In both type 1 and type 2 diabetes, the total number of insulin-producing β-cells in the body is reduced, and the pancreas is hard-pressed to produce the insulin the body needs. Therefore, scientists have searched for ways to generate new β-cells, which could be used to develop a constant, alternative source of insulin-producing cells for transplantation or to stimulate β-cell regeneration in vivo. But the idea that β-cells might regenerate from stem-cell-like precursors in the pancreas, through a process known as neogenesis, has been the subject of much debate.
“Overall, the paper puts one more nail in what was already becoming an increasingly tight coffin for what had been the prevailing hypothesis about β-cell neogenesis in adult mice,” said Fred Levine, who studies β-cell regeneration at Sanford Burnham Medical Research Institute in La Jolla, California and was not involved in the study. Still, he cautions, this negative result does not completely rule out adult neogenesis of β-cells in other injury models.
To detect neogenesis, George Gittes and colleagues applied an old cell tracking method in a new way. They used two fluorescent tags in transgenic mice: a red tag that targets a protein in the cell membrane of most cells in the body, except for insulin producing cells, which the group labeled with a green tag. The team then looked for cells turning on insulin for the first time—which was detected during a 40–48 hour window where the cells expressed both tags and, as a result, appeared yellow.
The yellow transition was detected in embryonic mice, where neogenesis is expected to occur. But when the researchers looked at adult cells, they saw no yellow cells—meaning no evidence of neogenesis. They repeated the process in several common models of pancreatic damage, including the pancreatic duct ligation model (PDL), which damages other pancreatic cell types but not β-cells.
The lack of neogenesis in these models “puts pressure on us to find models in which there is neogenesis,” said Gittes. But he remains “very confident” that there are other models in which neogenesis occurs.
In fact, several models not tested in this paper have shown evidence of neogenesis, including one of Gittes’ own. In 2011, his team found evidence of neogenesis in a mouse model created using a diphtheria toxin receptor to ablate pancreatic tissue, though that injury model is not compatible with the new labeling system and thus was not included in the current paper, says Gittes (2). In 2010, two other groups, including one headed by Levine, also demonstrated neogenesis in adult mice through trandifferentiation of preexisting α-cells in pancreatic islets into β-cells (3,4).
“Overall, I believe that the pathway by which β-cell regeneration occurs…is likely to vary depending on the stimulus for regeneration,” said Levine. Therefore, the current work does not rule out neogenesis, even from duct cells, in other models. “I would argue that the old cliché, ‘Absence of evidence is not evidence of absence’ should be kept in mind when evaluating studies like this.”
Update 4/29/2013: Included additional details as to why the mouse model in which Gittes team found evidence of neogenesis was not invluded the current paper.
1. Xiao, X., et al. 2013. No evidence for beta-cell neogenesis in murine adult pancreas. J Clin Invest., 123(5):2207-17.
2. Criscimanna, A., et al. 2011. Duct cells contribute to regeneration of endocrine and acinar cells following pancreatic damage in adult mice. Gastroenterology, 141(4):1451-62.
3. Thorel, F., et al. 2010. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature, 464(7292):1149-54.
4. Chung, C.H., et al. 2010. Pancreatic β-cell neogenesis by direct conversion from mature α-cells. Stem Cells, 28(9):1630-8.