Document Detail


Pancreatic mesenchyme regulates epithelial organogenesis throughout development.
MedLine Citation:
PMID:  21909240     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The developing pancreatic epithelium gives rise to all endocrine and exocrine cells of the mature organ. During organogenesis, the epithelial cells receive essential signals from the overlying mesenchyme. Previous studies, focusing on ex vivo tissue explants or complete knockout mice, have identified an important role for the mesenchyme in regulating the expansion of progenitor cells in the early pancreas epithelium. However, due to the lack of genetic tools directing expression specifically to the mesenchyme, the potential roles of this supporting tissue in vivo, especially in guiding later stages of pancreas organogenesis, have not been elucidated. We employed transgenic tools and fetal surgical techniques to ablate mesenchyme via Cre-mediated mesenchymal expression of Diphtheria Toxin (DT) at the onset of pancreas formation, and at later developmental stages via in utero injection of DT into transgenic mice expressing the Diphtheria Toxin receptor (DTR) in this tissue. Our results demonstrate that mesenchymal cells regulate pancreatic growth and branching at both early and late developmental stages by supporting proliferation of precursors and differentiated cells, respectively. Interestingly, while cell differentiation was not affected, the expansion of both the endocrine and exocrine compartments was equally impaired. To further elucidate signals required for mesenchymal cell function, we eliminated β-catenin signaling and determined that it is a critical pathway in regulating mesenchyme survival and growth. Our study presents the first in vivo evidence that the embryonic mesenchyme provides critical signals to the epithelium throughout pancreas organogenesis. The findings are novel and relevant as they indicate a critical role for the mesenchyme during late expansion of endocrine and exocrine compartments. In addition, our results provide a molecular mechanism for mesenchymal expansion and survival by identifying β-catenin signaling as an essential mediator of this process. These results have implications for developing strategies to expand pancreas progenitors and β-cells for clinical transplantation.
Authors:
Limor Landsman; Amar Nijagal; Theresa J Whitchurch; Renee L Vanderlaan; Warren E Zimmer; Tippi C Mackenzie; Matthias Hebrok
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-09-06
Journal Detail:
Title:  PLoS biology     Volume:  9     ISSN:  1545-7885     ISO Abbreviation:  PLoS Biol.     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-09-12     Completed Date:  2012-01-05     Revised Date:  2013-10-16    
Medline Journal Info:
Nlm Unique ID:  101183755     Medline TA:  PLoS Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e1001143     Citation Subset:  IM    
Affiliation:
Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America.
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MeSH Terms
Descriptor/Qualifier:
Animals
Diphtheria Toxin / pharmacology
Embryo, Mammalian / drug effects,  embryology,  physiology*
Epithelium / drug effects,  embryology,  physiology*
Gene Expression Regulation, Developmental
Mesoderm / drug effects,  embryology,  physiology*
Mice
Mice, Knockout
Organogenesis / drug effects,  physiology*
Pancreas / drug effects,  embryology,  physiology*
Grant Support
ID/Acronym/Agency:
DK60533/DK/NIDDK NIH HHS; K08 AI085042-03/AI/NIAID NIH HHS; P30 DK063720/DK/NIDDK NIH HHS; P30 DK63720/DK/NIDDK NIH HHS; R01 DK060533/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Diphtheria Toxin
Comments/Corrections

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