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Islet formation during the neonatal development in mice.

Miller K, Kim A, Kilimnik G, Jo J, Moka U, Periwal V, Hara M - PLoS ONE (2009)

Bottom Line: Our study has revealed long stretches of interconnected islets located along large blood vessels in the neonatal pancreas.Alpha-cells span the elongated islet-like structures, which we hypothesize represent sites of fission and facilitate the eventual formation of discrete islets.Mathematical modeling of the fission process in the neonatal islet formation is also presented.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, The University of Chicago, Chicago, IL, USA.

ABSTRACT
The islet of Langerhans is a unique micro-organ within the exocrine pancreas, which is composed of insulin-secreting beta-cells, glucagon-secreting alpha-cells, somatostatin-secreting delta-cells, pancreatic polypeptide-secreting PP cells and ghrelin-secreting epsilon-cells. Islets also contain non-endocrine cell types such as endothelial cells. However, the mechanism(s) of islet formation is poorly understood due to technical difficulties in capturing this dynamic event in situ. We have developed a method to monitor beta-cell proliferation and islet formation in the intact pancreas using transgenic mice in which the beta-cells are specifically tagged with a fluorescent protein. Endocrine cells proliferate contiguously, forming branched cord-like structures in both embryos and neonates. Our study has revealed long stretches of interconnected islets located along large blood vessels in the neonatal pancreas. Alpha-cells span the elongated islet-like structures, which we hypothesize represent sites of fission and facilitate the eventual formation of discrete islets. We propose that islet formation occurs by a process of fission following contiguous endocrine cell proliferation, rather than by local aggregation or fusion of isolated beta-cells and islets. Mathematical modeling of the fission process in the neonatal islet formation is also presented.

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Mathematical analysis of islet development.Log plots of the distribution of beta-cell mass at each time point of the developing pancreas. The numerical value of each beta-cell mass is converted to an effective diameter, s (i.e. a parameter that depicts the same area of a perfect circle) and is plotted as scattered dots. Note that the overall growth of beta-cells and islet development fit into a log normal function, where at P12 and thereafter, the distribution of islets larger than 200 µm in effective diameter falls off from the curve with a leftward shift, suggesting the possible occurrence of fission events in the interconnected islet-like structures. For a clearer view, the deviation between absolute islet-size distribution and the lognormal fit, Δn, is shown in histograms placed right on each distribution.
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pone-0007739-g003: Mathematical analysis of islet development.Log plots of the distribution of beta-cell mass at each time point of the developing pancreas. The numerical value of each beta-cell mass is converted to an effective diameter, s (i.e. a parameter that depicts the same area of a perfect circle) and is plotted as scattered dots. Note that the overall growth of beta-cells and islet development fit into a log normal function, where at P12 and thereafter, the distribution of islets larger than 200 µm in effective diameter falls off from the curve with a leftward shift, suggesting the possible occurrence of fission events in the interconnected islet-like structures. For a clearer view, the deviation between absolute islet-size distribution and the lognormal fit, Δn, is shown in histograms placed right on each distribution.

Mentions: We then employed a mathematical approach to define beta-cell proliferation and islet development in detail. When we used an “effective diameter” (defined as the diameter of a perfect disk of the same area as a given islet area) as an islet size parameter, s, the islet-size distribution strikingly fits the lognormal distribution (Fig. 3). Note that the shape of islet-size distributions does not change greatly with development, although total islet number increases (Table S1 for μ and σ at different postnatal days; Fig. S1B for total islet number). The invariance is a result of decreasing cell proliferation after initial rapid proliferation (Fig. 4B). Details of the derivation and the invariance of the lognormal distribution are described in the Materials and Methods section. It is of interest that no large islets (s>600 µm) exist after P12. Coincident with this observation, the islet-size distributions start to fall off from the lognormal curve at a certain islet size (s>100 µm). This result is more evident in the absolute islet-size distributions; Figure 3 shows the deviation between measured islet-size distributions and the lognormal fit. The discrepancy allowed us to interpret another islet-growth mechanism beyond the normal random growth that corresponds to the lognormal distribution. Fewer large islets (s>250 µm) and more small islets (100∼250 µm) than the expected number from the lognormal distribution are explained by the occurrence of islet fission, which is also supported by the morphology of large elongated islets in Fig. 1D. Islet fission may occur in large islets (s>250 µm at P18 and s>370 µm at P21) starting from around P12 to P14. The fission frequencies, calculated from the appearance of additional small islets beyond the expected number from the lognormal distribution, are 6±6 at P14; 57±9 at P18; and 166±25 at P21. Note that islet fission does not explain the enormous increase of islet number at P18 and P21, because most of this increase occurs in small beta-cell clusters (s<100 µm), sizes at which islet fission does not contribute significantly (Fig. S1). The increase in single cells and small clusters may reflect the cell division or differentiation of progenitor cells or neogenesis from the duct. In small islets (s>100 µm), however, 30 to 50% of existing small islets are a result of islet fission, while the remaining islets result from normal growth from single beta-cells.


Islet formation during the neonatal development in mice.

Miller K, Kim A, Kilimnik G, Jo J, Moka U, Periwal V, Hara M - PLoS ONE (2009)

Mathematical analysis of islet development.Log plots of the distribution of beta-cell mass at each time point of the developing pancreas. The numerical value of each beta-cell mass is converted to an effective diameter, s (i.e. a parameter that depicts the same area of a perfect circle) and is plotted as scattered dots. Note that the overall growth of beta-cells and islet development fit into a log normal function, where at P12 and thereafter, the distribution of islets larger than 200 µm in effective diameter falls off from the curve with a leftward shift, suggesting the possible occurrence of fission events in the interconnected islet-like structures. For a clearer view, the deviation between absolute islet-size distribution and the lognormal fit, Δn, is shown in histograms placed right on each distribution.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2770846&req=5

pone-0007739-g003: Mathematical analysis of islet development.Log plots of the distribution of beta-cell mass at each time point of the developing pancreas. The numerical value of each beta-cell mass is converted to an effective diameter, s (i.e. a parameter that depicts the same area of a perfect circle) and is plotted as scattered dots. Note that the overall growth of beta-cells and islet development fit into a log normal function, where at P12 and thereafter, the distribution of islets larger than 200 µm in effective diameter falls off from the curve with a leftward shift, suggesting the possible occurrence of fission events in the interconnected islet-like structures. For a clearer view, the deviation between absolute islet-size distribution and the lognormal fit, Δn, is shown in histograms placed right on each distribution.
Mentions: We then employed a mathematical approach to define beta-cell proliferation and islet development in detail. When we used an “effective diameter” (defined as the diameter of a perfect disk of the same area as a given islet area) as an islet size parameter, s, the islet-size distribution strikingly fits the lognormal distribution (Fig. 3). Note that the shape of islet-size distributions does not change greatly with development, although total islet number increases (Table S1 for μ and σ at different postnatal days; Fig. S1B for total islet number). The invariance is a result of decreasing cell proliferation after initial rapid proliferation (Fig. 4B). Details of the derivation and the invariance of the lognormal distribution are described in the Materials and Methods section. It is of interest that no large islets (s>600 µm) exist after P12. Coincident with this observation, the islet-size distributions start to fall off from the lognormal curve at a certain islet size (s>100 µm). This result is more evident in the absolute islet-size distributions; Figure 3 shows the deviation between measured islet-size distributions and the lognormal fit. The discrepancy allowed us to interpret another islet-growth mechanism beyond the normal random growth that corresponds to the lognormal distribution. Fewer large islets (s>250 µm) and more small islets (100∼250 µm) than the expected number from the lognormal distribution are explained by the occurrence of islet fission, which is also supported by the morphology of large elongated islets in Fig. 1D. Islet fission may occur in large islets (s>250 µm at P18 and s>370 µm at P21) starting from around P12 to P14. The fission frequencies, calculated from the appearance of additional small islets beyond the expected number from the lognormal distribution, are 6±6 at P14; 57±9 at P18; and 166±25 at P21. Note that islet fission does not explain the enormous increase of islet number at P18 and P21, because most of this increase occurs in small beta-cell clusters (s<100 µm), sizes at which islet fission does not contribute significantly (Fig. S1). The increase in single cells and small clusters may reflect the cell division or differentiation of progenitor cells or neogenesis from the duct. In small islets (s>100 µm), however, 30 to 50% of existing small islets are a result of islet fission, while the remaining islets result from normal growth from single beta-cells.

Bottom Line: Our study has revealed long stretches of interconnected islets located along large blood vessels in the neonatal pancreas.Alpha-cells span the elongated islet-like structures, which we hypothesize represent sites of fission and facilitate the eventual formation of discrete islets.Mathematical modeling of the fission process in the neonatal islet formation is also presented.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, The University of Chicago, Chicago, IL, USA.

ABSTRACT
The islet of Langerhans is a unique micro-organ within the exocrine pancreas, which is composed of insulin-secreting beta-cells, glucagon-secreting alpha-cells, somatostatin-secreting delta-cells, pancreatic polypeptide-secreting PP cells and ghrelin-secreting epsilon-cells. Islets also contain non-endocrine cell types such as endothelial cells. However, the mechanism(s) of islet formation is poorly understood due to technical difficulties in capturing this dynamic event in situ. We have developed a method to monitor beta-cell proliferation and islet formation in the intact pancreas using transgenic mice in which the beta-cells are specifically tagged with a fluorescent protein. Endocrine cells proliferate contiguously, forming branched cord-like structures in both embryos and neonates. Our study has revealed long stretches of interconnected islets located along large blood vessels in the neonatal pancreas. Alpha-cells span the elongated islet-like structures, which we hypothesize represent sites of fission and facilitate the eventual formation of discrete islets. We propose that islet formation occurs by a process of fission following contiguous endocrine cell proliferation, rather than by local aggregation or fusion of isolated beta-cells and islets. Mathematical modeling of the fission process in the neonatal islet formation is also presented.

Show MeSH
Related in: MedlinePlus