Nanoscale Assembly of Bioactive Ligands to Enhance Endothelial Differentiation
生物活性配体的纳米级组装以增强内皮分化
基本信息
- 批准号:8241196
- 负责人:
- 金额:$ 18.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-01-09 至 2013-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdhesivesAutologousBinding SitesBiomimeticsCD34 geneCellsCharacteristicsCysteineDevelopmental BiologyEndothelial CellsEngineeringExhibitsFibronectinsFutureHematopoieticHumanIntegrinsLigandsLiteratureMethodsMolecular StructurePeptidesPluripotent Stem CellsPositioning AttributeProductionProliferatingProtein EngineeringResearchResearch PersonnelSiteSourceStem cellsStentsStructureSurfaceTechnologyTestingTissuesUmbilical Cord BloodVariantVascular Endothelial Growth FactorsVascular GraftWorkbasebiological systemsdensitydesignexperiencehuman embryonic stem cellinduced pluripotent stem cellmimeticsnanoscaleneovascularizationpolypeptideself assemblystem cell technologysuccesssurface coatingsynergism
项目摘要
DESCRIPTION (provided by applicant): Endothelial cells have important biomedical applications ranging from enhancing the patency of engineered vascular grafts and stents to promoting neovascularization in ischemic tissues. But their limited availability hinders the success of endothelial-cell-related technologies. The advances in stem cell technology offer a unique opportunity to address this issue. In particular, endothelial cells have been derived from human pluripotent stem cells (hPSCs), which can proliferate extensively and virtually provide an unlimited cell source. The recent success in making induced PSCs (iPSCs) offers additional advantages in providing immunologically compatible autologous hPSCs and enabling "personalized" therapy in the future. The key to exploiting this opportunity to advance endothelial-cell-related technologies is our ability to guide endothelial differentiation. In currently used methods, hPSCs are differentiated into hemangioblasts, which have both hematopoietic and endothelial potentials, followed by differentiation of hemangioblasts into endothelial cells in the presence of VEGF and fibronectin(FN)-coated surfaces. VEGF and FN are both essential for efficient endothelial differentiation, and they exhibit a synergistic effect due to the unique structure of FN, which has a cell-adhesive site and a VEGF-binding site positioned in nanoscale proximity. However, naturally-derived FN has batch-to-batch variations. In addition, covalently immobilized FN has structural change that blocks the cell- adhesive ligand; physically adsorbed FN preserves the active cell-adhesive domain but does not allow precise control of surface ligand density. Therefore, cell microenvironments created with FN are not tightly controlled, hampering consistent production of endothelial cells from stem cells. This problem can be addressed by using well-controlled synthetic materials that recapitulate the essential molecular structure underlying the synergistic effect of VEGF and FN in regulating endothelial differentiation. The objective of this application is to develop synthetic materials having the essential structural characteristics underlying the synergistic effect of VEGF and FN and to use these materials to guide endothelial differentiation of human iPSC-derived hemangioblasts. Our central hypothesis is that a cell-adhesive peptide and a VEGF-mimetic peptide fused to a pair of heterodimerizing coiled-coils, respectively, can be brought into nanoscale proximity through coiled-coil self- assembly and the materials functionalized with the heterodimer, together with soluble factors, will create well- controlled cell microenvironments for efficient and reproducible endothelial differentiation of iPSC-derived hemangioblasts. The specific aims are: (1) design, synthesize, characterize, and immobilize the polypeptides that self-assemble to present a cell-adhesive peptide and a VEGF-mimetic peptide in nanoscale proximity; (2) examine endothelial differentiation of human iPSC-derived hemangioblasts on the polypeptide-functionalized substrates. Successful completion of this project will result in well-controlled, biomimetic cell microenvironments for efficient and robust endothelial differentiation of iPSC-derived hemangioblasts.
PUBLIC HEALTH RELEVANCE: The proposed project aims to engineer rationally designed, well-controlled synthetic cell microenvironments to guide efficient and reproducible endothelial differentiation of hemangioblasts derived from human induced pluripotent stem cells. Such derived endothelial cells will have important biomedical applications ranging from enhancing the patency of engineered vascular grafts and stents to promoting neovascularization in ischemic tissues.
描述(由申请人提供):内皮细胞具有重要的生物医学应用,从增强工程血管移植物和支架的通畅性到促进缺血组织中的新血管形成。但它们的有限可用性阻碍了内皮细胞相关技术的成功。干细胞技术的进步为解决这一问题提供了独特的机会。特别地,内皮细胞来源于人多能干细胞(hPSC),其可以广泛增殖并且实际上提供无限的细胞来源。最近在制备诱导的PSC(iPSC)方面的成功在提供免疫相容的自体hPSC和实现未来的“个性化”治疗方面提供了额外的优势。利用这一机会推进内皮细胞相关技术的关键是我们引导内皮分化的能力。在目前使用的方法中,将hPSC分化成具有造血和内皮潜能的成血管细胞,然后在VEGF和纤连蛋白(FN)涂覆的表面存在下将成血管细胞分化成内皮细胞。VEGF和FN都是有效的内皮分化所必需的,并且由于FN的独特结构,它们表现出协同效应,FN具有位于纳米级附近的细胞粘附位点和VEGF结合位点。然而,天然来源的FN具有批次间差异。此外,共价固定的FN具有阻断细胞粘附配体的结构变化;物理吸附的FN保留了活性细胞粘附结构域,但不允许精确控制表面配体密度。因此,用FN产生的细胞微环境没有得到严格控制,阻碍了干细胞持续产生内皮细胞。这个问题可以通过使用控制良好的合成材料来解决,这些材料概括了VEGF和FN在调节内皮分化中的协同作用的基本分子结构。本申请的目的是开发具有VEGF和FN的协同效应的基本结构特征的合成材料,并使用这些材料来引导人iPSC衍生的成血管细胞的内皮分化。我们的中心假设是,分别融合到一对异二聚化卷曲螺旋的细胞粘附肽和VEGF模拟肽可以通过卷曲螺旋自组装进入纳米级接近,并且用异二聚体官能化的材料与可溶性因子一起将产生良好控制的细胞微环境,用于iPSC衍生的成血管细胞的有效和可再现的内皮分化。具体目标是:(1)设计、合成、表征和鉴定自组装以纳米级接近呈现细胞粘附肽和VEGF模拟肽的多肽;(2)检查人iPSC衍生的成血管细胞在多肽功能化基底上的内皮分化。该项目的成功完成将导致良好控制的仿生细胞微环境,用于iPSC衍生的成血管细胞的有效和稳健的内皮分化。
公共卫生相关性:拟议的项目旨在设计合理设计,控制良好的合成细胞微环境,以指导来自人类诱导多能干细胞的成血管细胞的有效和可重复的内皮分化。这种衍生的内皮细胞将具有重要的生物医学应用,从增强工程血管移植物和支架的通畅性到促进缺血组织中的新血管形成。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Wei Shen其他文献
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{{ truncateString('Wei Shen', 18)}}的其他基金
Enhance myogenic transdifferentiation efficiency using engineering approaches
利用工程方法提高生肌转分化效率
- 批准号:
10647491 - 财政年份:2023
- 资助金额:
$ 18.09万 - 项目类别:
Nanoscale Assembly of Bioactive Ligands to Enhance Endothelial Differentiation
生物活性配体的纳米级组装以增强内皮分化
- 批准号:
8410532 - 财政年份:2012
- 资助金额:
$ 18.09万 - 项目类别:
Modular Assembly Approach to Engineer Prevascularized Large 3D Tissue Constructs
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- 批准号:
8138172 - 财政年份:2011
- 资助金额:
$ 18.09万 - 项目类别:
Modular Assembly Approach to Engineer Prevascularized Large 3D Tissue Constructs
用于设计预血管化大型 3D 组织结构的模块化组装方法
- 批准号:
8321540 - 财政年份:2011
- 资助金额:
$ 18.09万 - 项目类别:
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