TGF-beta superfamily signaling has long been strongly implicated in pancreatic endocrine cell development and specifically pancreatic beta cell formation. Because of the size and complexity of the superfamily it has been difficult to garner a clear understanding of signaling mechanisms. The smad family of transcription factors is a relatively small family that serves as the downstream mediator of TGF-beta superfamily signaling. Because of its relative simplicity, we have chosen to focus on smad signaling in order to begin to unravel the key mechanisms by which TGF-beta superfamily molecules regulate pancreatic islet cell formation, especially beta cells. We have preliminary evidence that TGF-beta superfamily signaling, through smads 2 and 3, control recruitment of endocrine progenitor cells from the multipotent pancreatic epithelium in the embryonic mouse. After this initial recruitment of endocrine progenitor cells, these smads seem to then regulate pancreatic endocrine maturation and proliferation. The function of these two smads appears to be critically modulated by one of the inhibitory smads, smad7. Importantly, we have also shown a potential parallel role for smads 2 and 3, and the inhibitory smad7, in the regeneration of new beta cells in the adult mouse pancreas in response to a partial pancreatectomy. It appears that most new beta cells form from previous beta cells, but little or nothing is know about endogenous extracellular signals that regulate this new formation of beta cells. Thus, this proposal will focus on smad signaling in the embryo and in the regenerating islet in order to better understand the extracellular signaling through TGF-beta superfamily that leads to the formation of new beta cells. The study of extracellular signaling mechanisms that lead to new pancreatic beta cell formation are important since engineering of cells for the treatment of diabetes mellitus ought to involve only extracellular manipulations rather than intracellular (genetic) manipulations. We have identified a key parallel between embryonic islet cell formation and adult islet regeneration that may give us insights into the mechanisms by which extracellular signaling may be used to engineer beta cells.

Public Health Relevance

The study of extracellular signaling mechanisms that lead to new pancreatic beta cell formation are important since engineering of cells for the treatment of diabetes mellitus ought to involve only extracellular manipulations rather than intracellular (genetic) manipulations. We have identified a key parallel between embryonic islet cell formation and adult islet regeneration that may give us insights into the mechanisms by which extracellular signaling may be used to engineer beta cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083541-04
Application #
8277292
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
2009-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$322,956
Indirect Cost
$109,784
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Xiao, Xiangwei; Prasadan, Krishna; Guo, Ping et al. (2014) Pancreatic duct cells as a source of VEGF in mice. Diabetologia 57:991-1000
El-Gohary, Yousef; Tulachan, Sidhartha; Wiersch, John et al. (2014) A smad signaling network regulates islet cell proliferation. Diabetes 63:224-36
Xiao, Xiangwei; Gaffar, Iljana; Guo, Ping et al. (2014) M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proc Natl Acad Sci U S A 111:E1211-20
Xiao, Xiangwei; Guo, Ping; Shiota, Chiyo et al. (2013) Neurogenin3 activation is not sufficient to direct duct-to-beta cell transdifferentiation in the adult pancreas. J Biol Chem 288:25297-308
Xiao, Xiangwei; Chen, Zean; Shiota, Chiyo et al. (2013) No evidence for * cell neogenesis in murine adult pancreas. J Clin Invest 123:2207-17
Xiao, Xiangwei; Wiersch, John; El-Gohary, Yousef et al. (2013) TGF? receptor signaling is essential for inflammation-induced but not ?-cell workload-induced ?-cell proliferation. Diabetes 62:1217-26
Xiao, Xiangwei; Guo, Ping; Chen, Zean et al. (2013) Hypoglycemia reduces vascular endothelial growth factor A production by pancreatic beta cells as a regulator of beta cell mass. J Biol Chem 288:8636-46
Guo, Ping; Xiao, Xiangwei; El-Gohary, Yousef et al. (2013) Specific transduction and labeling of pancreatic ducts by targeted recombinant viral infusion into mouse pancreatic ducts. Lab Invest 93:1241-53
El-Gohary, Yousef; Tulachan, Sidhartha; Guo, Ping et al. (2013) Smad signaling pathways regulate pancreatic endocrine development. Dev Biol 378:83-93
Shah, Sohail R; Esni, Farzad; Jakub, Adam et al. (2011) Embryonic mouse blood flow and oxygen correlate with early pancreatic differentiation. Dev Biol 349:342-9

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