A conserved rule for pancreatic islet organization

Abstract

Morphogenesis, spontaneous formation of organism structure, is essential for life. In the pancreas, endocrine α, β, and δ cells are clustered to form islets of Langerhans, the critical micro-organ for glucose homeostasis. The spatial organization of endocrine cells in islets looks different between species. Based on the three-dimensional positions of individual cells in islets, we computationally inferred the relative attractions between cell types, and found that the attractions between homotypic cells were slightly, but significantly, stronger than the attractions between heterotypic cells commonly in mouse, pig, and human islets. The difference between α-β cell attraction and β-β cell attraction was minimal in human islets, maximizing the plasticity of islet structures. Our result suggests that although the cellular composition and attractions of pancreatic endocrine cells are quantitatively different between species, the physical mechanism of islet morphogenesis may be evolutionarily conserved.

Figure 1. Cellular organization of pancreatic islets.

Three-dimensional spatial distribution of α cells (red) and β cells (green) is shown in (A) mouse, (B) pig, and (C) human islets. To show internal islet structures clearly, their corresponding two-dimensional sections are also shown in boxes.

Figure 2. Cellular compositions in mouse, pig, and human islets.

Fractions of β cells, depending on islets size, are calculated in mouse (empty bar), pig (hatched), and human (black solid) islets. Islet size is represented by the total number of cells in islets, and categorized as small (<1000 cells), medium (1000–2000), and large (>2000) islets. Mean ± SEM (n = 30). ^* P<0.005.

Figure 3. Cell-to-cell contact ratios in mouse, pig, and human islets.

Based on the contacts between neighboring cells, ratios of , , and contacts (, , and ), depending on islet size, are calculated in (A) mouse, (B) pig, and (C) human islets. Islet size is represented by the total number of cells in islets, and categorized as small (<1000 cells), medium (1000–2000), and large (>2000) islets. Given fractions of and cells ( and ), the , , and contact probabilities in random cell organization are theoretically , , and , respectively. The random organization (empty bar) is compared with the organization of native islets (black solid). Mean ± SEM. ^* P<0.005.

Figure 4. Schematic diagram of structural dependence on relative attractions between cell types.

A sorting structure of two cell types is changed to mixing structures, as heterotypic attraction increased compared with homotypic attractions: (A) complete sorting, (B) shell-core sorting, and (C) mixing structures.

Figure 5. Cellular attractions in mouse, pig, and human islets.

Relative attractions between cell types and their uncertainties are inferred from three-dimensional islet structures. Symbols represent individual islets: mouse (black circle), pig (blue square), and human islets (red triangle and pink inverse triangle). Each species has n = 30 islets. In particular, two sets of n = 30 islets are provided from two human (Human1 and Human2) subjects. The relationship between and is fitted with linear functions, , represented by solid lines with colors corresponding to each species. Note that the attraction between cells is defined as a reference attraction, .

Figure 6. Distinct structures of binary mixtures.

Complete sorting, shell-core sorting, and partial mixing structures are plotted for (A) cubic and (B) hexagonal close packed lattices. Here each lattice consists of 1357 cells with 10% cells (red) and 90% cells (green). The relative attractions are chosen to have the specific structures: 0.7 (left), 0.85 (middle), and 1.1 (right) for (A) the cubic lattice; and 0.7 (left), 0.93 (middle), and 1.1 (right) for (B) the hexagonal close packed lattice. Note that the homotypic attractions are fixed as a reference, , and the thermal fluctuation energy is .

Figure 7. Phase diagrams of binary mixtures.

Binary mixtures have complete sorting (white region), shell-core sorting (cyan region), partial mixing (yellow region), and complete sorting (gray region) structures depending on mixture fraction and relative adhesion strengths. Plotted are phase diagrams for (A) cubic and (B) hexagonal close packed lattices with 1357 cells. Symbols represent the observed β-cell fraction and the inferred relative attraction of mouse islets (black circle), pig (blue square), and human islets (red triangle and pink inverse triangle). Note that the homotypic attractions have a reference attraction, . Each species has n = 30 islets. Mean ± SD.

Figure 8. Cellular organization of human pancreatic islets.

Three-dimensional spatial distribution of cells (red), cells (green), and cells (blue) in human islets is shown. To show internal islet structures clearly, their corresponding two-dimensional sections are also shown in boxes. Note that islets are isolated from the Human3 subject for this plot.