.BETA. Cell Neogenesis from Ducts and Phenotypic Conversion of Residual Islet Cells in the Adult Pancreas of Glucose Intolerant Mice Induced by Selective Alloxan Perfusion.
Department of Internal Medicine and Molecular Science, Graduate School of Medicine, B5, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan. Endocrine Journal
(Impact Factor: 2).
11/2002; 49(5):561-72. DOI: 10.1507/endocrj.49.561
The aim of this study was to clarify the pattern of beta cell neogenesis in the alloxan-perfused, beta cells-depleted segment of glucose intolerant mice induced by selective alloxan perfusion. First, duct cells proliferated in the perfused segment, then cells co-expressing multiple islet hormones and transcription factors such as PDX-1, Nkx2.2, Isl1, and Pax6 were observed in duct cells, and newly formed islet-like cell clusters (ICCs) containing beta cells were recognized. In residual beta cell-depleted islets, glucagon or somatostatin and PDX-1 double-positive immature endocrine cells were recognized. Glucagon or somatostatin, insulin and PDX-1 triple-positive cells then appeared and these cells appeared to undergo terminal differentiation into beta cells. In conclusion, we demonstrated at least two different processes of beta cell neogenesis, i.e., formation of new ICCs from ductal epithelium and redifferentiation of residual non-beta islet cells in this model. In addition, transcription factors that appear in the processes of endocrine cell development may also play essential roles during beta cell neogenesis from duct cells.
Available from: PubMed Central
- "In addition, intraislet progenitors as well as centroacinar cells have been suggested as a site of islet neogenesis [18, 19, 26, 27]. Moreover, several studies indicate that in the adult pancreas duct and/or duct-lining cells have the propensity to differentiate into endocrine cells and give rise to functional beta-cells [16, 28–33]. Of high interest is the observation that compromising the glucagon-signaling pathway is associated with alpha-cell regeneration . "
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ABSTRACT: The pancreas is composed of two compartments that deliver digestive enzymes and endocrine hormones to control the blood sugar level. The endocrine pancreas consists of functional units organized into cell clusters called islets of Langerhans where insulin-producing cells are found in the core and surrounded by glucagon-, somatostatin-, pancreatic polypeptide-, and ghrelin-producing cells. Diabetes is a devastating disease provoked by the depletion or malfunction of insulin-producing beta-cells in the endocrine pancreas. The side effects of diabetes are multiple, including cardiovascular, neuropathological, and kidney diseases. The analyses of transgenic and knockout mice gave major insights into the molecular mechanisms controlling endocrine pancreas genesis. Moreover, the study of animal models of pancreas injury revealed that the pancreas has the propensity to undergo regeneration and opened new avenues to develop novel therapeutic approaches for the treatment of diabetes. Thus, beside self-replication of preexisting insulin-producing cells, several potential cell sources in the adult pancreas were suggested to contribute to beta-cell regeneration, including acinar, intraislet, and duct epithelia. However, regeneration in the adult endocrine pancreas is still under controversial debate.
Available from: intl-joe.endocrinology-journals.org
- "An alternative approach is to drive adult stem cells residing in the pancreas to restore the functional islet mass. Adult islet mass can be enhanced both by replication of existing islets (Bonner- Weir et al. 1993, Dor et al. 2004) and by neogenic commitment of precursor cells to new islets (Rosenberg et al. 1989, Bonner-Weir et al. 1993, Li et al. 2002, Peters et al. 2005). This latter process is termed islet neogenesis. "
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ABSTRACT: Islet neogenesis associated protein (INGAP) promotes the generation of new islet mass in adult animal models. It is not understood what factors control the expression of INGAP. In this study, factors that regulate the expression of INGAP promoter activity are reported. To determine factors that regulate INGAP expression, we previously cloned the promoter region for INGAP. Analysis of the INGAP promoter suggested that candidate regulators of INGAP expression include the transcription factors PDX-1, NeuroD, PAN-1, STAT and AP-1. Using gene addition experiments in the 293 cell line the activity of these transcription factors on an INGAP-promoter construct linked to the beta-galactosidase reporter has been determined. Induction of AP-1 activity or STAT activity using PMA or LIF stimulation respectively, or direct expression of PAN-1 specifically up-regulates INGAP promoter activity. In contrast, co-expression of PDX-1 but not NeuroD inhibits activation of the INGAP-promoter driven by PAN-1, PMA or LIF stimulation. PDX-1 binds directly to the INGAP promoter as determined in electromobility shift and antibody supershift assays. Expression of the INGAP-promoter-reporter construct in the HIT-T15 beta-cell line, a cell line that expresses endogenous PDX-1, did not reveal PMA-mediated stimulation of INGAP promoter activity. HIT-T15 cells however did efficiently transfect (> 68%) and respond (2-fold) to PMA-induced signal transduction to a transfected AP-1-CAT reporter. Partial reduction of PDX-1 expression in HIT-T15 cells was associated with recovery of PMA induced INGAP promoter activity. These data suggest that expression of PDX-1 is associated with a repression of stimulus-induced INGAP promoter activity that appears to be mediated by a direct DNA interaction. These findings implicate PDX-1 in a possible feedback loop to block unbridled islet expansion.
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ABSTRACT: A description is given of the implementation, operational experience and ongoing refinement of a computer-aided design tool for discrete component digital design in the department of electrical and computer engineering at the Air Force Institution of Technology. Specifically, a graphical user interface, simulation, and artificial intelligence technology are used to aid in the design of digital logic circuits. This is being incorporated into a first-quarter course to provide students with exposure to modern design techniques. The implementation and enhancements of a prototype design for an engineering workstation are described in detail
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