Stem cell-intrinsic mechanisms regulating adult hair follicle homeostasis

Abstract

Adult hair follicle stem cells (HFSCs) undergo dynamic and periodic molecular changes in their cellular states throughout the hair homeostatic cycle. These states are tightly regulated by cell-intrinsic mechanisms and by extrinsic signals from the microenvironment. HFSCs are essential not only for fuelling hair growth, but also for skin wound healing. Increasing evidence suggests an important role of HFSCs in organizing multiple skin components around the hair follicle, thus functioning as an organizing centre during adult skin homeostasis. Here, we focus on recent findings on cell-intrinsic mechanisms of HFSC homeostasis, which include transcription factors, histone modifications, DNA regulatory elements, non-coding RNAs, cell metabolism, cell polarity and post-transcriptional mRNA processing. Several transcription factors are now known to participate in well-known signalling pathways that control hair follicle homeostasis, as well as in super-enhancer activities to modulate HFSC and progenitor lineage progression. Interestingly, HFSCs have been shown to secrete molecules that are important in guiding the organization of several skin components around the hair follicle, including nerves, arrector pili muscle and vasculature. Finally, we discuss recent technological advances in the field such as single-cell RNA sequencing and live imaging, which revealed HFSC and progenitor heterogeneity and brought new light to understanding crosstalking between HFSCs and the microenvironment. The field is well on its way to generate a comprehensive map of molecular interactions that should serve as a solid theoretical platform for application in hair and skin disease and ageing.

Keywords: epigenetics; metabolism; skin stem cells; stem cell niche; transcription factors.

Figure 1.

Adult hair cycle. Adult hair follicles are maintained via repeated cycles of growth (anagen), regression (catagen), and quiescence (telogen). In telogen, primed HFSCs form a tight, ball-like structure in hair germ, underneath quiescent HFSCs in the bulge. Mesenchymal cells in DP send signals to activate primed HFSCs during telogen-anagen transition, and primed HFSCs undergo rapid proliferation and expansion to give rise to matrix progenitors during early anagen. Matrix cells further differentiate to form IRS, cortex, and hair shaft during anagen, after which differentiated cells undergo systematic cell death during subsequent catagen.

Figure 2.

Changes in HFSC states during hair cycle. Bulge HFSCs in catagen are yet uncommitted to one of two subsequent fates during anagen. At this stage a fraction of bulge HFSCs will take residence below the bulge to form the primed HFSCs in the hair germ. Recently studied TFs discussed in text are shown on the arrows corresponding to their described function.

Figure 3.

Model of epigenetic and cell plasticity states of HFSCs and progenitors. During quiescence bulge HFSCs maintain highest cell fate plasticity and lowest epigenetic identity as defined by low levels of histone H3 methylation marks. As bulge cells approach anagen for self-renewal, Bmp signal strength decrease and levels of histone H3 methylation marks increase, resulting in medium plasticity and epigenetic identity in proliferating bulge HFSCs. Matrix cells have high levels of histone H3 methylation marks associated with low cell plasticity and high epigenetic identity as progenitor cells.