Control of beta-cell differentiation by the pancreatic mesenchyme.
The importance of mesenchymal-epithelial interactions for normal development of the pancreas was recognized in the early 1960s, and mesenchymal signals have been shown to control the proliferation of early pancreatic progenitor cells. The mechanisms by which the mesenchyme coordinates cell proliferation and differentiation to produce the normal number of differentiated pancreatic cells are not fully understood. Here, we demonstrate that the mesenchyme positively controls the final number of beta-cells that develop from early pancreatic progenitor cells. In vitro, the number of beta-cells that developed from rat embryonic pancreatic epithelia was larger in cultures with mesenchyme than without mesenchyme. The effect of mesenchyme was not due to an increase in beta-cell proliferation but was due to increased proliferation of early pancreatic duodenal homeobox-1 (PDX1)-positive progenitor cells, as confirmed by bromodeoxyuridine incorporation. Consequently, the window during which early PDX1(+) pancreatic progenitor cells differentiated into endocrine progenitor cells expressing Ngn3 was extended. Fibroblast growth factor 10 mimicked mesenchyme effects on proliferation of early PDX1(+) progenitor cells and induction of Ngn3 expression. Taken together, our results indicate that expansion of early PDX1(+) pancreatic progenitor cells represents a way to increase the final number of beta-cells developing from early embryonic pancreas.
Attali
Myriam
M
Faculty of Medicine, University Paris-Descartes, Institut National de la Santé et de la Recherche Médicale, INSERM E363 and U845, Necker Hospital, Paris, France.
Stetsyuk
Volodymyr
V
Basmaciogullari
Annie
A
Aiello
Virginie
V
Zanta-Boussif
Maria A
MA
Duvillie
Bertrand
B
Scharfmann
Raphael
R
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D004622:Embryo, Mammalian; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D051526:Fibroblast Growth Factor 10 / Q000494:pharmacology; D006706:Homeostasis; D017403:In Situ Hybridization; D007328:Insulin / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009924:Organ Culture Techniques; D010179:Pancreas / Q000166:cytology* / Q000201:enzymology / Q000502:physiology; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar
D051792:Basic Helix-Loop-Helix Proteins; D051526:Fibroblast Growth Factor 10; D007328:Insulin; D009419:Nerve Tissue Proteins; C496464:Fgf10 protein, mouse; C407737:Neurog3 protein, mouse