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Differentiating Embryonic Stem Cells Toward Arterial and Venous Endothelial Cells

胚胎干细胞向动脉和静脉内皮细胞分化

基本信息

批准号：
8578314
负责人：
Guohao Dai
金额：
$ 38.92万
依托单位：
RENSSELAER POLYTECHNIC INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8578314
关键词：
3-Dimensional Address Animal Model Area Arteries Biochemical Biomechanics Blood Circulation Blood Vessels Blood capillaries Blood flow Bypass Cell Differentiation process Cells Cues Data Development Developmental Biology Endothelial Cells Engineering Environment Environmental Risk Factor Failure Feedback Goals Human In Vitro Knowledge Learning Mechanics Methods Mission Mus Nerve Neuropilin-1 Outcome Pattern Perfusion Phenotype Population Process Property Protocols documentation Public Health Research Signal Transduction Staging Stem cells Stimulus Technology Testing Therapeutic Thick Tissue Engineering Tissues Vascular Endothelial Cell Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Vascular Graft Vascularization Veins Venous base capillary disability driving force early onset embryonic stem cell hemodynamics human embryonic stem cell improved in vivo novel progenitor public health relevance response tool vascular tissue engineering

项目摘要

DESCRIPTION (provided by applicant): Embryonic stem cells (ESCs) derived endothelial cells (ECs) have enormous potential to be used in a variety of therapeutic areas such as tissue engineering of vascular grafts and re-vascularization of ischemic tissues. It is also much desired to obtain homogeneous culture of functional arterial or venous ECs for specific applications. To date, various protocols have been developed to differentiate ESCs toward vascular ECs. However, ECs derived from ESCs using current methods display predominantly venous phenotype. Therefore, developing refined method of arterial-venous differentiation is critically needed to address this gap. Based on the findings of vascular development, we hypothesize that embryonic stem cell derived Flk1+Nrp1+ cells serve as arterial EC progenitors. We think that this subset cell population is predisposed to arterial differentiation and can be selected to guide arterial differentiation in combination with environmental cues. Our preliminary data support this hypothesis. The goal of this study is to further test this hypothesis using human ESCs. We will then engineer optimal in vitro environments that guide ESCs into arterial and venous cell fate and compare their functional consequences in tissue engineering applications. Specifically, we will: (1) Validate that Nrp1 can be used to identify arterial EC progenitor from stem cells and define optimal in vitro environments that guide ESCs into arterial and venous cell fate. (2) Analyze the ability of ESC-derived arterial and venous ECs to form interconnected functional vascular network in tissue-engineered construct both in vitro and in vivo. (3) Determine the functional consequences of ESC-derived arterial and venous ECs in the remodeling of tissue engineered vascular graft both in vitro and in vivo.

描述（由申请人提供）：胚胎干细胞（ESC）衍生的内皮细胞（EC）具有用于各种治疗领域的巨大潜力，例如血管移植物的组织工程和缺血组织的血管重建。还非常需要获得用于特定应用的功能性动脉或静脉EC的均质培养物。迄今为止，已经开发了各种方案来区分 ESC 和血管 EC。然而，使用当前方法从 ESC 衍生的 EC 主要显示静脉表型。因此，迫切需要开发精细的动静脉分化方法来解决这一差距。基于血管发育的发现，我们假设胚胎干细胞衍生的 Flk1+Nrp1+ 细胞充当动脉 EC 祖细胞。我们认为这个子集细胞群易于动脉分化，并且可以被选择来结合环境线索指导动脉分化。我们的初步数据支持这一假设。本研究的目的是使用人类 ESC 进一步检验这一假设。然后，我们将设计最佳的体外环境，引导 ESC 进入动脉和静脉细胞命运，并比较它们在组织工程应用中的功能后果。具体来说，我们将：（1）验证Nrp1可用于识别干细胞中的动脉EC祖细胞，并定义引导ESC进入动脉和静脉细胞命运的最佳体外环境。 (2) 分析 ESC 衍生的动脉和静脉 EC 在体外和体内组织工程构建体中形成互连的功能性血管网络的能力。 (3) 确定 ESC 衍生的动脉和静脉 EC 在体外和体内重塑组织工程血管移植物中的功能后果。