Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration.
OBJECTIVE
The mammalian pancreas has a strong regenerative potential, but the origin of organ restoration is not clear, and it is not known to what degree such a process reflects pancreatic development. To define cell differentiation changes associated with pancreatic regeneration in adult mice, we compared regeneration following caerulein-induced pancreatitis to that of normal pancreatic development.


METHODS
By performing comparative histology for adult and embryonic pancreatic markers in caerulein-treated and control pancreas, we addressed cellular proliferation and differentiation (amylase, DBA-agglutinin, insulin, glucagon, beta-catenin, E-cadherin, Pdx1, Nkx6.1, Notch1, Notch2, Jagged1, Jagged2, Hes1), hereby describing the kinetics of tissue restoration.


RESULTS
We demonstrate that surviving pancreatic exocrine cells repress the terminal exocrine gene program and induce genes normally associated with undifferentiated pancreatic progenitor cells such as Pdx1, E-cadherin, beta-catenin, and Notch components, including Notch1 , Notch2 , and Jagged2 . Expression of the Notch target gene Hes1 provides evidence that Notch signaling is reactivated in dedifferentiated pancreatic cells. Although previous studies have suggested a process of acino-to-ductal transdifferentiation in pancreatic regeneration, we find no evidence to suggest that dedifferentiated cells acquire a ductal fate during this process.


CONCLUSIONS
Pancreatic regeneration following chemically induced pancreatitis in the mouse occurs predominantly through acinar cell dedifferentiation, whereby a genetic program resembling embryonic pancreatic precursors is reinstated.
Jensen
Jan Nygaard
JN
Barbara Davis Center for Childhood Diabetes, U. Colorado, HSC, 4200 E. 9th Avenue, B140, Denver, Colorado 80262 USA. jan.jensen@uchsc.edu
Cameron
Erin
E
Garay
Maria Veronica R
MV
Starkey
Thomas W
TW
Gianani
Roberto
R
Jensen
Jan
J
D000818:Animals; D002108:Ceruletide; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008938:Mitosis; D010179:Pancreas / Q000196:embryology* / Q000503:physiopathology*; D046790:Pancreas, Exocrine / Q000378:metabolism / Q000503:physiopathology; D010195:Pancreatitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D051880:Receptors, Notch; D012038:Regeneration; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism
D018398:Homeodomain Proteins; D008565:Membrane Proteins; C491328:Nkx6-1 protein, mouse; D051880:Receptors, Notch; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D002108:Ceruletide