD
Position title: Professor, Surgery
Our lab studies pancreatic lineage differentiation, including the differentiation of insulin-producing islet endocrine cells, from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). 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. We have devised and refined methods for differentiating cells to islet-like clusters that express genes and proteins typical of islet beta cells and secrete insulin.
Current work in the lab focuses on identifying key beta cell genes that correlate with functional maturity (robust insulin secretion) in vitro. Because cells accelerate maturation after transplantation into mice, and ECM in stem cell-derived islets is dysmorphic, we are also testing the impact of human pancreatic ECM hydrogel on the differentiation and function of stem cell-derived islets and using this natural ECM hydrogel as a basis for creating islet organoids. By incorporating vascular components and other supportive cells into these organoids, we propose to test whether these additional cellular and matrix components improve transplantation success. As we have access to human donor pancreases that we can use for research, we have formed collaborations with Dr. Lingjun Li’s lab and Dr. Dawn Davis’s lab for comprehensive mass spectrometry-based multiomics and proteomics analysis of the normal proteome, peptidome, matrisome and post-translational modifications of normal, T1D and T2D pancreata. This work had resulted in numerous recent publications (See below).
Another aspect of our current work involves using genome editing (e.g. CRISPR/Cas editing) to modify hESCs in order to render them hypoimmunogenic. The clinical relevance of this work is to be able to transplant cells to replace insulin secretion in diabetic patients and also avoid the need for systemic immunosuppression to prevent rejection and autoimmune diabetes recurrence. Fourteen different cell lines harboring various combinations of up to four different modifications were made by our collaborators at MSKCC (Dr. Huangfu lab). We have validated the lack of expression of HLA proteins and the overexpression of key transgenes inducibly expressed during the differentiation period and are testing the immunogenicity of the islet-like clusters generated from them using in vitro assays in collaboration with the Gumperz lab and in humanized mice in collaboration with the Brown lab and the Humanized mouse Core here at UW.
My colleague Dr. Sara Sackett and I are developing a novel, humanizable, immunodeficient mouse model of diabetes that is associated with improved characteristics compared to more commonly used streptozotocin based diabetes models.
Additionally, our Human Islet Core regularly isolates islets from human deceased donor pancreases for research.
- Sackett SD, Tremmel DM, Ma F, Feeney AK, Maguire RM, Brown ME, Zhou Y, Li X, O’Brien C, Li L, Burlingham WJ, Odorico JS. Extracellular matrix scaffold and hydrogel derived from decellularized and delipidized human pancreas. Sci Rep, 2018. 8(1): p. 10452. PMID 29993013.
- Ma F, Tremmel DM, Li Z, Leitz CB, Sackett SD, Odorico JS, Li L. In depth quantification of extracellular matrix proteins from human pancreas. J Proteome Res, 2019, 18(8):3156-3165, PMID 31200599.
- Li Z, Tremmel DM, Ma F, Yu Q, Ma M, Delafield DG, Shi Y, Wang B, Mitchell SA, Feeney AK, Jain VS, Sackett SD, Odorico JS, Li L. Proteome-wide and matrisome-specific alterations during human pancreas development and maturation. Nat Commun. 12(1):1020. PMID 33589611.
- Tremmel DM, Sackett SD, Feeney AK, Mitchell SA, Schaid MD, Polyak E, Chlebeck PJ, Gupta S, Kimple ME, Fernandez LA, Odorico JS. A human pancreatic ECM hydrogel optimized for 3-D modeling of the islet microenvironment. Sci Rep 2022 12(1):7188, doi: 10.1038/s41598-022-11085-z. PMID: 35504932.
- Sackett SD, Rodriguez A, Odorico JS. The Nexus of Stem Cell-Derived Beta Cells and Genome Engineering. Diabet. Stud. 14:39-50, 2017. PMID28632820.
- Odorico J, Markmann J, Melton D et al. Report of the Key Opinion Leaders Meeting on Stem Cell-derived Beta Cells. Transplantation, 2018 102(8):1223-1229. PMID 29781950
- Tremmel DM, Odorico JS. Rebuilding a better home for transplanted islets. Organogenesis, Sep 25:1-6. doi: 10.1080/15476278.2018.1517509. [Epub ahead of print] PMID:30252586
- Tremmel DM, Feeney AK, Mitchell SA, Chlebeck PJ, Raglin SA, Fernandez LA, Odorico JS, Sackett SD. Hypertension, but not body mass index, is predictive of increased pancreatic lipid content and islet dysfunction. Am J Transplant, 2020 Apr; 20(4):1105-1115, PMID:31715064.
- Tabang DN, Cui Y, Tremmel DM, Ford M, Li Z, Sackett SD, Odorico JS, Li L. Analysis of pancreatic extracellular matrix protein post-translational modifications via electrostatic repulsion-hydrophilic interaction chromatography coupled with mass spectrometry. Mol Omics 2021 Oct 17(5):652-664. PMID: 34318855
- Zhao K, Shi Y, Yu J, Yu L, Mael A, Li Y, Kolton A, Joyce T, Odorico J, Berggren PO, Yang S-N. Intracameral Microimaging of Maturation of Human iPSC Derivatives into Islet Endocrine Cells. Cell Transplantation, 2022 31:9636897211066508. PMID: 35156411.
- Yang D, Cho H, Tayyebi Z, Shukla A, Luo R, Dixon G, Ursu V, Stransky S, Tremmel DM, Sackett SD, Koche R, Kaplan S, Li QV, Park J, Zhu Z, Rosen BP, Pulecio J, Shi ZD, Bram Y, Schwartz RE, Odorico JS, Sidoli S, Wright V, Leslie C, Huangfu D. CRISPR screening uncovers a central requirement of HHEX in pancreatic lineage commitment and plasticity restriction. Nature Cell Biology, 2022, in press.
- Tremmel DM, Mitchell SA, Sackett SD, Odorico JS. Mimicking nature-made beta cells: recent advances towards stem cell-derived islets. Curr Opin Organ Transplant. 2019 Oct;24(5):574-581. doi: 10.1097/MOT.0000000000000687.PMID:31433306