A vascularized 3D biomimetic for islet function and physiology

用于胰岛功能和生理学的血管化 3D 仿生模型

• 批准号: 9169717
• 负责人: CHRISTOPHER S CHEN
• 金额: $ 7.2万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-20 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9169717
• 关键词: Adoption; Affect; American; Animal Model; Biomedical Engineering; Biomimetics; Cell Survival; Cell physiology; Cells; Cellular Structures; Cellular biology; Communities; Development; Developmental Cell Biology; Devices; Diabetes Mellitus; Direct Costs; Disease; Disease model; Endocrine; Event; Exposure to; Facilities and Administrative Costs; Failure; Functional disorder; Glucose; Goals; Health; Human; Immune; In Vitro; Insulin; Insulin-Dependent Diabetes Mellitus; Intestines; Islets of Langerhans; Lead; Liquid substance; Maintenance; Methods; Modeling; Molds; Molecular; Mus; Organoids; Patients; Performance; Phenotype; Physiology; Population; Positioning Attribute; Production; Protocols documentation; Rodent; Source; Staging; Stem cells; System; Tissues; design; diabetes mellitus therapy; experience; in vivo; induced pluripotent stem cell; innovation; islet; novel; portability; progenitor; programs; reconstitution; scaffold; success; tool

 DESCRIPTION: The goals of our proposal are to bring together an expert team of bioengineers and stem cell/developmental biologists to create a Human Islet Biomimetic that will facilitate (i) long term culture and manipulation of human islets and (ii) maturation of stem-cell derived or reprogrammed islets. Specifically, we will combine our expertise in cell and developmental biology with our experience molding three dimensional vascularized scaffolds in which cellular inputs, matrix composition, and microscale organization (including flow) can be varied with precision. Although much is known about islet function under homeostatic conditions in vivo, current methods for studying islet physiology and pathophysiology are severely limited. Studies that rely on model organisms - particularly mice - are hampered by cellular and molecular discrepancies between human and rodent islets. The use of human islets for studies of islet physiology is also problematic, as limited availability and exposure to non-physiological conditions during isolation impede the use of this cellular source. Most importantly, there is no system currently available which supports the full function of islets or b-cells for more than a fe days in culture. Thus, our understanding of islet function and dysfunction - particularly as it relates to type 1 diabetes (T1D) - has been constrained by the lack of tools for maintaining and studying human islets in vitro. Into this gap, we will take cadaveric human islets, pancreatic progenitors from human ES and iPS cells, and endocrine cells that are trans-differentiated from intestinal stem cells as starting material, and incorporate them into innovative scaffold devices that provide control over local structure, cellular content, and fluid dynamics to stabilize b-cell function. Overall, we plan to reconstitute human islet biomimetics that recapitulate the diverse cellular types and their organization within the natural human islet. In addition, we will use the system to explore the reasons why islets are prone to lose function when placed ex vivo and to model human islet diseases. This system will be critical for the success of other HIRN consortia, as well for the b-cell biology community at large by providing an accessory system for studying b-cell survival, immune interactions, and alternate sources of b-cells. Our Aims are as follows: Aim 1: To establish a human islet biomimetic for sustained islet viability and function in vitro. Aim 2: To optimize human islet biomimetic function with respect to glucose sensing, insulin release, and stable maintenance of islet phenotypes. Our study is designed to provide a deeper understanding of the molecular and cellular events that lead to islet dysfunction in T1D and related islet disorders and to help develop strategies to restore normal islet function in these disorders.

 描述：我们提案的目标是汇集生物工程师和干细胞/发育生物学家的专家团队，创建一种人类胰岛仿生学，它将促进（i）人类胰岛的长期培养和操作以及（ii）干细胞衍生或重新编程的胰岛的成熟。具体来说，我们将把我们在细胞和发育生物学方面的专业知识与我们塑造三维血管化支架的经验相结合，其中细胞输入、基质组成和微观组织（包括流动）可以精确变化。尽管人们对体内稳态条件下的胰岛功能了解很多，但目前研究胰岛生理学和病理生理学的方法受到严重限制。依赖模型生物体（尤其是小鼠）的研究因人类和啮齿动物胰岛之间的细胞和分子差异而受到阻碍。使用人类胰岛进行胰岛生理学研究也存在问题，因为在分离过程中有限的可用性和暴露于非生理条件阻碍了这种细胞来源的使用。最重要的是，目前还没有系统可以支持胰岛或 b 细胞在培养中超过 fe 天的全部功能。因此，我们对胰岛功能和功能障碍的理解，特别是与 1 型糖尿病 (T1D) 相关的知识，由于缺乏体外维持和研究人类胰岛的工具而受到限制。为了解决这个问题，我们将以人类尸体胰岛、来自人类 ES 和 iPS 细胞的胰腺祖细胞以及从肠干细胞转分化的内分泌细胞作为起始材料，并将它们纳入创新的支架装置中，以控制局部结构、细胞内容和流体动力学，以稳定 b 细胞 功能。总体而言，我们计划重建人类胰岛仿生学，以概括自然人类胰岛中的不同细胞类型及其组织。此外，我们将利用该系统探讨胰岛在离体放置时容易丧失功能的原因，并模拟人类胰岛疾病。该系统为研究 b 细胞存活、免疫相互作用和 b 细胞替代来源提供了辅助系统，对于其他 HIRN 联盟以及整个 b 细胞生物学界的成功至关重要。我们的目标如下： 目标 1：建立人类胰岛仿生体，以实现体外胰岛的持续活力和功能。目标 2：优化人类胰岛仿生功能，包括葡萄糖传感、胰岛素释放和胰岛表型的稳定维持。我们的研究旨在更深入地了解导致 T1D 和相关胰岛疾病中胰岛功能障碍的分子和细胞事件，并帮助制定恢复这些疾病中正常胰岛功能的策略。