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Pancreatic beta cells produce insulin and play a critical role in maintaining blood glucose levels; loss of these cells results in the development of diabetes. A primary goal in diabetes therapy is beta cell replacement; however, there is a short supply of donor pancreases and a need for alternative sources of beta cells. Xiangwei Xiao and colleagues examined adult mouse pancreases to determine if they are capable of making new beta cells (beta cell neogenesis). They generated mice that express different fluorescent reporters in a time sensitive manner, so that insulin producing cells produce GFP (green) while all other cells produce mTomato (red). Cells that develop into beta cells should transiently co-express both GFP and mTomato, appearing yellow. By tracking the mice throughout their development, Xiao and colleagues found that beta cell neogenesis primarily takes place during embryogenesis, decreases dramatically after birth, and is completely absent in adult mice. The accompanying confocal microscopy image shows the developing embryonic mouse pancreas. Developing beta islets (yellow) are visible in the left and middle panels (Embryonic day 13.5 and 14.5, respectively), but have completely disappeared by embryonic day 15.5 (right panel), leaving only fully-developed beta islets (green). These results demonstrate that beta cell neogenesis only occurs for a short period of time during development, but not in adult mice.
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Abstract
Whether facultative β cell progenitors exist in the adult pancreas is a major unsolved question. To date, lineage-tracing studies have provided conflicting results. To track β cell neogenesis in vivo, we generated transgenic mice that transiently coexpress mTomato and GFP in a time-sensitive, nonconditional Cre-mediated manner, so that insulin-producing cells express GFP under control of the insulin promoter, while all other cells express mTomato (INSCremTmG mice). Newly differentiated β cells were detected by flow cytometry and fluorescence microscopy, taking advantage of their transient coexpression of GFP and mTomato fluorescent proteins. We found that β cell neogenesis predominantly occurs during embryogenesis, decreases dramatically shortly after birth, and is completely absent in adults across various models of β cell loss, β cell growth and regeneration, and inflammation. Moreover, we demonstrated upregulation of neurogenin 3 (NGN3) in both proliferating ducts and preexisting β cells in the ligated pancreatic tail after pancreatic ductal ligation. These results are consistent with some recent reports, but argue against the widely held belief that NGN3 marks cells undergoing endocrine neogenesis in the pancreas. Our data suggest that β cell neogenesis in the adult pancreas occurs rarely, if ever, under either normal or pathological conditions.
Authors
Xiangwei Xiao, Zean Chen, Chiyo Shiota, Krishna Prasadan, Ping Guo, Yousef El-Gohary, Jose Paredes, Carey Welsh, John Wiersch, George K. Gittes
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)