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

Analysis of single nuclear chromatin accessibility reveals unique myeloid populations in human pancreatic ductal adenocarcinoma

“…Furthermore, FGF9 and FGF10 , genes recently shown to be involved in pancreatic development 59 and previously known to be important for neuronal development and maturation 60 play a role in the GO pathway developmental growth for the acinar cell cluster. In the endocrine cluster, the GO pathway neuron projection morphogenesis is characterised by Pax6 , a gene responsible for development of the pancreas and other neuroectodermal structures, 61 ISL1 , a gene important for beta cell function, 62 and ITGB1 , a gene coding for an integrin critical for islet cell development in the pancreas 63 and for neuronal cell migration 64 . ADM GO enrichment includes cell–cell junctions and adhesions, representing the transition of acinar cells to a more ductal‐like phenotype 15 .…”

Concurrent inhibition of IR, ITGB1, and CD36 perturbated the interconnected network of energy metabolism and epithelial‐to‐mesenchymal transition in breast cancer cells

“…It is also involved in the EMT‐mediated metabolic reprogramming of cancer cells. Studies reported a reduced expression of matured ITGB1 in mesenchymal phenotype in comparison to epithelial, thereby causing detachment from ECM 23 . This detachment from ECM induces the lysosomal degradation of the ITGB1/IR complex and metabolic reprogramming of aerobic glycolysis to FA oxidation.…”

Islet architecture in adult mice is actively maintained by Robo2 expression in β cells

“…Research continues to explore the essential role of extracellular matrix (ECM) proteins in regulating islet architecture, including supplementing Matrigel with key ECM factors (Tixi et al, 2022;Tremmel et al, 2022). Slit is the canonical ligand for Robo receptors, and has also been 9…”

“…Similarly, islets derived from stem cells function better when induced to form mature architecture (Balboa et al, 2022). Research continues to explore the essential role of extracellular matrix (ECM) proteins in regulating islet architecture, including supplementing Matrigel with key ECM factors (Tixi et al, 2022; Tremmel et al, 2022). Slit is the canonical ligand for Robo receptors, and has also been shown to impact islet formation in developing mice (Gilbert et al, 2020).…”