Student Theses and Dissertations

Author

Kenneth Lay

Date of Award

2017

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Fuchs Laboratory

Abstract

Adult stem cells are endowed with the remarkable ability to maintain, regenerate and repair tissues throughout the lifetime of the organism. Whether parsimonious utilization of adult stem cells is necessary to preserve their long-term potential has not been fully explored. I investigated this issue using the adult murine hair follicle stem cell (HFSC) as my paradigm. HFSCs reside in their niche called the bulge, and mostly remain in a quiescent state, becoming mobilized only transiently to fuel cyclical bouts of hair follicle regeneration. By ablating a key HFSC transcription factor, Forkhead Box C1 (FOXC1), I discovered that hair follicles underwent more rounds of regeneration and yet were unable to result in a thickening of the animal’s hair coat. Mechanistically, unlike WT HFSCs, FOXC1-deficient HFSCs failed to remain in prolonged durations of quiescence. Instead, they were primed to re-enter the cell cycle and launch new rounds of hair regeneration prematurely. After activation, they failed to re-establish quiescence promptly, and remained in a primed state to proliferate. In turn, their expression of cell adhesion proteins remained low. As new hairs grew, wild-type (WT) HFSCs that had returned to quiescence and restored their repertoire of adhesion-associated proteins were able to anchor their bulge niche and the older hairs in place. However, FOXC1- deficient HFSCs were unable to do so, resulting in the gradual loss of their bulge and old hair coats. As the bulge is also a cellular source of HFSC-inhibitory factors, its loss exacerbated the inability of FOXC1-deficient HFSCs to maintain quiescence. Consequently, as these mutant mice aged, their hair coat appeared sparse. Indeed, their HFSC numbers and ability to regenerate new hairs upon stimulation had declined. Therefore, through FOXC1, HFSCs couple their quiescence to an adhesion-mediated niche maintenance to achieve long-term tissue homeostasis.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

Available for download on Wednesday, May 01, 2019

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