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.
The proposed research is relevant to public health because differentiating human embryonic stem cells into arterial and venous endothelial cells and studying their functional consequences are ultimately expected to improve our current strategies in tissue revascularization and tissue engineered vascular graft for human therapies. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge and new tools that will help to reduce the burdens of human disability.
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