Abstract
Hair follicle regeneration is dependent on reciprocal signaling between epithelial cells and underlying mesenchymal cells within the dermal papilla. Hair follicle dermal stem cells reside within the hair follicle mesenchyme, self-renew in vivo, and function to repopulate the dermal papilla and regenerate the connective tissue sheath with each hair cycle. The identity and temporal pattern of signals that regulate hair follicle dermal stem cell function are not known. Here, we show that platelet-derived growth factor signaling is crucial for hair follicle dermal stem cell function and platelet-derived growth factor deficiency results in a progressive depletion of the hair follicle dermal stem cell pool and their progeny. Using αSMACreERT2:RosaYFP:Pdgfrαflox mice, we ablated Pdgfrα specifically within the adult hair follicle dermal stem cell lineage. This led to significant loss of hair follicle dermal stem cell progeny in connective tissue sheath and dermal papilla of individual follicles, and a progressive reduction in total number of anagen hair follicles containing YFP+ve cells. As well, over successive hair cycles, fewer hair follicle dermal stem cells were retained within each telogen hair follicle suggesting an impact on hair follicle dermal stem cell self-renewal. To further assess this, we grew prospectively isolated hair follicle dermal stem cells (Sox2GFP+ve αSMAdsRed+ve) in the presence or absence of platelet-derived growth factor ligands. Platelet-derived growth factor-BB enhanced proliferation, increased the frequency of Sox2+ve hair follicle dermal stem cell progeny and improved inductive capacity of hair follicle dermal stem cells in an ex vivo hair follicle formation assay. Similar effects on proliferation were observed in adult human SKPs. Our findings impart novel insights into the signals that comprise the adult hair follicle dermal stem cell niche and suggest that platelet-derived growth factor signaling promotes self renewal, is essential to maintain the hair follicle dermal stem cell pool and ultimately their regenerative capacity within the hair follicle.
Highlights
The hair follicle (HF) is a unique model system of adult tissue regeneration
We found that conditional genetic deletion of Pdgfrα in HF dermal sheath stem cells (hfDSCs) resulted in a significant decline in hfDSC progeny, within the connective tissue sheath (CTS) compartment
We show that platelet-derived growth factor (PDGF) signaling is an important contributor to maintenance and proliferation of adult hfDSCs within the HF niche in vivo and can be used to robustly expand isolated hfDSCs in vitro, while maintaining an enhanced inductive capacity
Summary
The hair follicle (HF) is a unique model system of adult tissue regeneration. To initiate the regenerative cycle, stem cells residing in the epithelial bulge and secondary germinal zone are activated by signals emanating from specialized mesenchymal cells that comprise the dermal papilla (DP). Recent work has identified the existence of a self-renewing mesenchymal stem cell that resides within the adult HF and functions to regenerate the connective tissue sheath (CTS) and contribute new cells to the DP with each new hair cycle.[3] Genetic depletion of these HF dermal sheath stem cells (hfDSCs) resulted in impaired hair growth and prevented conversion to a larger hair type,[3] a process that requires an increase in DP cells,[4] indicating their importance in repopulating these dermal lineages within the HF and in maintaining sufficient numbers of DP cells to enable inductive competency throughout life. SKPs are thought to be the in vitro derivative of hfDSCs3 as, like hfDSCs, transplanted SKPs are able to induce de novo HF formation or reconstitute the DP and CTS of existing follicles and subsequently modify the type of hair that was produced[5] thereby distinguishing them from other fibroblast populations within the skin and highlighting their significant therapeutic potential
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