Analysis of expression profiles of islet-associated transcription and growth factors during beta-cell neogenesis from duct cells in partially duct-ligated mice.
BACKGROUND
Beta-cell neogenesis from pancreatic duct cells has been reported to occur in duct-ligated rat. Nevertheless, detailed process of this phenomenon has not been clarified.


OBJECTIVE
To clarify the mechanism of beta-cell neogenesis, a partial pancreatic duct ligation mouse model was created. Proliferation of duct cells, beta-cell neogenesis, and expression of transcription factors and differentiation/growth factors were studied by immunohistochemistry, cDNA array, and RT-PCR methods.


RESULTS
In the duct-ligated portion of the pancreas, newly formed islet-like cell clusters (ICCs) were observed arising from the ducts on day 7 and afterward. Transcription factors, such as pancreatic and duodenal homeobox gene-1 (PDX-1), paired box factor 6 (Pax6), islet1 and Nkx2.2-positive cells, and protein gene product 9.5 (PGP9.5) were also induced in duct lining cells. By cDNA microarray analysis, expression of insulin-like growth factor-1 (IGF-1) and transforming growth factor beta1 (TGF-beta1) were above control levels on day 5, and RT-PCR showed an increase from day 5 to day 28. IGF-1 and activin A-positive cells were detected in ducts. In addition, expression of betacellulin (BTC), heparin-binding epidermal growth factor-like growth factor (HB-EGF), and TGF-alpha were also increased from day 3 or 5.


CONCLUSIONS
These findings suggest that beta-cell or endocrine precursors are localized among duct lining cells. Induction of several islet cell-associated transcription factors and differentiation and/or growth factors may play important roles during beta-cell neogenesis in this model.
Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Suita, Japan.
Ming
M
Li
Jun-ichiro
J
Miyagawa
Makoto
M
Moriwaki
Ming
M
Yuan
Qin
Q
Yang
Junji
J
Kozawa
Koji
K
Yamamoto
Akihisa
A
Imagawa
Hiromi
H
Iwahashi
Yoshihiro
Y
Tochino
Kazuya
K
Yamagata
Yuji
Y
Matsuzawa
D028341:Activins / Q000032:analysis; D000681:Amylases / Q000097:blood; D000818:Animals; D002455:Cell Division / Q000235:genetics; D020869:Gene Expression Profiling; D005951:Glucose Tolerance Test; D006133:Growth Substances / Q000235:genetics*; D000090322:Homeobox Protein Nkx-2.2; D007150:Immunohistochemistry / Q000379:methods; D028322:Inhibin-beta Subunits / Q000032:analysis; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D007515:Islets of Langerhans / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D008026:Ligation; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010183:Pancreatic Ducts / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics
D006133:Growth Substances; D000090322:Homeobox Protein Nkx-2.2; C000715627:Nkx2-2 protein, mouse; C000715628:Nkx2-2 protein, rat; D012333:RNA, Messenger; D014157:Transcription Factors; C422405:activin A; D028341:Activins; D007334:Insulin-Like Growth Factor I; D028322:Inhibin-beta Subunits; D000681:Amylases; D043222:Ubiquitin Thiolesterase