The biosociology of pancreatic B cells

Pipeleers, Daniël

doi:10.1007/bf00299019

Cited by 165 publications

(124 citation statements)

References 94 publications

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“…Although, the density of insulin labeling in the secretory granules of Pax4 ϩ cells was lower as compared to insulin granules in adult ␤ cells (reflecting differences in intracellular insulin content) histotypic differentiation was capable to increase the maturation stage of insulin-positive cells in vitro. This would support the idea that a characteristic ''biosociology'' of pancreatic endocrine cells is necessary for tissue-specific functions (35).…”

Section: Discussionsupporting

confidence: 63%

“…Although Pax4 expression in ES cells resulted in up to 80% insulin-producing cells, remaining undifferentiated cells may still possess oncogenic properties. Lineage selection by using cell-trapping systems (6) and͞or fluorescence-activated cell sorting methods similar to those developed for the isolation of ␤ cells (35) have to be further adapted to prevent tumor formation.…”

Section: Discussionmentioning

confidence: 99%

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Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells

Błyszczuk

Czyż

Kania

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

408

322

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Mouse embryonic stem (ES) cells differentiate into cells of all three primary germ layers including endodermal cells that produce insulin in vitro.We show that constitutive expression of Pax4 (Pax4 ؉ ), and to a lesser extent Pdx1 (Pdx1 ؉ ), affects the differentiation of ES cells and significantly promote the development of insulin-producing cells. In Pax4 overexpressing R1 ES cells, isl-1, ngn3, insulin, islet amyloid polypeptide, and glucose transporter 2 (Glut-2) mRNA levels increase significantly. The number of nestinexpressing (nestin؉) cells also increases. Constitutive Pax4 expression combined with selection of nestin؉ cells and histotypic culture conditions give rise to spheroids containing insulin-positive granules typical of embryonal and adult ␤ cells. In response to glucose, Pax4 ؉ and wild-type ES-derived cells release insulin. Transplantation of these cells into streptozotocin-treated diabetic mice results in a normalization of blood glucose levels. We conclude that constitutive expression of Pax4 in combination with histotypic cultivation facilitates ES cell differentiation into the pancreatic lineage, which leads to the formation of islet-like spheroid structures that produce increased levels of insulin.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells

Błyszczuk

Czyż

Kania

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

408

322

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“…It is not clear whether these beta cells exhibit the same functional activities as those which are organized in islets. However, their occurrence as single cells and/or their different environmental conditions are expected to keep them in a different functional state [11], and their smaller size is compatible with an earlier stage in their life cycle. Single beta cells might represent an early stage of differentiation, which is thought to proceed during budding from their progenitors in the ductal epithelium [2, 12±14].…”

Section: Discussionmentioning

confidence: 99%

Extra-insular beta cells associated with ductules are frequent in adult human pancreas

1998

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The light-microscopic structure of the mammalian pancreas is characterized by a lobular arrangement of exocrine acini which are interconnected by ducts. Intercalated ducts are the smallest branches of the intralobular ducts and penetrate the acinus to terminate in centroacinar cells. It is generally assumed that pancreatic lobules are mainly composed of acinar cells with only a small proportion of ductal cells [1]. It is not known whether the postnatal ductal system is a source for new islet cells as it is in the prenatal stage [2,3]. The present study investigates whether ductal cells in the adult human pancreas are also associated with pancreatic endocrine cells as has been observed in fetal pancreata [3]. This work takes advantage of the ability to recognize ductal cells through immunocytochemical markers. Cell proliferation was also assessed immunocytochemically. Materials and methodsCollection and preparation of tissue. Human pancreasta from heart-beating cadaveric non-diabetic donors were procured under the auspices of a European multicentre programme on islet cell transplantation. Upon arrival at the control unit in Brussels, fragments were taken from the pancreatic body and the remaining tissue was then digested for islet isolation. Fragment sections were examined microscopically after fixation in 4 % formaldehyde and embedding in paraffin [4]. The quantitative data reported in this study were collected in tissue samples from 9 consecutive donor organs. Donors (5 men, 4 women) were between 17 and 49 years of age. Tissue was also obtained during autopsy, within 6 h after death, from three patients who died from either cardiogenic shock, bronchopneu- Summary Routine immunohistochemical analysis of human donor pancreata indicated the frequent occurrence of single insulin-immunoreactive cells. In a quantitative analysis of nine organs consecutively recruited from adult donors, 15 percent of all beta cells were found in units with a diameter less than < 20 mm and without associated glucagon-, somatostatin-, or pancreatic polypeptide cells. These single beta-cell units are located in or along ductules, from which they appear to bud as previously noticed in fetal and neonatal organs. They contain significantly smaller beta cells than endocrine aggregates with a larger diameter. The use of ductal cell markers such as cytokeratin 19, carbonic anhydrase-II and carbohydrate antigen 19.9 identified a close topographical association between ductal cells and budding beta cells; it also indicated that pancreatic lobules are composed of nearly one third ductal cells. The presence of Ki67 proliferation marker-immunoreactive ductal cells (0.05 %) and absence of Ki67-immunoreactive budding beta cells is compatible with the view that betacell neogenesis depends on ductal cell proliferation and differentiation. The high proportion of budding beta cells in the adult human pancreas suggests the presence of numerous loci with a potential for betacell neogenesis. [Diabetologia (1998) 41: 629±633]

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“…Since Type i diabetes is an autoimmune disease, it is not surprising that several factors such as cytokines have been suggested to be involvedin the initial secretory alterations [9]. Moreover, a preferential destruction of a high glucose-sensitive beta-cell subpopulation with preservation of less glucose-sensitive cells, could be occurring at early stages of the disease [10].…”

Section: Discussionmentioning

confidence: 99%

Human pancreatic islet function at the onset of Type 1 (insulin-dependent) diabetes mellitus

et al. 1993

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Summary. Viable human pancreatic islets isolated from a recent-onset Type 1 (insulin-dependent) diabetic patient were used to perform in vitro studies. Pre-proinsulin mRNA and insulin content, as well as insulin response were analyse d . Insulin response to glucose and forskolin was completely absent in diabetic islets, as compared to control islets. Insulin content was reduced to only one-third of control values (395.0 + 3.5 vs 989.0 _+ 46.3 gU/islet) and 20.7 + 3.9 % of islets from the diabetic pancreas contained insulin-positive cells in immunofluorescence studies. Northern blot analysis revealed a severe reduction in the content of pre-proinsulin mRNA in diabetic pancreatic tissue. Our results indicate that although markedly decreased, beta cells in human pancreatic islets at the onset of Type 1 diabetes are still present. Nevertheless, pancreatic islet function is disproportionately impaired with a complete absence of an insulin response. Key words:Human islets, islet function, onset of Type 1 (insulin-dependent) diabetes mellitus.Type i (insulin-dependent) diabetes mellitus is an autoimmune disease caused by the selective destruction of islet beta cells. Attempts have been made to define the immunopathological aspects of this destruction. This has shown that pancreatic tissue from newly-diagnosed Type i diabetic patients presents several distinct features including: severely reduced beta-cell mass, various degrees of expression of MHC class I and class II antigens in islet cells and lymphocytic infiltrates [1][2][3]. However, the beta-cell secretory function of this clinical entity has only been evaluated in in vivo studies [4].We report here the first study in which viable human pancreatic islets were isolated from a recent-onset Type 1 diabetic patient and thus were used to perform in vitro functional studies. Subjects and methodsAfter obtaining the family's informed consent and with the approval of the Hospital Ethics Committee, human pancreatic islets were isolated from the pancreas of a islet cell antibody positive 18-year-old woman who had died 6 h after her admission because of diabetic ketoacidosis. She had been asymptomatic up to 2 days prior to admission when polydipsia, polyuria and polyphagia were observed. Islets were obtained following a modification of Ricordi's automatic digestion technique [5]. The pancreas from the diabetic patient was treated in the same manner as the pancreata obtained from the control cadaveric organ donors with a similar time period between death and pancreas removal. Briefly, after the pancreatic duct was cannulated, Hanks' balanced salt solution (HBSS) at 37 ~ containing 1% newborn calf serum (NCS; Gibco, Paisley, UK), 2.5 mg/ml collagenase (Type P; Boehringer Mannheim, Mannheim, FRG) and 0.04mg/ml deoxyribonuclease (DNAseI; Sigma, St.Louis, Mo., USA) was injected. The pancreas was loaded into a digestion chamber and was connected to a closed circuit with recircularization of the medium and continuously shaken. Samples were taken every 3 min, stained with dithizone ...

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The biosociology of pancreatic B cells

Cited by 165 publications

References 94 publications

Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells

Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells

Extra-insular beta cells associated with ductules are frequent in adult human pancreas

Human pancreatic islet function at the onset of Type 1 (insulin-dependent) diabetes mellitus

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