EGF-induced proliferation of adult human pancreatic duct cells is mediated by the MEK/ERK cascade.
Human postnatal pancreatic duct cells are a potential source of new beta cells. Factors regulating proliferation of human pancreatic duct cells in vitro are unknown. In several other cell types, this process is influenced by ligands of the ErbB receptor family. The expression and functionality of the ErbB family members and their possible role in duct cell proliferation were determined. In cultured adult human pancreatic duct cells the different members of the ErbB family (ErbB1-4) were present at transcript and protein level. Stimulation of the duct cells with epidermal growth factor (EGF) and betacellulin results in Tyr-phosphorylation of ErbB1 and ErbB2, followed by activation of Shc, MEK1/2 and ERK1/2. Duct cells with activated ErbB signaling changed morphology and motility. EGF induced proliferation of a fraction of the duct cells and treatment with PD98059 prevented Ki67 expression in EGF-supplemented cells. When transduced with recombinant adenovirus expressing constitutively activated MEK1, duct cells proliferate and spread even in the absence of EGF. Importantly, the adult human duct cells retain their capacity to recapitulate ngn3-induced embryonic (neuro)endocrine differentiation after proliferation. Therefore, the present data support a possible role for human adult pancreatic duct cells, following expansion and transdifferentiation, as a source of insulin by transplantation to type I diabetes patients.
Rescan
Claude
C
The JDRF Center for Beta Cell Therapy in Europe, University of Florence, Italy.
Le Bras
Stéphanie
S
Lefebvre
Véronique H
VH
Frandsen
Ulrik
U
Klein
Tino
T
Foschi
Marco
M
Pipeleers
Daniel G
DG
Scharfmann
Raphael
R
Madsen
Ole D
OD
Heimberg
Harry
H
D000293:Adolescent; D000328:Adult; D066259:Betacellulin; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010183:Pancreatic Ducts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D020133:Reverse Transcriptase Polymerase Chain Reaction
C587851:BTC protein, human; D066259:Betacellulin; D005419:Flavonoids; D036341:Intercellular Signaling Peptides and Proteins; D004815:Epidermal Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases; D048369:MAP Kinase Kinase 1; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one