Role of cell polarity during islet progenitor specification and differentiation

细胞极性在胰岛祖细胞规范和分化过程中的作用

• 批准号: 8132196
• 负责人: Leilani Marie Marty-Santos
• 金额: $ 2.89万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8132196
• 关键词: Architecture; Automobile Driving; Back; Beta Cell; Blood Glucose; Cell Lineage; Cell Polarity; Cells; DNA Sequence Rearrangement; Data; Development; Diabetes Mellitus; Disease; Embryo; Endocrine; Epithelial; Epithelial Cells; Epithelium; Event; Generations; Goals; Image; In Vitro; Insulin; Islet Cell; Islets of Langerhans; Life; Morphogenesis; Multipotent Stem Cells; Mus; Natural regeneration; Organogenesis; Pancreas; Pancreatic Bud; Patients; Process; Replacement Therapy; Reporter; Research; Resolution; Role; Series; Staging; Stem cells; Stratification; Structure; Structure of beta Cell of islet; Testing; Thinking; Time; Tissues; Transgenic Organisms; Work; beta cell replacement; blood glucose regulation; diabetic; islet; pancreas development; progenitor; regenerative therapy; therapy development

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. PUBLIC HEALTH RELEVANCE: Pancreatic islet cells are essential regulators of blood glucose homeostasis, a process required for life that is defective in patients with diseases such as diabetes. Islet cells, including insulin-producing beta cells, arise from multipotent progenitor cells (MPCs) within the early developing pancreas. Here, we focus on elucidating the role of epithelial cell polarity and 3D architecture on the specification of MPCs, as we have found that embryonic pancreatic epithelium undergoes an unusual transient cellular rearrangement (stratification) and loss of cell polarity. Understanding the steps underlying islet cell formation applies directly to efforts at creating new insulin-producing beta cells for replacement therapy in diabetics.

描述（由申请人提供）：产生所有胰岛内分泌细胞（包括产生胰岛素的β细胞）的胰腺多能祖细胞（MPC）出现在早期胰芽上皮内。在此期间，胰腺上皮经历剧烈且短暂的分层，上皮细胞在生成多层结构时失去极性，但随后随着上皮分解和胰腺分支开始而迅速恢复极性[4]。这种快速的形态变化以及细胞极性的潜在动态变化的机制和后果是完全未知的。作为支持，该领域当前的想法已经转向承认 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，以及相关的细胞极性变化，直接影响内分泌细胞的命运。该提案旨在表征胰腺分层和解析过程中的细胞极性，并测试极性决定因素 Numb、Numb-like 和 Par3 是否是胰腺形态发生、MPC 规范和内分泌分化所必需的。了解内分泌β细胞获得其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动细胞替代疗法治疗糖尿病的努力，因为这些步骤将被模仿以进行体外分化或再生。 公众健康相关性：胰岛细胞是血糖稳态的重要调节因子，血糖稳态是糖尿病等疾病患者生命所必需的过程。胰岛细胞，包括产生胰岛素的β细胞，由早期发育的胰腺内的多能祖细胞（MPC）产生。在这里，我们重点阐明上皮细胞极性和 3D 结构对 MPC 规范的作用，因为我们发现胚胎胰腺上皮经历了不寻常的短暂细胞重排（分层）和细胞极性丧失。了解胰岛细胞形成的步骤直接适用于创造新的产生胰岛素的β细胞以用于糖尿病患者的替代治疗。