(Neuro-)endocrinology of epithelial hair follicle stem cells

Abstract

The hair follicle is a repository of different types of somatic stem cells. However, even though the hair follicle is both a prominent target organ and a potent, non-classical site of production and/or metabolism of numerous polypetide-and steroid hormones, neuropeptides, neurotransmitters and neurotrophins, the (neuro-) endocrine controls of hair follicle epithelial stem cell (HFeSC) biology remain to be systematically explored.Focussing on HFeSCs, we attempt here to offer a "roadmap through terra incognita" by listing key open questions, by exploring endocrinologically relevant HFeSC gene profiling and mouse genomics data, and by sketching several clinically relevant pathways via which systemic and/or locally generated (neuro-)endocrine signals might impact on HFeSC. Exemplarily, we discuss e.g. the potential roles of glucocorticoid and vitamin D receptors, the hairless gene product, thymic hormones, bone morphogenic proteins (BMPs) and their antagonists, and Skg-3 in HFeSC biology. Furthermore, we elaborate on the potential role of nerve growth factor (NGF) and substance P-dependent neurogenic inflammation in HFeSC damage, and explore how neuroendocrine signals may influence the balance between maintenance and destruction of hair follicle immune privilege, which protects these stem cells and their progeny. These considerations call for a concerted research effort to dissect the (neuro)-endocrinology of HFeSCs much more systematically than before. The hair follicle (HF) and its special, associated mesenchyme (i.e. the connective tissue sheath, CTS) are repositories of different types of somatic stem cells (epithelial, mesenchymal, neural, mesenchymal) (Cotsarelis, 2006; Kruse et al., 2006;Millar, 2005;Ohyama et al., 2006;Tiede et al. 2007;Waters et al., 2007;Yu et al., 2006). These HFassociated stem cell populations are critical for HF development and function, including HF pigmentation (Nishimura et al., 2002(Nishimura et al., , 2005Sarin and Artandi, 2007). Fig. 1 shows several important, recognized hair follicle-associated stem cell populations and their bestcharacterized location(s) in the pilosebaceous unit, though it must be kept in mind that the indicated ones are unlikely to be the only stem cell population associated with mammalian skin appendages (Tiede et al. 2007). Clinical importance of hair follicle stem cellsHair follicle epithelial stem cells (HFeSCs) are clinically important, since they can be key targets for pathological processes, such as an autoaggressive inflammatory cell attack on HFeSC, e.g. in lupus erythematosus or lichen planopilaris, where the destruction of bulge HFeSCs (see Fig.1) abolishes the hair follicle's capacity to cycle and to rhythmically regenerate itself, leading to scarring alopecia (Cotsarelis, 2006;Hiroi et al., 2006;Mobini et al., 2005;Paus, 2006). Likewise, a gradual loss of HF melanocyte stem cells may exhaust the HF pigmentary unit's capacity to generate itself and to produce melanin and thus likely plays a key role in hair graying (Commo et al., 2004;...

Commonalities in the endocrinology of stem cell biology and organ regeneration

“…In the uterus, the induction of IGFBPs by IGF signalling limits further IGF1 action. IGFBPs have been noted in the hair follicle and seem likely to be relevant (Paus et al, 2008), questioning whether this autoregulation is also true of the gut epithelium (Rowland and Brubaker, 2008) and haematopoietic niches (Garrett and Emerson, 2008). On the basis of colony formation in culture and distinct gene expression profiles, the stem or progenitor cells for the uterine epithelium are thought to be different from those for its underlying stroma (Gargett et al, 2008).…”

“…Of course, arbitrarily dividing clinical specialties is biological nonsense and with bone and blood production juxtaposed perhaps it should be expected that the major hormone orchestrating the deposition and resorption of bone by osteoblasts and osteoclasts should also turn out to regulate the haematopoietic niche. It transpires that PTH signals through the osteoblast, at least in part via the local production of insulin-like growth factor-1 (IGF1), to increase the number of Tiede, Arck and Paus review the hair follicle stem cell, a critical component of the skin's ability to regenerate (Paus et al, 2008). It transpires that this niche potentially harbours a local version of the hypothalamic-anterior pituitary-adrenal cortex axis but whether glucocorticoid directly targets the stem cell, or whether effects are indirect, remains unclear.…”

“…The result is ten articles (Berry et al, 2008;Gargett et al, 2008;Garrett and Emerson, 2008;Gray, 2008;Hanley et al, 2008;Hoffman, 2008;Ishizuya-Oka and Shi, 2008;Kristensen et al, 2008;Paus et al, 2008;Rowland and Brubaker, 2008) that should be considered alongside a previous review in Molecular & Cellular Endocrinology on the regeneration of the adrenal cortex from resident stem cells (Kim and Hammer, 2007). To complement these in vivo paradigms, three examples are included here of current in vitro stem cell work aiming to generate terminally differentiated cell-types for clinical therapy (Best et al, 2008;Moore et al, 2008;Tare et al, 2008): an endocrine twist on cell therapy meets regenerative biology.…”

“…Here, author teams have been encouraged to speculate on potential as well as proven mechanisms. In other locations such as the intestine (Rowland and Brubaker, 2008), testis (Hoffman, 2008) and skin (Paus et al, 2008), the presence of true adult stem cells is established (listed in bold type in Table 1). In this setting, authors have included the potential for endocrine and growth factor regulation that has previously been largely unscripted.…”

“…Tiede, Arck and Paus review the hair follicle stem cell, a critical component of the skin's ability to regenerate (Paus et al, 2008). It transpires that this niche potentially harbours a local version of the hypothalamic-anterior pituitary-adrenal cortex axis but whether glucocorticoid directly targets the stem cell, or whether effects are indirect, remains unclear.…”