Understanding the functional contribution of dermal stem cells to hair follicle regeneration and skin wound healing

Journal Title
Journal ISSN
Volume Title
Identifying the underlying cellular and molecular mechanisms that are involved in wound healing and tissue regeneration is the subject of intense investigation. Previous studies have identified various epithelial stem/progenitor cells in the hair follicle (HF) and skin, and their essential roles in HF regeneration and skin homeostasis. Conversely, the functional diversity amongst fibroblasts, particularly within the mesenchymal compartments of the HF (dermal papilla and dermal sheath) and their role in HF regeneration and wound repair remain poorly understood. The overarching goal of this research was to characterize the functional significance of HF dermal stem/progenitor cells in HF regeneration and during skin wound healing. Previous lineage tracing studies in our laboratory uncovered a previously unappreciated bipotent population of mesenchymal stem/progenitors (HF dermal stem cells, hfDSCs) that regenerate the dermal sheath (DS) and maintain dermal papilla (DP) cell number (by providing new cells) over multiple successive hair cycles. To investigate the functional role of hfDSCs during telogen (quiescent stage of hair cycle) and mid-early anagen (growth phase of HF regeneration), I used a targeted genetic ablation strategy to specifically deplete these cells. The results demonstrated that hfDSCs have a role in anagen initiation, progression, and hair type specification. To understand the role of dermal progenitor populations in wound healing, I performed fate mapping experiments in two different transgenic mouse models (αSMACreERT2:ROSAYFP and Hic1CreERT2:tdTomato) that label hfDSCs or hfDSCs and reticular/hypodermal progenitors, respectively. I showed that hfDSCs and their progeny are activated after injury, migrate into the wound bed and integrate into the mesenchymal compartments of newly formed HFs. Surprisingly, hfDSC progeny only comprised a small subset of the total mesenchymal cells within each neogenic hair follicle. The same wound in Hic1CreERT2:tdTomato mice which marks both hfDSCs and a population of reticular/hypodemal progenitors, revealed that Hic1 lineage cells comprised >90% of the inductive mesenchyme in the de novo HFs. Moreover, I showed that extra-follicular Hic1 lineage cells can adopt an inductive mesenchymal fate (in an ex vivo setting) are able to induce new HF formation. This suggests that reticular dermal fibroblasts are not predetermined to generate a fibrotic response after injury and can acquire a “regenerative” mesenchymal fate if provided with a permissive environment. Finally, I asked whether changes in hfDSC function might contribute to the rapid hair growth that occurs in HFs residing immediately adjacent to a wound. Wound-induced hair follicle growth (WIHG) occurs when injury-evoked factors stimulate quiescent HFs surrounding the wound to initiate a new anagen phase. Performing small cutaneous wounds on the dorsal skin of mice at different stages of the hair cycle showed that injury biases the fate of hfDSC progeny to adopt an inductive DP fate with greater frequency than during homeostasis, and that this occurs in a hair-cycle dependent manner. Overall, my findings suggest that hfDSCs may be in the important cellular target to prevent DP related cell loss associated with HF miniaturization associated with aging or alopecia; stimulating hfDSCs proliferation or commitment to a DP fate could prevent the loss of (or restore) inductive function necessary for sustained hair growth. In addition, these experiments increase our knowledge of skin wound healing and provide a useful model for studying drug and stem cell-based therapies that prevent fibrotic scar formation and promote tissue regeneration.
Veterinary Science
Abbasi, S. (2017). Understanding the functional contribution of dermal stem cells to hair follicle regeneration and skin wound healing (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/28568