Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas

Abstract

SUMMARYOne major unresolved question in the field of pancreas biology is whether ductal cells have the ability to generate insulinproducing b-cells. Conclusive examination of this question has been limited by the lack of appropriate tools to efficiently and specifically label ductal cells in vivo. We generated Sox9CreER T2 mice, which, during adulthood, allow for labeling of an average of 70% of pancreatic ductal cells, including terminal duct/centroacinar cells. Fate-mapping studies of the Sox9 + domain revealed endocrine and acinar cell neogenesis from Sox9 + cells throughout embryogenesis. Very small numbers of non-b endocrine cells continue to arise from Sox9 + cells in early postnatal life, but no endocrine or acinar cell neogenesis from Sox9 + cells occurs during adulthood. In the adult pancreas, pancreatic injury by partial duct ligation (PDL) has been suggested to induce b-cell regeneration from a transient Ngn3 + endocrine progenitor cell population. Here, we identify ductal cells as a cell of origin for PDL-induced Ngn3 + cells, but fail to observe b-cell neogenesis from duct-derived cells. Therefore, although PDL leads to activation of Ngn3 expression in ducts, PDL does not induce appropriate cues to allow for completion of the entire b-cell neogenesis program. In conclusion, although endocrine cells arise from the Sox9 + ductal domain throughout embryogenesis and the early postnatal period, Sox9 + ductal cells of the adult pancreas no longer give rise to endocrine cells under both normal conditions and in response to PDL.

Sox9 plays multiple roles in the lung epithelium during branching morphogenesis

“…All mice used in these studies were housed at the University of Michigan mouse facility and were maintained according to the University of Michigan's Committee on Use and Care of Animals (UCUCA)'s protocols. ShhCre, Sox9CreER, Sox9 Flox , β-Catenin Flox , Rosa-rtTa, SftpC-rtTa, Lrp5/6 Flox , and Sox9-eGFP mice have all been previously described (35,36,45,(80)(81)(82). Description of the Rosa26-tetO-Sox9 mice is currently under review elsewhere (Philip A. Seymour, Hung Ping Shih, Richard Behringer, Mark Magnuson, and Maike Sander).…”

Reprogrammation des cellules pancréatiques en cellules β

“…Neurog3, comme mentionné ci-dessus, est un gène impliqué dans le développement embryonnaire des cellules endocrines, et dont l'expression n'est normalement plus détectable à l'âge adulte. Néanmoins, les relations de lignage entre précurseurs canalaires, cellules exprimant Neurog3 et cellules endocrines restent floues et controversées [15,24] (➜). Après avoir confirmé par immunomarquage la réex-pression de Neurog3 dans les cellules canalaires des animaux transgé-niques exprimant Pax4 dans les cellules , nous avons croisé ces souris avec un autre modèle transgénique, ce qui nous a permis d'observer le devenir de ces cellules canalaires [26].…”

G rowth factors and medium hyperglycemia induce Sox9 + ductal cell differentiation into β cells in mice with reversal of diabetes

“…Although it has been consistently reported that pancreatic ductal epithelial cells give rise to insulin-producing β cells during embryonic development (14)(15)(16)(17), whether the pancreatic ductal progenitors can give rise to insulin-producing β cells in neonates and adult mice remains controversial. Using a Cre-based lineage tracing with a human carbonic anhydrase II (CAII) promoter, Inada et al reported that pancreatic ductal cells were able to give rise to insulin-producing β cells in neonates and in pancreatic duct ligation (PDL)-treated adult mice (5).…”

“…Conversely, using a lineage-tracing model with a hepatocyte nuclear factor 1-β (Hnf1β) promoter, Solar et al found that pancreatic ductal cells did not give rise to β cells in neonates, PDL-treated adult mice, or Alloxan-induced diabetic adult mice treated for 1 wk with GE (14). Using a lineage-tracing model with a SRY (sex-determining region Y)-box 9 (Sox9) promoter, Kopp et al also showed that Sox9 + ductal cells did not give rise to β cells postnatally after β-cell ablation or after PDL (17,18). Similarly, Furuyama et al reported that Sox9 + pancreatic ductal cells were not able to give rise to β cells in PDL-treated adult mice or streptozotocin (STZ)-induced diabetic mice (16).…”