The bulge HFSCs that go into the hair germ are subsequently replenished at anagen by self-renewing symmetric divisions of the bulge SCs ( Zhang et al., 2009 Zhang et al., 2010). In anagen, signals from the environment, including the fat progenitors ( Goldstein and Horsley, 2012), activate the quiescent HFSCs in the hair germ to produce a new hair bulb with a newly growing hair shaft ( Cotsarelis, 2006).
The skin loses most of its fat in the hypodermis, shrinks considerably in thickness, and the HFs enter the resting phase, or telogen. At catagen a subset of quiescent HFSCs leave the bulge, and form the secondary hair germ, which replaces the apoptotic hair bulb. HFs undergo morphologically recognizable and synchronous phases of remodeling, known as catagen (bulb destruction), telogen (quiescence and rest) and anagen (bulb growth). During hair cycle, bulge HFSCs periodically regenerate the temporary lower HF region (bulb), which grows downward into the hypodermis ( Cotsarelis, 2006). HFSCs reside in the upper segment of the hair follicle (HF) known as the bulge, and are embedded deep into the skin dermis. Previously, we proposed a hypothetical model in which adult epithelial HFSCs cluster in their tissue residence (the bulge) to produce gradients of signaling molecules that might remodel the surrounding microenvironment ( Fuchs et al., 2004 Tumbar et al., 2004). Little is known about skin vasculature cross-talking with adult hair follicle stem cells (HFSCs). Reverse signaling, from SCs to the neighboring niche, was also shown in zebrafish where a hematopoietic SC can indeed remodel the perivascular niche ( Tamplin et al., 2015). An intimate molecular communication from the vascular niche to the SCs contributes to tissue homeostasis and repair.
Adult neural, mesenchymal, and hematopoietic SCs neighbor the vasculature, which not only supplies oxygen and nutrients but also provides molecular signals to the stem cells ( Goldberg and Hirschi, 2009 Gómez-Gaviro et al., 2012 Oh and Nör, 2015 Waldau, 2015), particularly through endothelial cells ( Azevedo et al., 2017 Gao et al., 2018 Perlin et al., 2017). Stem cell (SC) maintenance and function depend on signals from their local microenvironment, the SC niche. We suggest a working model in which coordinated remodeling and molecular cross-talking of the adult epithelial and endothelial skin compartments modulate timing of HFSC activation from quiescence for proper tissue homeostasis of adult skin.
Conversely, the HFSC activator Runx1 regulates secreted proteins with previously demonstrated roles in vasculature remodeling. Suggestively, skin vasculature produces BMP4, a well-established HFSC quiescence-inducing factor, thus contributing to a proliferation-inhibitory environment near the HFSC. Increased density of HPuHG can be induced by reciprocal mutations in the epithelium ( Runx1) and endothelium ( Alk1) in adult mice, and is accompanied by prolonged HFSC quiescence and by delayed entry and progression into the hair growth phase (anagen).
Specifically, a horizontal plexus under the secondary hair germ (HPuHG) transiently neighbors the HFSC activation zone during the quiescence phase (telogen). Skin vasculature undergoes dramatic remodeling during adult mouse hair cycle. Skin vasculature cross-talking with hair follicle stem cells (HFSCs) is poorly understood.