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Transdifferentiation of pancreatic acinar cells

A technology of acinar cells and transdifferentiation, applied in the fields of diabetes and beta cell insufficiency, which can solve problems such as difficulties

Inactive Publication Date: 2005-04-27
MCGILL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Determination of acinar to β-cell transdifferentiation presents the same difficulties as detection of duct-associated neogenesis

Method used

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  • Transdifferentiation of pancreatic acinar cells
  • Transdifferentiation of pancreatic acinar cells
  • Transdifferentiation of pancreatic acinar cells

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1 - Partial catheter occlusion

[0026] [23] Fourteen 8-week-old female golden hamsters (Charles River, Quebec) were anesthetized and made a midline laparotomy. The head of the pancreas was exposed, and a 2 mm wide transparent adhesive strip (Imperial Tobacco, Montreal, QC) was wrapped around the pancreas and fixed in place. Two weeks after partial ductal occlusion (PDO), hamsters were injected with 2 μCi of tritiated thymidine ( 3 H-TdR) and sacrificed after 1 hour (n=7) or 6 weeks (n=7). Animals were anesthetized and pancreatectomy was performed at the time of sacrifice. Tissues were fixed in formalin and processed for autoradiography, or in 1% glutaraldehyde and 4% formaldehyde in 200 mOsm phosphate buffer and processed for electron microscopy.

[0027] [24] Percent cell replication was determined by counting a minimum of 5000 cells per animal. Briefly, if 5 or more silver particles are found on the nucleus, acinar and endocrine cells are identified as 3 H...

Embodiment 2

[0031] Example 2 - Administration of INGAP Peptides

[0032] [28] Eight-week-old female golden hamsters were randomly assigned to receive daily intraperitoneal injections of INGAP peptide (Ile-Gly-Leu-His-Asp-Pro-Ser-His-Gly-Thr-Leu-Pro-Asn-Gly- Ser) (250 μg twice a day) or an equal volume of saline for 10 days (saline n=10, INGAP n=15) or 30 days (S n=10, In=15). At the end of the study period, animals were bled and the pancreas was excised through a midline laparotomy for morphological and morphometric analyses.

[0033] [29] embedded the samples in paraffin and cut 4 μm thick sections. Sections were processed for routine histological examination and as previously described (22), using the AB complex method (streptavidin-biotin-horseradish peroxidase complex, Dako Corp., Santa Barbara, CA) Insulin, CK19 (antibody dilution 1:750, 1:100, respectively, Dako Corp., Santa Barbara, CA), glucagon, somatostatin and pancreatic polypeptide (antibody dilution 1:750, Biogenex, San Ra...

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Abstract

Induction of beta-cell neogenesis has been associated with ductal epithelium, however aee80% 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.

Description

[0001] [01] This application claims priority to Provisional US Application Serial No. 60 / 346,890, filed January 11,2002. [0002] [02] Portions of the disclosure of this patent document contain material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of this patent document or the patent disclosure, as in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever. field of invention [0003] [03] The present invention relates to the field of diabetes and beta cell dysfunction. It involves an in vivo method for increasing beta cell mass and number by transdifferentiation. Background of the invention [0004] [04] It has long been known that β-cell neogenesis (the formation of new β-cells from non-β-cell precursors) results in an expansion of β-cell mass (1). Only recently has induction of β-cell neogenesis attracted attention as a therapy for diabetes. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00A61K9/16A61K35/39A61K38/10A61K38/17A61L27/00A61P1/18A61P3/10A61P5/48A61P5/50C12N5/071
CPCC12N2501/998A61K38/1709C12N5/0676A61P1/18A61P3/10A61P5/48A61P5/50C12N5/0602
Inventor L·罗森堡
Owner MCGILL UNIV