Human islet transplantation on microporous scaffolds

描述(申请人提供)：在1型糖尿病中，胰岛中分泌胰岛素的ss细胞的自身免疫破坏导致高血糖及其相关的急性和慢性并发症。最近使用Edmonton方案的胰岛移植的成功表明，胰岛移植可以有效地逆转与糖尿病相关的代谢异常；然而，这些结果也清楚地表明，肝脏可能损害长期的胰岛功能，需要替代部位。我们建议研究人胰岛的肝外移植，目的是设计微孔支架将胰岛与宿主组织植入，这与将胰岛与宿主组织隔离以保护免疫反应的封装方法不同。植入方法的最终转化将依赖于目前临床使用的免疫抑制方案。利用小鼠模型，我们已经证明了支架为附着提供了支持，维持了细胞渗透的空间，并且可以提供通常由细胞外基质(ECM)提供的信号。在纯化过程中胰岛细胞外基质的破坏被认为是限制胰岛在体内存活和功能的一个因素，支架可以取代这些蛋白质。我们还提出，从支架中运送蛋白质有可能促进移植的胰岛的存活、植入和功能。这项提议试图将小鼠胰岛的成功转化为人类的胰岛。小鼠和人类的胰岛具有根本不同的结构，因此可能对细胞外环境有不同的要求。因此，目前的研究将针对微孔支架可以用来创造微环境以促进移植的人胰岛的植入、存活和功能的假说。本项目的具体目标是：1)通过检测支架孔径和厚度对胰岛植入的影响，为将人胰岛移植到微孔支架上奠定基础；2)研究细胞外基质蛋白在微孔支架上呈现对移植的人胰岛植入和功能的影响；3)验证聚合物支架可用于输送多肽激素(exendin-4和催乳素)以增强人胰岛植入和功能的假说。这个成功的项目将确定限制人类胰岛植入的因素，以及细胞外基质蛋白和营养因子是否具有克服这些限制的潜力。 与公共卫生相关：移植胰岛，或最终移植来自其他来源的胰岛素分泌细胞，是治疗糖尿病的一种潜在方法，糖尿病是由免疫系统破坏胰岛素分泌细胞引起的。为了加强糖尿病的细胞替代治疗，我们开发了用于将胰岛或胰岛素分泌细胞移植到腹膜脂肪中的支架，并在小鼠模型中取得了成功。在这个方案中，我们研究了支架增强人类胰岛植入和功能的能力。

DESCRIPTION (provided by applicant): In type 1 diabetes, autoimmune destruction of insulin-secreting ss-cells in pancreatic islets results in hyperglycemia and its related acute and chronic complications. Recent successes in islet transplantation using the Edmonton protocol have demonstrated that islet transplantation can effectively reverse the metabolic abnormalities associated with diabetes; however, these results have also clearly demonstrated that the liver can be detrimental to long-term islet function, and alternative sites are needed. We propose to investigate the extrahepatic transplantation of human islets, with the objective of designing microporous scaffolds to engraft the islets with the host tissue, which contrasts with the encapsulation approach to isolate the islets from the host tissue to protect against the immune response. The ultimate translation of the engraftment approach would rely on the immunosuppressive regimens that are currently used clinically. Using a mouse model, we have demonstrated that the scaffold provides a support for attachment, maintains a space for cell infiltration, and can present signals that would normally be provided by the extracellular matrix (ECM). Disruption of the islets' ECM during purification has been implicated as a factor that limits islet survival and function in vivo and the scaffold can replace these proteins. We are also proposing that protein delivery from the scaffold has the potential to promote the survival, engraftment, and function of transplanted islets. This proposal seeks to translate the success with murine islets to human islets. Mouse and human islets have a fundamentally different architecture and thus may have differing requirements for the extracellular environment. Thus, the current study will address the hypothesis that microporous scaffolds can be used to create a microenvironment to promote the engraftment, survival and function of transplanted human islets. The Specific Aims for this project are: 1) to establish a foundation for the transplantation of human islets on microporous scaffolds by examining the role of scaffold pore size and thickness on islet engraftment, 2) to investigate the impact of presenting extracellular matrix proteins on the microporous scaffold on the engraftment and function of transplanted human islets, and 3) to test the hypothesis that polymer scaffolds can be used to deliver peptide hormones (exendin-4 and prolactin) to enhance the engraftment and function of human islets. The successful project will identify factors limiting human islet engraftment and whether ECM proteins and trophic factors have the potential to overcome these limitations. PUBLIC HEALTH RELEVANCE: Transplantation of islets or, ultimately, insulin-secreting cells from other sources represents a potential cure for diabetes, which results from destruction of insulin-secreting cells by the immune system. To enhance cell replacement therapy for diabetes, we have developed scaffolds for transplantation of islets or insulin-secreting cells into peritoneal fat that have been successful in a mouse model. In this proposal, we investigate the ability of the scaffolds to enhance engraftment and function of human islets.