Role of cell polarity during islet progenitor specification and differentiation

描述（由申请人提供）：胰腺多能祖细胞（MPCs）产生所有胰岛内分泌细胞，包括产生胰岛素的β细胞，出现在早期胰腺芽上皮中。在此期间，胰腺上皮经历了戏剧性和短暂的分层，上皮细胞在形成多层结构时失去极性，但在上皮分解和胰腺分支开始时迅速恢复极性。这种快速形态变化的机制和后果，以及细胞极性的潜在动态变化，是完全未知的。为了支持这一观点，目前该领域的思想已经转向承认3D架构对β细胞命运的潜在影响[5]。推动这项工作的假设提出，胰腺上皮在发育过程中快速分层和去分层的过程，以及细胞极性的相关变化，直接影响内分泌细胞的命运。本研究旨在表征胰腺分层和分化过程中的细胞极性，并测试极性决定因子Numb， Numb-like和Par3是否在胰腺形态发生，MPC规范和内分泌分化中是必需的。了解内分泌β细胞获得命运并分化为功能成熟的胰岛素生成细胞的逐步过程，将推进细胞替代疗法治疗糖尿病的努力，因为这些步骤将被模拟用于体外分化或再生。

DESCRIPTION (provided by applicant): Pancreatic multipotent progenitors (MPCs) that give rise to all islet endocrine cells, including insulin-producing beta cells, emerge within the early pancreatic bud epithelium. During this time, the pancreatic epithelium undergoes a dramatic and transient stratification, with epithelial cells losing their polarity as they generate a multilayered structure, but then quickly regaining it as the epithelium resolves and pancreatic branching begins [4]. The mechanisms and consequences of this rapid morphological change, and of the underlying dynamic shifts in cell polarity, are completely unknown. In support, current thinking in the field has shifted towards acknowledging the potential impact of 3D architecture on beta cell fate [5]. The hypothesis driving this work proposes that the process of rapid stratification and de- stratification of the pancreatic epithelium during development, along with the associated changes in cell polarity, directly impacts endocrine cell fate. This proposal aims to characterize cell polarity during pancreatic stratification and resolution, and to test whether the polarity determinants Numb, Numb-like and Par3 are required for pancreatic morphogenesis, MPC specification and endocrine differentiation. Understanding the stepwise processes by which endocrine beta cells acquire their fate and differentiate into functionally mature insulin-producing cells will advance efforts towards cell replacement therapies to treat diabetes, as these steps will be mimicked for in vitro differentiation or regeneration.