Title:
TRANSDIFFERENTIATION OF PANCREATIC ACINAR CELLS
Document Type and Number:
WIPO Patent Application WO2003057862
Kind Code:
A3
Abstract:
Induction of beta-cell neogenesis has been associated with ductal epithelium, however ≈80% of the pancreas is composed of acinar cells. Surprisingly, pancreatic acinar cells contribute to beta-cell neogenesis. Partial duct obstruction (PDO) of the pancreas is a known inducer of beta-cell neogenesis leading to expansion of beta-cell mass, and the effect appears to be mediated by INGAP, an acinar cell protein originally identified in the regenerating hamster pancreas. We examined the effects of PDO on the incorporation of tritiated thymidine by acinar and beta-cells of the pancreas in female Syrian hamsters. A single dose of tritiated thymidine was administered to all animals 2 weeks after PDO. Animals were then sacrificed at 1 hr, or at 6 weeks post-injection. Tritiated thymidine incorporation into acinar cells was highest at 2 weeks after PDO and declined at 8 weeks after PDO. Incorporation of tritiated thymidine into beta-cells was inversely related to that observed in acinar cells. Two weeks following PDO, beta-cell tritiated thymidine uptake was relatively low and it increased significantly at 8 weeks after PDO, consistent with beta-cell neogenesis from an acinar cell origin. Electron microscopy demonstrated cells with both zymogen and endocrine granules, further suggesting acinar to endocrine cell transdifferentiation. In a second experiment, hamsters were administered either a pentadecapeptide of INGAP protein or an equivalent volume of saline for 10 days. There was a 2-fold increase in the number of extra-islet acinar-associated beta-cell clusters in the INGAP peptide-treated hamsters resulting in a 2.8-fold increase in the overall extra-islet beta-cell mass. Acinar-to-beta-cell differentiation provides an alternate pathway to beta-cell neogenesis; INGAP peptide plays a significant role in this process.
Inventors:
ROSENBERG LAWRENCE (CA)
Application Number:
PCT/CA2003/000013
Publication Date:
October 02, 2003
Filing Date:
January 10, 2003
Export Citation:
Assignee:
UNIV MCGILL (CA)
ROSENBERG LAWRENCE (CA)
ROSENBERG LAWRENCE (CA)
International Classes:
A61K38/00; A61K9/16; A61K35/39; A61K38/10; A61K38/17; A61L27/00; A61P1/18; A61P3/10; A61P5/48; A61P5/50; C12N5/071; (IPC1-7): C07K14/47; A61K35/39; A61K38/10; A61K9/16; A61L27/00; A61P1/18; A61P5/48
Domestic Patent References:
| WO1996026215A1 | 1996-08-29 |
Other References:
RAFAELOFF RONIT ET AL: "Cloning and sequencing of the pancreatic islet neogenesis associated protein (INGAP) gene and its expression in islet neogenesis in hamsters", JOURNAL OF CLINICAL INVESTIGATION, NEW YORK, NY, US, vol. 99, no. 9, 1997, pages 2100 - 2109, XP002173530, ISSN: 0021-9738
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