Pancreatic Mesenchyme Regulates Islet Cellular Composition in a Patched/Hedgehog-Dependent Manner.

Daniel Hibsher,Limor Landsman,Nufar Oren,Alona Epshtein

doi:10.1038/srep38008

Abstract

Pancreas development requires restrained Hedgehog (Hh) signaling activation. While deregulated Hh signaling in the pancreatic mesenchyme has been long suggested to be detrimental for proper organogenesis, this association was not directly shown. Here, we analyzed the contribution of mesenchymal Hh signaling to pancreas development. To increase Hh signaling in the pancreatic mesenchyme of mouse embryos, we deleted Patched1 (Ptch1) in these cells. Our findings indicate that deregulated Hh signaling in mesenchymal cells was sufficient to impair pancreas development, affecting both endocrine and exocrine cells. Notably, transgenic embryos displayed disrupted islet cellular composition and morphology, with a reduced β-cell portion. Our results indicate that the cell-specific growth rates of α- and β-cell populations, found during normal development, require regulated mesenchymal Hh signaling. In addition, we detected hyperplasia of mesenchymal cells upon elevated Hh signaling, accompanied by them acquiring smooth-muscle like phenotype. By specifically manipulating mesenchymal cells, our findings provide direct evidence for the non-autonomous roles of the Hh pathway in pancreatic epithelium development. To conclude, we directly show that regulated mesenchymal Hh signaling is required for pancreas organogenesis and establishment of its proper cellular composition.

Highlights

IntroductionRegulated Hh signaling within the pancreatic epithelium was shown by others and by us to be required for proper endocrine mass and β-cell function[26,27]
During pancreas organogenesis, mesenchymal cells support various developmental stages
By manipulating mesenchymal cells, our findings provide direct evidence for the non-autonomous roles of the Hh pathway in pancreatic epithelium development

Summary

Introduction

Regulated Hh signaling within the pancreatic epithelium was shown by others and by us to be required for proper endocrine mass and β-cell function[26,27] Of note, these epithelial-specific manipulations did not fully recapitulate the developmental phenotype observed upon pancreatic-wide manipulation of this pathway[19,23,24,25]. We manipulated pancreatic mesenchymal Hh signaling and studied the resultant effects on epithelial development, focusing on the endocrine pancreas To this end, we combined the use of Ptch1flox mice, which allows Cre-dependent deletion of this gene[28], with Nkx3.2-Cre[11,29], expressed by the pancreatic mesenchyme, to generate embryos with elevated levels of Hh signaling in their pancreatic mesenchyme. By manipulating mesenchymal cells, our findings provide direct evidence for the non-autonomous roles of the Hh pathway in pancreatic epithelium development

Methods

Results

Conclusion