The Identification of Bipotent Dermal Stem Cells and The Role of Anti-Inflammatory Macrophages During Hair Follicle Regeneration

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The mechanisms underlying tissue regeneration span a broad spectrum of distinct yet interconnected biological processes that are largely modulated by tissue resident stem cells and the host immune system. In the skin, epithelial stem cells, the adjacent mesenchyme, and resident immune cells play important roles in regulating adult hair follicle (HF) regeneration. Previous work has uncovered distinct hair follicle stem cell (HFSC) populations responsible for maintaining the epithelial compartments of the HF. However, the cellular dynamics within the mesenchymal compartments of the HF (the dermal sheath and dermal papilla) are less understood. Indeed, how these specialized inductive cells are maintained over successive cycles of regeneration and degeneration is an unresolved question. Through in vivo fate mapping of adult HF dermal sheath (DS) cells, I found that a subset of DS cells is retained following each hair cycle, exhibit self-renewal, and repopulate the DS and dermal papilla (DP) with new cells. In vivo clonal analysis of DS cells revealed that individual DS cells exhibited bipotency and self-renewal, thus providing evidence for the existence of a stem cell within the adult HF mesenchyme. Ablating bipotent HF dermal stem cells (hfDSCs) retarded hair regrowth and altered hair type specification. This work has valuable implications toward restoration of hair growth after injury, disease and aging. Immune cells integral players during wound healing and tissue regeneration. The HF affords a unique model to gain insight into the cellular and molecular mechanisms by which cutaneous macrophages influence stem cell function during tissue regeneration. I took advantage of wound-induced hair growth (WIHG), a phenomenon by which skin injury triggers regeneration of surrounding HFs, to explore the relationship between wound macrophages, HFSCs, and tissue regeneration. Using a variety of transgenic approaches, I show that 8-10 days after injury, CD11b+ CX3CR1hi CCR2+ Ly6Clo macrophages increase the perifollicular concentrations of TGF1, activate epithelial stem/progenitors within the secondary hair germ and ultimately stimulate HF regeneration. Furthermore, WIHG was abolished in mice deficient for CX3CR1 but not CCR2. These findings identify a novel mechanism by which anti-inflammatory macrophages stimulate HFSCs to trigger HF regeneration in response to skin injury.
Biology--Cell, Immunology
Rahmani, W. (2016). The Identification of Bipotent Dermal Stem Cells and The Role of Anti-Inflammatory Macrophages During Hair Follicle Regeneration (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from doi:10.11575/PRISM/28173