Human Embryonic Stem Cells, Polymer Scaffolds & Pancreatic Islets

人胚胎干细胞、聚合物支架

• 批准号: 7684202
• 负责人: William L Lowe
• 金额: $ 12.41万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7684202
• 关键词: Address; Angiogenic Factor; Angiogenic Peptides; Animal Disease Models; Beta Cell; Biological Models; Biomedical Engineering; Cell Differentiation process; Cell Survival; Cell Therapy; Cell Transplants; Cells; Cellular biology; Condition; Development; Diabetes Mellitus; Diabetic mouse; Disease; Endothelial Cells; Engraftment; Exposure to; Extracellular Matrix; Genetic; Goals; Growth; Hepatic; Histocytochemistry; Human; Hyperglycemia; Image; Imaging Techniques; Insulin-Dependent Diabetes Mellitus; Interdisciplinary Study; Islets of Langerhans; Islets of Langerhans Transplantation; Left; Liver; Magnetic Resonance Imaging; Maps; Modeling; Mus; Peptides; Phenotype; Polymers; Process; Replacement Therapy; Research; Research Personnel; SCID Mice; Science; Site; Stem Cell Research; Stem cells; Streptozocin; Technology; Testing; Translating; Transplantation; Vascularization; human embryonic stem cell; in vivo; islet; multidisciplinary; nonhuman primate; novel; novel strategies; scaffold; stem cell therapy; success

The recent successes using islet cell transplantation have demonstrated that cell replacement therapy has the potential to be a viable treatment for type 1 diabetes. However, for cell replacement therapy to be broadly applied will require that several obstacles be overcome. Two of these are: (i) the supply of cells available for transplantation, and (ii) development of means to enhance the engraftment and function of transplanted cells through the creation of a platform and extra-hepatic site for the transplantation of insulin- secreting cells. The goal of this proposal is to develop means of overcoming these obstacles. To accomplish this, we have formed a multidisciplinary team of investigators with expertise in stem cell biology, diabetes, islet transplantation, bioengineering and materials science, and imaging. This multidisciplinary research team will develop approaches using scaffold technologies to enhance the engraftment and function of transplanted human embryonic stem cells (hESCs) and of differentiating them into insulin-secreting cells. They will accomplish this by addressing the hypothesis that microporous scaffolds capable of controlled delivery of peptides and co-transplantation of endothelial cells can be used to create a microenvironment that will promote the differentiation of hESCs into insulin-secreting cells and support the transplantation and engraftment of insulin-secreting cells into extra-hepatic sites. The specific aims for this study are as follows. (1) To develop an optimal approach to cell-based therapies for diabetes that can be applied to differentiated hESCs using mature human islets as a model system. Human islets seeded onto microporous scaffolds will be transplanted into NOD-SCID mice with streptozotocin-induced diabetes. The impact of controlled delivery of angiogenic peptides and co-transplantation of endothelial cells on islet survival and vascularization and the ability of the islets to correct hyperglycemia will be assessed. (2) To use scaffold technologies to create a microenvironment to optimize the transplantation and engraftment of hESCs. hESCs differentiated in embryoid bodies will be seeded onto synthetic scaffolds and transplanted into mice. The ability of the scaffold to impact the vascularization and survival of cells will be assessed via histochemistry and fate- mapping using novel magnetic resonance imaging techniques. (3) To develop means to differentiate hESCs into insulin-secreting cells. Modulation of culture conditions and exposureto a microenvironment created by the synthetic scaffolds will be used to develop means of generating insulin-secreting cells from hESCs. The ability of the differentiated hESCs to correct hyperglycemia will be tested by transplanting them on scaffolds into murine models of diabetes. Approaches established in Aims 1 and 2 will be used to help direct the transplantation studies. Successful completion of the proposed studies will leave us poised to translate these studies into non-human primates and subsequently humans.

使用胰岛细胞移植的最新成功表明，细胞替代疗法已有 成为1型糖尿病的可行治疗的潜力。但是，要使细胞替代疗法为 广泛应用将需要克服几个障碍。其中两个是：（i）细胞的供应 可用于移植，以及（ii）增强植入和功能的手段 通过创建平台和肝外部位移植细胞，用于移植胰岛素 分泌细胞。该提议的目的是开发克服这些障碍的手段。到 做到这一点，我们组成了一个多学科的研究人员，具有干细胞生物学专业知识， 糖尿病，胰岛移植，生物工程和材料科学以及成像。这个多学科 研究团队将使用脚手架技术开发方法来增强植入和功能 移植的人类胚胎干细胞（HESC），并将其区分为分泌胰岛素的细胞。 他们将通过解决能够受控的微孔支架的假设来实现这一目标 肽的递送和内皮细胞的共转移可用于创建微环境 这将促进hESC的分化为分泌胰岛素分泌细胞，并支持移植和 植入分泌胰岛素的细胞进入肝外部位。这项研究的具体目的如下。 （1）为糖尿病的基于细胞的疗法开发一种最佳方法，可以应用于分化 使用成熟的人类胰岛作为模型系统的hESC。播种到微孔支架上的人类胰岛将 用链蛋白酶诱导的糖尿病将其移植到NOD-SCID小鼠中。受控交付的影响 在胰岛存活和血管形成上的血管生成肽和内皮细胞的共转移 将评估胰岛纠正高血糖的能力。 （2）使用脚手架技术创建 一种微环境，以优化hESC的移植和植入。 hESC在其中区分了 胚胎体将被播种到合成支架上，并将其移植到小鼠中。能力 脚手架会影响细胞的血管化和存活，将通过组织化学和命运评估 使用新型磁共振成像技术进行映射。 （3）开发分化赫斯克的手段 进入分泌胰岛素的细胞。调节培养条件和Exposureto的微环境 合成支架将用于开发从hESC产生分泌胰岛素分泌细胞的方法。这 分化的hESC纠正高血糖的能力将通过在脚手架上移植来测试它们 进入糖尿病的鼠模型。目标1和2中建立的方法将用于帮助指导 移植研究。拟议研究的成功完成将使我们准备翻译 这些研究对非人类灵长类动物和随后的人类研究。