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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL118245-03
Application #
8883696
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Lee, Albert
Project Start
2013-09-01
Project End
2018-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
3
Fiscal Year
2015
Total Cost
$383,140
Indirect Cost
$77,651
Name
Rensselaer Polytechnic Institute
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
002430742
City
Troy
State
NY
Country
United States
Zip Code
12180
Dorsey, Taylor B; Kim, Diana; Grath, Alexander et al. (2018) Multivalent biomaterial platform to control the distinct arterial venous differentiation of pluripotent stem cells. Biomaterials 185:1-12
Xu, Cancan; Lee, Wenhan; Dai, Guohao et al. (2018) Highly Elastic Biodegradable Single-Network Hydrogel for Cell Printing. ACS Appl Mater Interfaces 10:9969-9979
Dorsey, Taylor B; Grath, Alexander; Wang, Annling et al. (2018) Evaluation of Photochemistry Reaction Kinetics to Pattern Bioactive Proteins on Hydrogels for Biological Applications. Bioact Mater 3:64-73
Lu, Yao Wei; Lowery, Anthony M; Sun, Li-Yan et al. (2017) Endothelial Myocyte Enhancer Factor 2c Inhibits Migration of Smooth Muscle Cells Through Fenestrations in the Internal Elastic Lamina. Arterioscler Thromb Vasc Biol 37:1380-1390
Lee, Vivian K; Dai, Guohao (2017) Printing of Three-Dimensional Tissue Analogs for Regenerative Medicine. Ann Biomed Eng 45:115-131
Luo, Jiesi; Qin, Lingfeng; Kural, Mehmet H et al. (2017) Vascular smooth muscle cells derived from inbred swine induced pluripotent stem cells for vascular tissue engineering. Biomaterials 147:116-132
Dorsey, Taylor B; Grath, Alexander; Xu, Cancan et al. (2017) Patterning Bioactive Proteins or Peptides on Hydrogel Using Photochemistry for Biological Applications. J Vis Exp :
Gui, Liqiong; Dash, Biraja C; Luo, Jiesi et al. (2016) Implantable tissue-engineered blood vessels from human induced pluripotent stem cells. Biomaterials 102:120-9
Cui, Xiaofeng; Lu, Yao Wei; Lee, Vivian et al. (2015) Venous Endothelial Marker COUP-TFII Regulates the Distinct Pathologic Potentials of Adult Arteries and Veins. Sci Rep 5:16193
Gui, Liqiong; Niklason, Laura E (2014) Vascular Tissue Engineering: Building Perfusable Vasculature for Implantation. Curr Opin Chem Eng 3:68-74

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