Investigating The Role Of Runx1 In Hair Follicle Stem Cell Development And Homeostasis
Tissue specific stem cells are functionally defined as cells that can self renew and differentiate for the entire life of the organism. As an entry point to understand whether a subset of regulatory pathways is responsible for the functional properties of adult stem cells I analyzed the function on the skin of the transcription factor Runx1, a master regulator of hematopoietic stem cell emergence. I discovered that Runx1 is expressed in the hair follicle from the beginning of its development, at the placode stage, and there on is expressed throughout the life of the organism. Besides its follicular expression Runx1 is highly expressed in the mesenchymal compartment of the skin during morphogenesis but this expression decreases and is completely gone postnatally. By employing tissue specific ablation, lineage tracing studies and cell culture experiments I delineated Runx1 function in the skin at two different stages hair morphogenesis and regeneration. During embryonic hair morphogenesis I uncovered that two distinct population of Runx1 expressing cells are becoming specified. One population will contribute to the formation of the embryonic hair rudiment while the second population will contribute to definitive compartment of the hair follicle the ORS and bulge. This lineage tracing studies helped elucidating the behavior of adult HFSCs during embryonic development. Analysis of an epithelial conditional Runx1 knock out (cKO) during hair morphogenesis showed that Runx1 is important during embryonic hair morphogenesis to promote hair follicle induction, in vivo and in vitro cell proliferation and, in vitro keratinocyte cell migration. This developmental role of Runx1 is accomplished in part by modulating the activity of the canonical Wnt signaling pathway, known to be necessary in the skin for normal hair follicle morphogenesis and homeostasis. Furthermore, during adulthood, Runx1 promotes HFSCs activation during normal tissue homeostasis but is not necessary for the injury-triggered stem cell activation mechanism. Collectively all these results demonstrated that besides the HSCs Runx1 function is necessary in a second population of hair follicle stem cell of the bulge.
dissertation or thesis