Stem cell dynamics in the hair follicle niche

Abstract

Hair follicles are appendages of the mammalian skin that have the ability to periodically and stereotypically regenerate in order to continuously produce new hair over our lifetime. The ability of the hair follicle to regenerate is due to the presence of stem cells that along with other cell populations and non-cellular components, including molecular signals and extracellular material, make up a niche microenvironment. Mounting evidence suggests that the niche is critical for regulating stem cell behavior and thus the process of regeneration. Here, we review the literature concerning past and current studies that have utilized mouse genetic models, combined with other approaches to dissect the molecular and cellular composition of the hair follicle niche. We also discuss our current understanding of how stem cells operate within the niche during the process of tissue regeneration and the factors that regulate their behavior.

Keywords: Fate; Hair follicle; Niche; Regeneration; Stem cells.

Figure 1. Anatomy and molecular heterogeneity of the hair follicle niche

Scheme of the mouse hair follicle at the resting phase of the hair regeneration cycle. Hair follicle stem cells reside in the bulge, while a pool of progenitor cells, which forms the hair germ, is situated directly below and in contact with the mesenchymal dermal papilla. Other epithelial cell populations exist in defined anatomical tissue compartments located above the bulge. The hair follicle niche displays a pronounced molecular heterogeneity, which is evident by the distribution and level of expression of various genes.

Figure 2. The hair follicle niche microenvironment and stem cell fate

a) Scheme of the hair follicle depicting the various factors that constitute the niche microenvironment. b) Scheme of stem cell behavior in homeostasis and after injury. Under physiological conditions stem cells in the upper portion of the bulge do not participate directly to hair regeneration and are more likely to self-renew. Cells in the lower bulge generate precursors that populate the ORS during hair growth, while those that survive the regressing phase return to the niche to form, at least in part, the new hair germ before the onset of a new regeneration cycle. Cells in the hair germ directly contribute to hair growth producing all the differentiated cell types. Following niche injury, non-hair epithelial cells above the bulge may enter the niche changing their fate to actively participate in hair regeneration.

Figure 3. Cell dynamics in the hair cycle

The figure depicts side views of live hair follicles, at rest (telogen) and sequential stages of hair growth (anagen), as visualized by multiphoton microscopy using a K14-H2BGFP reporter. At the onset of a new regeneration cycle the lower portion of the hair follicle begins to rapidly proliferate and expands downwards into the dermis. a) At the initial stages of hair growth cell proliferation is spatially regulated, occurring predominately within the hair germ and with an axis of division parallel to the long axis of hair follicle growth. b) Epithelial nuclei actively re-organize around the mesenchymal dermal papilla progressively surrounding it while the matrix is formed. c) Epithelial precursor cells in the matrix generate all the differentiated cell types that form the seven concentric layers of the hair shaft and inner root sheath (IRS), which expand upwards and toward the surface of the skin. At the same time the basal outer root sheath (ORS) layer also expands through localized proliferation and downward cell migration.