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：
10161781
负责人：
RONALD M EVANS
金额：
$ 86.5万
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/10161781
关键词：
3-Dimensional Anatomy Anti-Inflammatory Agents Beta Cell Blood Glucose Cell Death Cell Transplantation 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 Immunocompetent 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 Pharmacology Polymers Production Protocols documentation Receptor Signaling Risk Role Safety Signal Transduction Streptozocin Stress System T-Lymphocyte Techniques Teratoma Testing Therapeutic Transplantation Undifferentiated Vitamin D Vitamin D3 Receptor base cell growth cell replacement therapy clinical application cytokine diabetes mellitus therapy diabetic differentiation protocol efficacy evaluation endocrine pancreas development endoplasmic reticulum stress human pluripotent stem cell improved in vivo inhibitor/antagonist insulin secretion islet mouse model next generation novel organoid transplantation post-transplant preclinical study programmed cell death ligand 1 response stem cells systemic inflammatory response transcriptomics type I diabetic wound healing

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.

抽象的胰岛移植提供了1型糖尿病的长期治疗，但是短缺捐助者和对免疫抑制药物的需求限制了其治疗效用。产生的胰岛状类队来自人类多能干细胞（PSC）是一种有吸引力的替代方法。而且，鉴于增加对多细胞组织在组织成熟和维护组织中的作用的欣赏，与单独的β细胞相比，胰岛样的类器官具有出色功能的潜力。目标的目标项目是为了有效和免疫反射移植。潜在的假设是新型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械将启用 Hilos在体内的免疫能力环境中长期生存和功能。为了实现这一目标， AIM 1提案以建立HILOS的长期效率和安全性，该功能已成为该功能经过广泛的体外验证。目标2通过工程表达来发展免疫耐受性HILOS的建议 PD-L1的含量，并证明了人源性免疫能力糖尿病小鼠的效率。进一步扩展保护移植的Hilos，目标3提案，将维生素D信号的药物激活应用于减轻了移植的Hilos的细胞因子胁迫。目的是确定是否对这些调节提高生存的策略以及最大程度地减少对移植的Hilos的拒绝拒绝的策略将导致无限用于治疗糖尿病的治疗性工程胰岛的供应。