Engineering human islet-like organoids for transplantation

工程化人类胰岛样器官用于移植

基本信息

批准号：
9788431
负责人：
RONALD M EVANS
金额：
$ 84.93万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9788431
关键词：
3-Dimensional Anatomy Anti-inflammatory Beta Cell Blood Glucose Cell Death Cell Transplantation Cell Transplants Cell physiology Cell surface Cells Clinical Diabetes Mellitus Diabetic mouse Engineering Environment Functional disorder Generations Genetic Transcription Glucose Goals Graft Rejection Human Human Engineering Hyperglycemia Immune Immune Evasion Immune Tolerance Immune system Immunodeficient Mouse Immunosuppressive Agents In Vitro Inflammation Inflammatory Inflammatory Response Insulin-Dependent Diabetes Mellitus Islets of Langerhans Transplantation Ligands Maintenance Mesenchymal Metabolic Methods Molecular Monitor Mus NOD/SCID mouse Natural Killer Cells Organ Organoids PDCD1LG1 gene Pharmaceutical Preparations Pharmacology Polymers Production Protocols documentation Receptor Signaling Risk Role Safety Signal Transduction Stem cells Streptozocin Stress System T-Lymphocyte Techniques Teratoma Testing Therapeutic Transplantation Undifferentiated Vitamin D Vitamin D3 Receptor Wound Healing base beta cell replacement cell growth clinical application cytokine diabetes mellitus therapy diabetic endocrine pancreas development endoplasmic reticulum stress human pluripotent stem cell improved in vivo inhibitor/antagonist insulin secretion islet mouse model next generation novel post-transplant preclinical study response transcriptomics type I diabetic

项目摘要

ABSTRACT Pancreatic islet transplantation offers long-term treatment for Type 1 diabetes, however the shortage of donors and the need for immunosuppressive drugs restrict its therapeutic utility. Islet-like organoids generated from human pluripotent stem cells (PSCs) are an attractive alternative. Moreover, given the increasing appreciation for the role of multi-cellular organization in the functional maturation and maintenance of organs, islet-like organoids have the potential for superior functionality compared to β cells alone. The goal of this project is to develop the next generation of human islet-like organoids (HILOs) from stem cells for efficient and immune evasive transplantation. The underlying hypothesis is that a combination of a novel 3D differentiation protocol, modulation of cell surface signaling, and anti-inflammation transcriptional machinery will enable HILOs to survive long-term and function in an immune competent environment in vivo. To achieve this goal, Aim 1 proposes to establish the long-term efficacy and safety profile of HILOs, of which the function has been validated extensively in vitro. Aim 2 proposes to develop immune-tolerant HILOs by engineering the expression of PD-L1 and demonstrating the efficacy in humanized immune-competent diabetic mice. To further extend protection of transplanted HILOs, Aim 3 proposes to apply pharmacological activation of vitamin D signaling to alleviate cytokine stress on transplanted HILOs. The goal is to determine whether the incorporation of these strategies to improve survival as well as minimize allo-rejection of transplanted HILOs will result in an unlimited supply of therapeutically viable engineered islets for treating diabetes.

抽象的胰岛移植为 1 型糖尿病提供了长期治疗，但缺乏供体和对免疫抑制药物的需求限制了其产生的胰岛样类器官的治疗用途。来自人类多能干细胞（PSC）的细胞是一种有吸引力的替代品。了解多细胞组织在器官功能成熟和维护中的作用，与单独的 β 细胞相比，胰岛样类器官具有卓越的功能潜力。该项目的目的是利用干细胞开发下一代人类胰岛类器官（HILO），以实现高效和免疫逃避移植的基本假设是新颖的 3D 分化的组合。协议、细胞表面信号传导的调节和抗炎转录机制将使 HILO 能够在体内的免疫环境中长期存活并发挥作用。目标 1 提议建立 HILO 的长期功效和安全性概况，其功能已被主要在体外进行验证，目标 2 建议通过改造表达来开发免疫耐受的 HILO。 PD-L1 并证明其在人源化免疫功能正常的糖尿病小鼠中的功效。为了保护移植的 HILO，目标 3 提出应用维生素 D 信号传导的药理学激活减轻移植 HILO 上的细胞因子应激目标是确定这些是否并入。提高存活率并尽量减少移植 HILO 的同种异体排斥的策略将导致无限的提供治疗上可行的工程胰岛来治疗糖尿病。