Date of Award

12-2020

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology/Molecular, Cellular, and Organismal Biology

First Advisor

Jayaraj Rajagopal

Second Advisor

Linda Huang

Third Advisor

Alexey Veraksa

Abstract

The airway epithelium is the outermost cellular sheet of the lungs at their interface with the external environment. It is the place where important physiological functions, such as retention of body fluids, absorption of nutrients, elimination of toxic products as well as tissue repair are performed. Therefore, maintaining tissue integrity is important for lung function. The airway epithelium has a remarkable ability to regenerate in response to tissue injury that can vary in severity. During severe airway injury that denudes the epithelial lining, it was recently demonstrated that myoepithelial cells from submucosal glands act as reserve stem cells that migrate and regenerate the missing surface epithelium. However, glands are anatomically restricted to the most proximal part of the airways. I studied an in vivo model of severe airway injury and regeneration and described the regenerative potential of different stem cell pools in the airways including glands, surface cells, and a newly identified epithelial regions called “hillocks.” In addition, I co-developed an ex vivo explant system to study severe airway epithelium injury and regeneration with live imaging and single cell tracking. I used cell type-specific lineage tracing to demonstrate that basal cells are the major contributors of the epithelial surface stem cell pool. I demonstrated that at the border of the wound, only cells within 100 micrometers contribute to repair of the epithelial surface, and that proximity of a particular epithelial stem cell niche (gland, surface, or hillock) determines the origin of regenerating cells. Finally, we use live imaging to demonstrate relative resistance to injury and disproportionate contribution to regeneration by the hillock stem cell pool. The functional characterization of resident stem cells that play a role during tissue regeneration is important for understanding tissue function and focusing on strategies with therapeutic potential when organ function has been compromised due to injury or disease.

Comments

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