Date of Degree

2-2021

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biochemistry

Advisor

Karen Hubbard

Advisor

Mark Pezzano

Committee Members

Linda Spatz

Ben Ortiz

Derek Sant'Angelo

Subject Categories

Developmental Biology | Other Immunology and Infectious Disease

Keywords

Thymus, Thymic Epithelial cell, Adaptive Immunity, Hematopoietic Stem cell

Abstract

The thymus plays a critical role in adaptive immunity by providing a suitable microenvironment for developing and selecting the functional self-tolerant T-cell population. Thymic epithelial cells play an essential role in the development of a naïve, self-tolerant T-cell population. Paradoxically thymus undergoes acute age-related involution, which in turn causes loss of functional T-cell populations. Involution reduces the functionality of the thymus markedly, but the thymus can still develop self-tolerant naïve T-cells. It is crucial to understand how the thymic microenvironment is maintained to provide a suitable T-cell population for life. It has been previously demonstrated that the thymic epithelial homeostasis is maintained by the thymic epithelial progenitor cells (TEPCs). Apart from TEPCs, thymic microenvironment maintenance is also regulated via different signal transduction pathways. In this current study, we focused on understanding the key players in maintaining the thymic epithelial microenvironment. Our study challenged the established dogma of thymus organogenesis. It demonstrated a unique hematopoietic stem cell derived bone marrow population expressing pan-hematopoietic marker, CD45, and thymic epithelial cell marker, EpCAM, that can migrate to the thymus and differentiate into keratin-expressing thymic epithelial cells.

Canonical Wnt signaling has been previously shown to be critical for thymocyte maturation and proliferation in addition to maintenance of thymic epithelial architecture. Overexpression of DKK1, a Wnt inhibitor, leads to loss of thymic progenitor and rapid thymic degeneration in the thymus. Thus, Wnt signaling has involved the maintenance of adult thymic epithelial progenitor cells. Therefore, we hypothesized Wnt signaling could also be involved in the fetal thymic epithelial progenitor cell maintenance and development. But no characterization of the fetal thymic epithelial cell undergoing Wnt signaling is documented. In this study, using a new H2BGFP Wnt reporter model, we identified which specific thymic epithelial cell populations were undergoing active canonical Wnt signaling during the critical crosstalk dependent stages of fetal thymic development.

In summary, this study addresses the dual aspect of thymic epithelial microenvironment maintenance. Identification of bone marrow derived TEPC and deciphering which TEC populations undergo active Wnt signaling during fetal development equip future studies with a better understanding of TEC development and maintenance. These data should provide additional targets for overcoming thymic atrophy and hence the development of more strategic therapies for immunological-based diseases and cancer.

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