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）具有巨大的潜力，可用于多种治疗区域，例如血管移植物的组织工程和缺血性组织的重新血管化。也希望获得特定应用的功能动脉或静脉EC的均匀培养。迄今为止，已经制定了各种方案，以将ESC分化为血管EC。但是，使用当前方法从ESC中得出的ECS主要显示为静脉表型。因此，需要急需开发精致的动脉 - 观测方法来解决这一差距。根据血管发育的发现，我们假设胚胎干细胞得出的FLK1+ NRP1+细胞是动脉EC祖细胞。我们认为该子集细胞群体易于动脉分化，可以选择与环境线索结合进行动脉分化。我们的初步数据支持这一假设。这项研究的目的是使用人类ESC进一步检验该假设。然后，我们将设计最佳的体外环境，这些环境将指导转化为动脉和静脉细胞命运，并比较其在组织工程应用中的功能后果。具体而言，我们将：（1）验证NRP1可用于从干细胞中识别动脉EC祖细胞，并定义指导转化为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在体外和体内形成组织工程构建体中互连功能性血管网络的能力。（3）确定ESC衍生的动脉和静脉EC在体外和体内进行组织工程血管移植物重塑时的功能后果。