A Bioengineering Approach to Create Immunorejection Free Human Pancreatic Islets

一种创建无免疫排斥的人胰岛的生物工程方法

• 批准号: 8579189
• 负责人: LUGUANG LUO
• 金额: $ 37.04万
• 依托单位: ROGER WILLIAMS HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-17 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579189
• 关键词: Activities of Daily Living; Address; Allogenic; Biological Preservation; Biology; Biomedical Engineering; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell; CDKN2A gene; Cell Communication; Cell physiology; Cells; Cellular Structures; Clinic; Coculture Techniques; Coupling; Data; Diabetes Mellitus; Diabetic mouse; Drug Formulations; Encapsulated; Fibroblasts; Generations; Glucose; Goals; Human; Hydrogels; Hyperglycemia; Immune system; Immunodeficient Mouse; Immunosuppression; In Vitro; Incidence; Islets of Langerhans; Islets of Langerhans Transplantation; Lead; Legal patent; Longevity; Mediating; Membrane; Modeling; Mus; Natural regeneration; PDGF Signaling Pathway; Platelet-Derived Growth Factor; Population; Protocols documentation; RNA; Rattus; Recruitment Activity; Reporting; Resistance; SCID Mice; Solutions; Stem cells; Structure; System; Technology; Testing; Tissues; Translations; Transplantation; Vascular Endothelial Growth Factors; Vascularization; Xenograft procedure; blood glucose regulation; capsule; cell growth; cytokine; diabetes mellitus therapy; diabetic; improved; in vitro Model; in vivo; islet; islet allograft; nanoparticle; novel; novel strategies; paracrine; pre-clinical; prevent; public health relevance; screening

DESCRIPTION (provided by applicant): By 2015, it is estimated that one tenth of the U.S. population will suffer from diabetes. Islet transplantation has great potential for the treatment o diabetes, but must first overcome issues associated with islet survival, function and immunorejection. Combining bioengineering and islet biology has great potential for overcoming these challenges. We have reported that human bone marrow (BM), either in vitro or in vivo, significantly improves human islet function and survival, but the mechanisms underlying this beneficial effect are largely unknown. We have preliminary data, that BM facilitates human islet survival and function in vitro by initiating revascularization and stimulating human islet regeneration. To address immunorejection of human islets, we propose a bioengineering approach of encapsulation of human islet/BM co- cultures and we will test this in vivo using mice engrafted with a functional human immune system (humanized mice). We hypothesize that co-encapsulated BM plus islets creates a favorable microenvironment via which BM paracrine activity facilitates revascularization of human islets, enhances ¿ cell self regeneration and prevents immunorejection. We will investigate mechanisms of how BM sustains human islet function/survival and prevents human immunorejection in humanized mice and the benefits of using nanoparticles with selected cytokines incorporated for local release to the islets. To understand how human BM facilities human islet survival and function within an encapsulated microenvironment, we will (1) evaluate revascularization and ¿-cell regeneration that occurs within a 3D construction of the encapsulated islet and BM tissues; (2) evaluate the ability of encapsulated islets plus BM to overcome human immunorejection and restore glucose homeostasis in diabetic humanized mice, and determine whether nanoparticles carrying cytokines in a semi-permeable hydrogel capsule facilitate support of encapsulated functional islets by recruiting progenitor cells, and (3) identify the mechanisms by which BM enhances human islet survival and function in an encapsulated microenvironment by identifying the effect of BM paracrine Platelet-derived growth factor (PDGF or other factors) and Mir-RNA 24-2 to modulate PDGF signaling pathways on islet survival and function. Our long term goal is to identify the mechanism(s) by which encapsulated islets plus BM cells sustain islet function in vivo and prevent islet rejection in the absence of generalized immunosuppression for translation to the clinic.

描述（由申请人提供）：到2015年，估计十分之一的美国人口将患有糖尿病。胰岛移植在糖尿病治疗中具有巨大的潜力，但首先必须克服与胰岛存活、功能和免疫排斥相关的问题。生物工程和胰岛生物学的结合具有克服这些挑战的巨大潜力。我们已经报道了人骨髓（BM），无论是在体外还是在体内，显着改善人类胰岛功能和生存，但这种有益的影响的机制在很大程度上是未知的。我们有初步的数据，BM通过启动血管再生和刺激人胰岛再生促进体外人胰岛存活和功能。为了解决人胰岛的免疫排斥，我们提出了包封人胰岛/BM共培养物的生物工程方法，并且我们将使用移植有功能性人免疫系统的小鼠（人源化小鼠）在体内测试该方法。我们假设共包封的BM+胰岛创造了有利的微环境，通过该微环境BM旁分泌活性促进人类胰岛的血管再生，增强细胞自我再生并防止免疫排斥。我们将研究BM如何维持人胰岛功能/存活和防止人源化小鼠中的人免疫排斥的机制，以及使用具有选定细胞因子的纳米颗粒用于局部释放到胰岛的益处。为了了解人类BM如何在包封的微环境中促进人类胰岛的存活和功能，我们将（1）评估在包封的胰岛和BM组织的3D构建中发生的血管再生和细胞再生;（2）评价包封的胰岛加BM克服人免疫排斥和恢复糖尿病人源化小鼠中葡萄糖稳态的能力，并确定在半渗透性水凝胶胶囊中的携带细胞因子的纳米颗粒是否通过募集祖细胞而促进对封装的功能性胰岛的支持，和（3）通过鉴定BM旁分泌血小板的作用，鉴定BM在包封的微环境中增强人胰岛存活和功能的机制。衍生生长因子（PDGF或其它因子）和Mir-RNA 24-2来调节胰岛存活和功能的PDGF信号传导途径。我们的长期目标是确定囊化胰岛加BM细胞在体内维持胰岛功能并在缺乏全身免疫抑制的情况下预防胰岛排斥的机制，以用于临床。