Date of Award

8-26-2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical and Chemical Engineering

Advisor(s)

Zhen Ma

Keywords

extraembryonic lineage cells, induced pluripotent stem cells, mesenchymal stem cells, neural crest stem cells, targeted differentiation

Subject Categories

Biomedical Engineering and Bioengineering | Engineering

Abstract

Over the past decade, mesenchymal stem cells have increasingly gained interest as a cell source for the treatment of a variety of diseases. This is because they play several roles in tissue homeostasis and regeneration, such as altering the immune response to limit inflammation, aiding tissue repair through the release of various proteins, cytokines and growth factors, or differentiating into functional cells in specific tissues. The interest in MSCs for biomanufacturing applications has resulted in the development of various protocols to differentiate them from pluripotent sources. These protocols, however, fail to account for the differences that exist between MSCs from various tissue sources. To show that controlling the differentiation trajectory of iMSCs results in the generation of MSCs with distinct transcriptomic signature, we used a stepwise differentiation of neural crest stem cells and extraembryonic linage cells towards the respective MSCs populations. Through a comparison of their transcriptome, we were able to not only distinguish the iMSCs from each other as well as their parent cells, but also match them to various tissue derived MSCs. In addition, the iMSCs were shown to secrete extracellular vesicles (EVs). These iMSC-EVs showed immunomodulatory effects by limiting the infiltration of macrophages and neutrophils in vivo as a well as induction of various pro-inflammatory cytokines. Lastly, we integrated an in vitro mesenchymal tissue experimental model with a volumetric contraction-based computational model to investigate the effects of geometric designs of tissue mechanical constraints on the tissue remodeling process. This experimental-computational integrated model can be potentially used for rational design of engineered mesenchymal tissue fabrication. Overall, our study validates the use of specific developmental trajectories to generate MSCs that are not easily accessible for patient care.

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Open Access

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