Distinct Cell Clusters Touching Islet Cells Induce Islet Cell Replication in Association with Over-Expression of Regenerating Gene (REG) Protein in Fulminant Type 1 Diabetes

BackgroundPancreatic islet endocrine cell-supporting architectures, including islet encapsulating basement membranes (BMs), extracellular matrix (ECM), and possible cell clusters, are unclear.ProceduresThe architectures around islet cell clusters, including BMs, ECM, and pancreatic acinar-like cell clusters, were studied in the non-diabetic state and in the inflamed milieu of fulminant type 1 diabetes in humans.ResultImmunohistochemical and electron microscopy analyses demonstrated that human islet cell clusters and acinar-like cell clusters adhere directly to each other with desmosomal structures and coated-pit-like structures between the two cell clusters. The two cell-clusters are encapsulated by a continuous capsule composed of common BMs/ECM. The acinar-like cell clusters have vesicles containing regenerating (REG) Iα protein. The vesicles containing REG Iα protein are directly secreted to islet cells. In the inflamed milieu of fulminant type 1 diabetes, the acinar-like cell clusters over-expressed REG Iα protein. Islet endocrine cells, including beta-cells and non-beta cells, which were packed with the acinar-like cell clusters, show self-replication with a markedly increased number of Ki67-positive cells.ConclusionThe acinar-like cell clusters touching islet endocrine cells are distinct, because the cell clusters are packed with pancreatic islet clusters and surrounded by common BMs/ECM. Furthermore, the acinar-like cell clusters express REG Iα protein and secrete directly to neighboring islet endocrine cells in the non-diabetic state, and the cell clusters over-express REG Iα in the inflamed milieu of fulminant type 1 diabetes with marked self-replication of islet cells.背景：胰腺胰岛内分泌细胞的支持性结构，包括包裹胰岛的基底膜（basement membranes, BMs）、细胞外基质（extracellular matrix, ECM）以及潜在细胞簇，目前尚不明确。 方法：本研究针对人类非糖尿病状态以及暴发性1型糖尿病炎症环境中的胰岛细胞簇周围结构（包括BMs、ECM以及胰腺腺泡样细胞簇）展开分析。 结果：免疫组织化学与电子显微镜分析显示，人类胰岛细胞簇与腺泡样细胞簇可通过细胞间桥粒结构以及包被小窝样结构直接相互黏附。两类细胞簇均被由共同BMs/ECM构成的连续被膜包裹。腺泡样细胞簇内含有携带再生（REG）Iα蛋白的囊泡，此类囊泡可直接向胰岛细胞分泌REG Iα蛋白。在暴发性1型糖尿病的炎症环境中，腺泡样细胞簇会过度表达REG Iα蛋白。与腺泡样细胞簇聚集的胰岛内分泌细胞（包括β细胞与非β细胞）可发生自我复制，Ki67阳性细胞数量显著增加。 结论：与胰岛内分泌细胞直接接触的腺泡样细胞簇具有独特性：此类细胞簇与胰腺胰岛簇聚集，并被共同的BMs/ECM所包裹。此外，在非糖尿病状态下，腺泡样细胞簇可表达REG Iα蛋白并直接向邻近的胰岛内分泌细胞分泌；而在暴发性1型糖尿病的炎症环境中，此类细胞簇会过度表达REG Iα，同时伴随胰岛细胞的显著自我复制。