Coordination between ECM and cell-cell adhesion regulates the development of islet aggregation, architecture, and functional maturation.
Publication Year:
2023
PubMed ID:
37610090
Public Summary:
Within our bodies, there are tiny clusters of cells in our pancreas known as “pancreatic islets” that are critical for controlling blood sugar. The correct organization of these islets is essential for their proper function, and poor organization may lead to health issues like diabetes. Our research, supported by CIRM's dedication to stem cell and regenerative medicine, delves into understanding how these islets organize during their development. Using advanced techniques, we discovered that both cell-cell adhesion (how cells stick to one another) and cell-ECM (extracellular matrix) adhesion (how cells interact with their surroundings) are coordinately regulated. Disruptions in these adhesion processes can lead to changes in islet size and interactions with blood vessels. Specifically, molecules like integrin β1 (cells use this protein to attach to ECM) and α-catenin (cells use this protein to stick to one another) play crucial roles in this organization. Better understanding these molecules might unlock new avenues in regenerative medicine. Our findings highlight the potential of using stem cells to recreate these vital islets in the lab. This research not only offers hope for innovative diabetes treatments but also underscores CIRM's commitment to advancing stem cell therapies for a healthier future.
Scientific Abstract:
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 beta1 disrupted blood vessel interactions but promoted cell-cell adhesion and the formation of larger islets. In contrast, ablation of cell-cell adhesion molecule alpha-catenin promoted blood vessel interactions yet compromised islet clustering. Simultaneous removal of integrin beta1 and alpha-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.