Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Engineering Science

Program

Biomedical Engineering

Supervisor

Mequanint, Kibret

Abstract

Notch signaling plays a critical role in regulating vascular morphogenesis. In vascular interventions, the endothelial cells (ECs) are often damaged, and EC-SMC contact is compromised. The objective of this study was to investigate if immobilized Jagged1 can act as an EC-surrogate material to direct and control vascular smooth muscle cell (VSMC) behavior via Notch signaling. It was shown that immobilized Jagged1 induced vascular differentiation of iPSC-derived mesenchymal stem cells and mouse embryonic multipotent cells. Immobilized Jagged1 was insufficient to induce mature contractile markers in coronary artery SMCs; therefore, serum starvation and TGFβ1 treatment were investigated. Although Notch signaling is mechanosensitive in nature, it was also determined that a pulling force was not needed for Notch3 activation. Overall, it is concluded that immobilized Jagged1 is an essential regulator in SMC phenotype and SMC differentiation. These findings may have clinical relevance for modulating VSMC phenotype in cardiovascular disease states and in tissue engineering.

Summary for Lay Audience

To treat atherosclerotic vessels, stent deployment is a common intervention, but unintentional damage to the endothelial cell (EC) layer can cause smooth muscle cell (SMC) dysregulation. The Notch signaling pathway plays a critical role in regulating SMC phenotype switching through Jagged1-Notch3 signaling between EC and SMCs. Little is known on biomaterial approaches to direct Notch signaling and how ligand presentation strategies affect SMC response. Therefore, this study proposed bead-bound Jagged1 cell surrogates as a model in regulating the contractile VSMC phenotype. This study aimed to determine how immobilization strategies, crosstalk and cell source affected signaling response. Jagged1 was attached to magnetic nanoparticles and targeted binding to the Notch3 receptor on human coronary artery SMCs, iPSC-MSC, or pre-differentiated 10T1/2 cells. The use of bead-bound Jagged1 suggests high potential in modulating the development and maturation of the vasculature. Findings may have clinical importance and therapeutic potential for modulating vascular SMC phenotype during various cardiovascular disease states and in tissue engineering, with the possible application for bioactive stent materials.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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