We have collaborated with the Hara laboratory in formulating a quantitative understanding of various aspects of islet development from their data: (1) Emerging reports on the organization of the different hormone-secreting cell types (alpha, glucagon;beta, insulin;and delta, somatostatin) in human islets have emphasized the distinct differences between human and mouse islets, raising questions about the relevance of studies of mouse islets to human islet physiology. Here, we examined the differences and similarities between the architecture of human and mouse islets. We studied islets from various mouse models including ob/ob and db/db and pregnant mice. We also examined the islets of monkeys, pigs, rabbits and birds for further comparisons. Despite differences in overall body and pancreas size as well as total b-cell mass among these species, the distribution of their islet sizes closely overlaps, except in the bird pancreas in which the d-cell population predominates (both in singlets and clusters) along with a small number of islets. Markedly large islets (>10,000 μm2) were observed in human and monkey islets as well as in islets from ob/ob and pregnant mice. The fraction of alpha-, beta- and delta-cells within an islet varied between islets in all the species examined. Furthermore, there was variability in the distribution of a- and d-cells within the same species. The islets of Langerhans are micro-organs mainly composed of insulin-secreting beta-cells and a smaller number of glucagon-secreting alpha-cells that function together to maintain normoglycemia. The cellular signals, both extra- and intracellular, which regulate beta-cell proliferation and maturation and islet formation, are poorly understood. 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. The alpha-cells at these putative cleavage sites express both prohormone convertase 2 and 1/3 (PC2 and PC1/3, respectively), whereas alpha-cells in the adult express only PC2. The expression of PC1/3 in these neonatal alpha-cells results in the processing of the proglucagon precursor into glucagon-like peptide 1 (GLP-1), thereby leading to local production of this important beta-cell growth factor. 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. In summary, human and mouse islets share common architectural features that may reflect demand for insulin. Comparative studies of islet architecture may lead to a better understanding of islet development and function. (2) The pancreatic islets consist of a few to several thousands of endocrine cells independent of species over a range of body sizes, suggesting an optimal size for the function. To examine their development producing a certain size range of islets, we used a novel method that images all the islets in an intact pancreas of the transgenic mice expressing a fluorescent protein specifically in beta cells. Based on changes of the islet size distribution from postnatal day 1 to week 20, we analyzed islet developmental processes such as birth, growth and fission with mathematical modeling. No new islets were formed after postnatal week 4. Regarding islet growth, cell prolfieration in smaller islets occurred more actively than the one in larger islets at early postnatal days. However, the size dependence as well as the proliferation rate diminished with time, and every bata cell in different sized islets ultimately has equally small proliferation potential in adulthood. In addition to this limited islet growth, fission of large islets, most actively occurred at postnatal week 3, contributed to retain a certain range of islet size. On the other hand, under a tumor (insulinoma) progression, we found unlimited islet growth, especially more accelerated cell proliferation in larger islets. We conclude that islet size is constrained by size-dependent islet growth and fission of large islets at early postnatal period.
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