Perivascular Hair Follicle Stem Cells Associate with a Venule Annulus

Abstract

The perivascular microenvironment helps maintain stem cells in many tissues. We sought to determine if there is a perivascular niche for hair follicle stem cells. The association of vessels and follicle progenitor cells began by embryonic day 14.5 (E14.5), when nascent hair placodes had blood vessels approaching them. By birth, a vascular annulus stereotypically surrounded the Keratin 15 negative (K15−) stem cells in the upper bulge, and remained associated with the K15− upper bulge throughout the hair cycle. The angiogenic factor Egfl6 was expressed by the K15− bulge and localized adjacent to the vascular annulus, which was comprised of post-capillary venules. Although denervation altered the phenotype of upper bulge stem cells, the vascular annulus persisted in surgically denervated mouse skin. The importance of the perivascular niche was further suggested by the fact that vascular annuli formed around the upper bulge of de novo reconstituted hair follicles prior to their innervation. Together, these findings demonstrate that the upper bulge is associated with a perivascular niche during the establishment and maintenance of this specialized region of hair follicle stem cells.

Emerging interactions between skin stem cells and their niches

“…Although arteries and veins are located in the lower (reticular) dermis, arborizing capillary networks can be found in the region above the bulge 96 (Fig. 1).…”

“…These capillary networks might influence hair cycling: when angiogenesis is inhibited, anagen induction is delayed, indicating that angiocrine factors may regulate HFSC activity 97 . Intriguingly, the cells above the bulge express angiogenic factor EGFL6, an ECM protein 96 . Whether EGFL6 recruits blood vessels to the hair follicle remains to be explored.…”

Multi‐tasking epidermal stem cells: Beyond epidermal maintenance

“…The papillary dermis contains a wide variety of epidermis‐associated dermal cell populations derived from different germ layers. For example, the hair follicle epidermal basal layer abuts a variety of fibroblasts (Driskell & Watt, ; Rahmani et al., ), arrector pili muscles (Fujiwara et al., ), sensory nerve endings (Zimmerman, Bai, & Ginty, ) and vessel capillary networks (Xiao et al., ). Below the papillary dermis lies the reticular dermis, which has dense collagen fibers.…”

Markers of Epidermal Stem Cell Subpopulations in Adult Mammalian Skin

“…CD34 þ bulge cells are infrequently dividing and label retaining as well as able to self-renew in culture to form colonies (Trempus et al 2003). Significant overlap is found between expression of CD34 and K15 (Lyle et al 1998), which is expressed at low levels throughout the epidermal basal layer and enriched in the bulge (Troy et al 2011;Xiao et al 2013). There are two distinct layers of CD34 þ bulge stem cells , one of which expresses high levels of a6 integrin and is attached to the basement membrane, whereas the other, which appears only after the first hair cycle, is suprabasal and expresses low levels of a6 integrin .…”