Coordination between ECM and cell-cell adhesion regulates the development of islet aggregation, architecture, and functional maturation

• DOI: 10.7554/elife.90006
• Publication Date: 2023-08-23T11:20:14Z
• Authors: Wilma Tixi; Maricela Maldonado; Ya-Ting Chang; Amy Chiu; Wilson Yeung; Nazia Parveen; Michael S Nelson; Ryan Hart; Shihao Wang; Wu Jih Hsu; Patrick Fueger; Janel L Kopp; Mark O Huising; Sangeeta Dhawan; Hung Ping Shih
• Keywords: α-Catenin; 570; Biomedical and clinical sciences; integrin; QH301-705.5; 1.1 Normal biological development and functioning; Science; Autoimmune Disease; developmental biology; 03 medical and health sciences; 617; Cell Adhesion; 2.1 Biological and endogenous factors; Animals; Biology (General); Metabolic and endocrine; mouse; Cell Aggregation; 0303 health sciences; ECM; islet; Integrin beta1; Diabetes; Q; R; Health sciences; cell adhesion; Biological Sciences; endocrine cells; Extracellular Matrix; Biological sciences; Medicine; Biochemistry and Cell Biology; alpha Catenin; Developmental Biology

Pancreatic islets are three-dimensional cell aggregates consisting of unique cellular composition, cell-to-cell contacts, and interactions with blood vessels. Cell aggregation is essential for islet endocrine function; however, it remains unclear how developing islets establish aggregation. By combining genetic animal models, imaging tools, and gene expression profiling, we demonstrate that islet aggregation is regulated by extracellular matrix signaling and cell-cell adhesion. Islet endocrine cell-specific inactivation of extracellular matrix receptor integrin β1 disrupted blood vessel interactions but promoted cell-cell adhesion and the formation of larger islets. In contrast, ablation of cell-cell adhesion molecule α-catenin promoted blood vessel interactions yet compromised islet clustering. Simultaneous removal of integrin β1 and α-catenin disrupts islet aggregation and the endocrine cell maturation process, demonstrating that establishment of islet aggregates is essential for functional maturation. Our study provides new insights into understanding the fundamental self-organizing mechanism for islet aggregation, architecture, and functional maturation.