Generation of functional beta cells from stem and progenitor cells

描述(申请人提供)：从多能和成人干细胞中产生功能性β细胞的能力将为移植治疗1型糖尿病、研究它们在疾病状态中的作用以及旨在确定关键调控因子控制其增殖和成熟的机制的筛选提供无限数量的此类细胞。这项提案概述了由七个不同研究小组进行的一系列综合研究，这些研究将组织工程和细胞处理技术与干细胞和内皮细胞生物学相结合，利用人类胚胎干细胞、人类诱导多能干细胞(统称为多能干细胞)和成人胰腺干细胞产生的分化细胞生成具有功能的胰岛样结构。第一个目标是确定信号通路和细胞间的相互作用，这些信号通路和细胞间的相互作用调节多能干细胞产生胰岛素细胞的发育和成熟。第二个目标将使用类似的方法来研究控制最近在成人胰腺中发现的干细胞的增殖和分化的调控途径和细胞群。第三个目标中概述的实验侧重于从不同来源产生内皮祖细胞群体，并调查这些群体促进β细胞分化、存活和成熟的能力。最终目标是测试该项目中通过移植到不同糖尿病小鼠模型中产生的细胞群体和工程组织的功能。这些研究的结果将为调控干细胞和祖细胞在培养中的发育和成熟提供重要的新见解。这些信息将有助于制定在培养中常规和大规模生产功能性β细胞的策略，并促进胰腺内干细胞的再生。这些进展将为开发新的贝塔细胞替代和/或贝塔细胞再生疗法治疗1型糖尿病铺平道路。 公共卫生相关性：目标是研究控制从多能干细胞和成人胰腺来源干细胞产生和成熟产生胰岛素的β细胞的过程。这项工作产生的新信息将为建立产生无限数量的β细胞用于移植治疗1型糖尿病的方法提供基础。

DESCRIPTION (provided by applicant): The ability to generate functional beta cells from pluripotent and adult stem cells will provide access to unlimited numbers of these cells for transplantation for the treatment of type 1 diabetes, for studying their role in disease states and for screens aimed at defining the mechanisms by which key regulators control their proliferation and maturation. This proposal outlines an integrative series of studies by seven different research groups that combine tissue engineering and cell-processing strategies with stem cell and endothelial cell biology to generate functional islet like structures with differentiated cells generated from human embryonic stem cells, human induced pluripotent stem cells (collectively referred to as pluripotent stem cells) and adult pancreatic stem cells. The first aim focuses on defining the signaling pathways and cellular interactions that regulate development and maturation of insulin producing cells from pluripotent stem cells. The second aim will use similar approaches to study the regulatory pathways and cell populations that control the proliferation and differentiation of a recently identified stem cell in the adult human pancreas. The experiments outlined in the third aim focus on generating endothelial progenitor populations from different sources and investigating the capacity of these populations to promote beta cell differentiation, survival and maturation. The goal of the final aim is to test the function of the cell populations and engineered tissues generated in the project by transplantation into different mouse models of diabetes. The outcome of these studies will provide important new insights into the regulation of beta cell development and maturation from stem and progenitor populations in culture. This information will be instrumental in developing strategies for the routine and large-scale production of functional beta cells in culture and for promoting regeneration from stem cells within the pancreas. These advances will pave the way to develop novel beta cell replacement and/or beta cell regeneration therapies for the treatment of type 1 diabetes. PUBLIC HEALTH RELEVANCE: The goals are to study the processes that control the generation and maturation of insulin producing beta cells from pluripotent stem cells and adult pancreatic-derived stem cells. The new information generated from this work will provide the basis for establishing methods to produce unlimited numbers of beta cells for transplantation for the treatment of type 1 diabetes.