Neurogenin3 Activation Is Not Sufficient to Direct Duct-to-Beta Cell Transdifferentiation in the Adult Pancreas

Abstract

Background: Whether neurogenin3 activation represents beta cell neogenesis in adults is controversial. Results: Neurogenin3-activated pancreatic duct cells do not become beta cells. Conclusion: Neurogenin3 activation is not a signature for adult beta cell neogenesis. Significance: Our data strongly argue against the widely held belief that neurogenin3 is a marker of beta cell neogenesis in the adult pancreas, especially from duct cells.

Increase of beta cell mass by beta cell replication, but not neogenesis, in the maternal pancreas in mice

“…However, the proposed contribution of beta cell neogenesis to postnatal beta cell growth/regeneration has been disputed by a series of elegant studies [10][11][12][13][14][15][16][17]. However, most of the previous studies have been focused on beta cell regeneration models like partial pancreatectomy and respectively), compared with non-pregnant mice (G0) of the same age.…”

“…Briefly, the pancreata were trimmed of all non-pancreatic tissue, weighed, fixed with 4% Paraformaldehyde for 6 hours, and then cyroprotected in 30% sucrose overnight in a way to allow atic cells is sufficient to demonstrate absence of beta cell neogenesis in the adult pancreas. Since beta cells were reported to express low levels of Neurgo3 [8,12,17,21], we thus checked Neurog3 levels in the exocrine pancreas deprived of islets. To test the sensitivity of the system, cDNA from a Neurog3-expressing cell line was added to G0 exocrine pancreas samples in a 1:800 ratio as a control, showing significantly higher levels of Neurgo3.…”

“…creas [8,9,12,17,21,30]. Nevertheless, it appears that Neurog3 activation is required for beta cell neogenesis, since Neurog3-independent beta cell differentiation has never been convincing reported.…”

“…However, although more and more studies have proved the insufficiency of using Neurog3 as a marker for adult beta cell neogenesis [8,12,17,21], it appears that its activation is required for beta cell differentiation or transdifferentiation, since no Neurog3-independent beta cell differentiation has ever been convincingly shown. Therefore, failure of detection of Neurog3 expression should be sufficient to demonstrate absence of beta cell neogenesis in the adult pancreas.…”

M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7

“…PDL is a model of complete destruction of exocrine acinar cells in the ligated portion of the pancreas, along with a severe local inflammation, as evident from the significant local infiltration by CD45 + (panleukocyte marker) cells, and accumulation of inflammatory factors IL-6, IFN-γ, and tumor necrosis factor (TNF) (15). We and others have previously shown that, in C57BL/6 mice, there is no substantial beta-cell neogenesis (7,(34)(35)(36)(37)(38)(39)(40)(41), but an increase in beta-cell proliferation in the ligated pancreas early after PDL (15,36,38,42). Indeed, a 7-d continuous labeling with BrdU (15,43,44) immediately after PDL showed a significant increase in beta-cell proliferation.…”