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

Abstract

SUMMARYPancreatic islets are 3-dimensional aggregates consisting of unique cellular composition, cell-to-cell contacts, and interactions with blood vessels. Islet cell aggregation is essential for proper endocrine cell function; however, it remains unclear how developing islets establish aggregation. By combining genetic animal models, imaging tools, and gene expression profiling, we demonstrate that the formation of islet aggregates is regulated by extracellular matrix signaling and cell-cell adhesion. Islet endocrine progenitor cell-specific inactivation of extracellular matrix receptor Integrin β1 disrupted vasculature but promoted cell-cell adhesion and the formation of larger islets, while ablation of cell-cell adhesion molecule α-Catenin promoted vasculature formation yet compromised islet clustering. Simultaneous removal of Integrin β1 and α-Catenin abrogates islet aggregation. These mutants exhibit disruption of 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.HIGHLIGHTSIslet vascularization and aggregation are regulated via ECM-Itgb1 signalingECM-Itgb1 signaling negatively controls islet aggregation via regulation of cell-cell adhesion during developmentCell-cell adhesion negatively regulates the interaction of endocrine cell-vasculature in isletsDifferential cell adhesion regulates the establishment of islet architectureEndocrine functional maturation depends on islet aggregation regulated by the coordination of ECM-Itgb1 signaling and cell-cell adhesion