Advisor(s)

Jianyi Zhang

Committee Member(s)

Mary Sewell-Loftin
Min Xie
Vahid Serpooshan
Ye Lei

Document Type

Dissertation

Date of Award

2-3-2026

Degree Name

Doctor of Philosophy (PhD)

School

Joint Health Sciences (Interdisciplinary)

Department

Biomedical Engineering

Abstract

Ischemic limb disease continues to pose major clinical challenges. The effect of this disease causes restricted blood flow, which is followed by a limited ability to regenerate in the vascular tissues. The purpose of this study is to address the current limitations in producing large-scale generation of Smooth Muscle Cells (SMCs) derived from human induced pluripotent stem cells (hiPSCs) and then assessing their potential therapeutic efficiency individually and in combination with endothelial cells (ECs) for vascular repair. A dynamic three-dimensional (3D) culture system was integrated with a two- dimensional (2D) expansion to enhance cell culture yield while maintaining contractile marker expression, resulting in a nine-fold increase in SMC production compared to previously established methods. Mouse hindlimb ischemia models were utilized to assess therapeutic efficacy. hiPSC-SMCs maintain structural stability, but optimized hiPSC- ECs alone enhanced functional perfusion and both vessel and arteriole density compared to both the hiPSC-EC+SMC co-transplantation group and the hiPSC-SMC only group. This is due to the release of EC-related paracrine factors that are beneficial and have an enhanced angiogenic effect. This combined approach demonstrates a GMP-compatible method that’s scalable. The demonstrated ability of hiPSC-ECs to induce superior therapeutic angiogenesis through paracrine mechanisms validates a mechanically defined, singular cell construct for vascular engineering, offering a new approach from multi-cellular co-transplantation strategies for addressing chronic ischemic limb disease.

ProQuest Publication Number

32285020

ISBN

9798273398658

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