The overall objective of this proposal is to identify and characterize putative stem/progenitor cells in the adult pancreas. The identification of such cells would facilitate the development of a cell replacement therapy for patients with diabetes. Such therapy, though highly effective, is currently limited by the shortage of transplantable islets from cadaver tissue. Adult progenitors would be a particularly attractive source for the differentiation of replacement insulin-producing beta-cells, as they could possibly be isolated from the patient's own pancreas, thereby avoiding the immune response associated with the transplantation of foreign tissue. It is, however, still unclear whether a stem or progenitor cell population resides in the pancreas beyond the embryonic period. In preliminary studies, we have identified the transcription factor SOX9 as a marker for progenitor cells in the embryonic pancreas and found that Sox9 is essential for their expansion and maintenance. Strikingly, its expression persists in the adult pancreas exclusively in a subset of ductal cells; a cell type that is regarded as a potential reservoir of pancreatic stem/progenitor cells. Given the crucial role of SOX9 in maintaining undifferentiated, pluripotent progenitors of the embryonic pancreas, we hypothesize that this factor also marks and maintains a stem cell compartment in the adult pancreas. Experiments are proposed to test whether SOX9 plays a role in pancreas regeneration and whether the cells marked by SOX9 in adult pancreas can function as pluripotent pancreas progenitor cells. Using inducible gene ablation, Aim 1 is to define the role of Sox9 in pancreatic cell differentiation and maintenance throughout development and adulthood.
Aim 2 examines if Sox9 is required for pancreas regeneration after partial pancreatectomy or STZ treatment.
Aim 3 will define whether Sox9-expressing cells have characteristics and properties of multipotential stem/progenitor cells. This will be tested by transcriptional profiling of isolated cells and by tracking their fate in cell transplantation experiments. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK078803-02
Application #
7489009
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
2007-09-01
Project End
2008-09-30
Budget Start
2008-08-01
Budget End
2008-09-30
Support Year
2
Fiscal Year
2008
Total Cost
$60,801
Indirect Cost
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Kopp, Janel L; Dubois, Claire L; Schaeffer, David F et al. (2018) Loss of Pten and Activation of Kras Synergistically Induce Formation of Intraductal Papillary Mucinous Neoplasia From Pancreatic Ductal Cells in Mice. Gastroenterology 154:1509-1523.e5
Wortham, Matthew; Benthuysen, Jacqueline R; Wallace, Martina et al. (2018) Integrated In Vivo Quantitative Proteomics and Nutrient Tracing Reveals Age-Related Metabolic Rewiring of Pancreatic ? Cell Function. Cell Rep 25:2904-2918.e8
Serrill, Jeffrey D; Sander, Maike; Shih, Hung Ping (2018) Pancreatic Exocrine Tissue Architecture and Integrity are Maintained by E-cadherin During Postnatal Development. Sci Rep 8:13451
Zeng, Chun; Mulas, Francesca; Sui, Yinghui et al. (2017) Pseudotemporal Ordering of Single Cells Reveals Metabolic Control of Postnatal ? Cell Proliferation. Cell Metab 25:1160-1175.e11
Shih, Hung Ping; Panlasigui, Devin; Cirulli, Vincenzo et al. (2016) ECM Signaling Regulates Collective Cellular Dynamics to Control Pancreas Branching Morphogenesis. Cell Rep 14:169-79
Barrionuevo, Francisco J; Hurtado, Alicia; Kim, Gwang-Jin et al. (2016) Sox9 and Sox8 protect the adult testis from male-to-female genetic reprogramming and complete degeneration. Elife 5:
Wortham, M; Sander, M (2016) Mechanisms of ?-cell functional adaptation to changes in workload. Diabetes Obes Metab 18 Suppl 1:78-86
Fox, Raymond G; Lytle, Nikki K; Jaquish, Dawn V et al. (2016) Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma. Nature 534:407-411
Kopp, Janel L; Grompe, Markus; Sander, Maike (2016) Stem cells versus plasticity in liver and pancreas regeneration. Nat Cell Biol 18:238-45
Shih, Hung Ping; Seymour, Philip A; Patel, Nisha A et al. (2015) A Gene Regulatory Network Cooperatively Controlled by Pdx1 and Sox9 Governs Lineage Allocation of Foregut Progenitor Cells. Cell Rep 13:326-36

Showing the most recent 10 out of 31 publications