Cellular Dynamics In The Niche Of Infrequently Dividing Hair Follicle Stem Cells In The Mouse Mus Musculus
Tissue stem cells (TSCs) are cells that can self-renew for extended periods of time and differentiate into all cell lineages within the regenerating tissue. Self-renewal and differentiation are the two defining properties of TSCs, and failure of either will lead to the disruption of tissue homeostasis. In invertebrates, it has been shown that TSCs adopt asymmetric cell divisions to accomplish self-renewal and differentiation simultaneously. However, whether this mechanism universally applies to mammalian TSCs remains unclear. In our lab, we use the mouse hair follicle as a model system to study the regulatory mechanism for TSC functions. Mouse hair grows in a cyclic pattern consisting of quiescence, growth, and regression phases. The hair follicle stem cells (HFSCs) are documented to reside in storage stem cell niche - the bulge. Our cell division tracking results using Tet-off H2B-GFP transgenic mice confirm the infrequently dividing property of bulge cells and suggest that differentiation of progenitor cells occurs at different times and tissue locations than self-renewal of stem cells. Further single bulge cell lineage tracing using the inducible Cre system reveals that a single bulge cell will either leave the bulge to contribute to the new hair growth, or stay in the bulge to replenish the stem cell pool. Long term single bulge cell tracing data indicate a symmetric daughter-cell fate determination model for HFSCs. Moreover, we provide data suggesting that the self-renewing divisions of HFSCs within the bulge are symmetric with respect to an important niche component the basement membrane; whereas the divisions of differentiating progenitors are both symmetric and asymmetric. Finally, we identify Gata6 as a crucial transcription factor for HFSC differentiation whose loss impairs the proliferation, differentiation and survival of progenitors in the skin epithelium. Collectively, our findings propose a population mechanism for clustering TSCs whose maintenance involves symmetric cell division and fate determination, as well as specific genetic regulators.
dissertation or thesis