Generation of functional beta cells from stem and progenitor cells

描述（由申请人提供）：从多能干细胞和成体干细胞中生成功能性β细胞的能力将为1型糖尿病的移植治疗提供无限数量的这些细胞，用于研究它们在疾病状态中的作用，以及旨在确定关键调节因子控制其增殖和成熟的机制的筛选。本提案概述了七个不同研究小组的一系列综合研究，这些研究将组织工程和细胞处理策略与干细胞和内皮细胞生物学结合起来，利用从人类胚胎干细胞、人类诱导多能干细胞（统称为多能干细胞）和成人胰腺干细胞中产生的分化细胞产生功能性胰岛样结构。第一个目标侧重于定义信号通路和细胞相互作用，调节多能干细胞的胰岛素产生细胞的发育和成熟。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，并研究这些群体促进β细胞分化、存活和成熟的能力。最终目标是通过移植到不同的糖尿病小鼠模型中，测试该项目中产生的细胞群和工程组织的功能。这些研究的结果将为从培养的干细胞和祖细胞群体中调控β细胞的发育和成熟提供重要的新见解。这一信息将有助于制定常规和大规模培养功能性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β细胞替代和/或β细胞再生疗法治疗1型糖尿病铺平道路。

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.