Coordination between ECM and cell-cell adhesion regulates the development of islet aggregation, architecture, and functional maturation.
Coordination between ECM and cell-cell adhesion regulates the development of islet aggregation, architecture, and functional maturation.
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DOI：
10.7554/elife.90006
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发表时间：
2023-08-23
期刊：
影响因子：
7.7
通讯作者：
Shih HP
中科院分区：
文献类型：
--
作者：
Tixi W;Maldonado M;Chang YT;Chiu A;Yeung W;Parveen N;Nelson MS;Hart R;Wang S;Hsu WJ;Fueger P;Kopp JL;Huising MO;Dhawan S;Shih HP
胰岛是三维细胞聚集体，由独特的细胞组成、细胞与细胞的接触以及与血管的相互作用组成。细胞聚集对于胰岛内分泌功能是必不可少的;然而，尚不清楚发育中的胰岛如何建立聚集。通过结合遗传动物模型、成像工具和基因表达谱，我们证明胰岛聚集受细胞外基质信号传导和细胞-细胞粘附的调节。胰岛内分泌细胞特异性灭活细胞外基质受体整合素β1破坏了血管相互作用，但促进了细胞间粘附和较大胰岛的形成。相比之下，细胞-细胞粘附分子α-连环蛋白的消融促进了血管相互作用，但损害了胰岛聚集。同时去除整合素β1和α-连环蛋白破坏胰岛聚集和内分泌细胞成熟过程，表明胰岛聚集体的建立对功能成熟至关重要。我们的研究为理解胰岛聚集、结构和功能成熟的基本自组织机制提供了新的见解。
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.