The Basement Membrane of Hair Follicle Stem Cells Is a Muscle Cell Niche

Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, UK.
Cell (Impact Factor: 32.24). 02/2011; 144(4):577-89. DOI: 10.1016/j.cell.2011.01.014
Source: PubMed


The hair follicle bulge in the epidermis associates with the arrector pili muscle (APM) that is responsible for piloerection ("goosebumps"). We show that stem cells in the bulge deposit nephronectin into the underlying basement membrane, thus regulating the adhesion of mesenchymal cells expressing the nephronectin receptor, α8β1 integrin, to the bulge. Nephronectin induces α8 integrin-positive mesenchymal cells to upregulate smooth muscle markers. In nephronectin knockout mice, fewer arrector pili muscles form in the skin, and they attach to the follicle above the bulge, where there is compensatory upregulation of the nephronectin family member EGFL6. Deletion of α8 integrin also abolishes selective APM anchorage to the bulge. Nephronectin is a Wnt target; epidermal β-catenin activation upregulates epidermal nephronectin and dermal α8 integrin expression. Thus, bulge stem cells, via nephronectin expression, create a smooth muscle cell niche and act as tendon cells for the APM. Our results reveal a functional role for basement membrane heterogeneity in tissue patterning. PAPERCLIP:

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Article: The Basement Membrane of Hair Follicle Stem Cells Is a Muscle Cell Niche

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    • "These cells are known to highly express periostin, which is a major component of the tendon extracellular matrix (ECM). Accordingly it has been concluded that bulge stem cells serve as tendon cells for the APM.[7] "
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    ABSTRACT: The arrector pili muscle (APM) consists of a small band of smooth muscle that connects the hair follicle to the connective tissue of the basement membrane. The APM mediates thermoregulation by contracting to increase air-trapping, but was thought to be vestigial in humans. The APM attaches proximally to the hair follicle at the bulge, a known stem cell niche. Recent studies have been directed toward this muscle's possible role in maintaining the follicular integrity and stability. This review summarizes APM anatomy and physiology and then discusses the relationship between the follicular unit and the APM. The potential role of the APM in hair loss disorders is also described, and a model explaining APM changes in hair loss is proposed.
    International Journal of Trichology 07/2014; 6(3):88-94. DOI:10.4103/0974-7753.139077
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    • "ß1 integrin signaling has long been thought to be important in murine epidermal and HF epithelial SCs (eSCs) [15–17]. In the HF, eSCs and partially differentiated epithelial progenitor cells (ePCs) can give rise to all epithelial cell types of the hair, the epidermis, and the sebaceous gland and are mostly found within the HF bulge [18–20]. The eSCs within this HF compartment [16,21] are slow-cycling, and show clonogenicity and proliferative capacity [22]. "
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    ABSTRACT: β1 integrin regulates multiple epithelial cell functions by connecting cells with the extracellular matrix (ECM). While β1 integrin-mediated signaling in murine epithelial stem cells is well-studied, its role in human adult epithelial progenitor cells (ePCs) in situ remains to be defined. Using microdissected, organ-cultured human scalp hair follicles (HFs) as a clinically relevant model for studying human ePCs within their natural topobiological habitat, β1 integrin-mediated signaling in ePC biology was explored by β1 integrin siRNA silencing, specific β1 integrin-binding antibodies and pharmacological inhibition of integrin-linked kinase (ILK), a key component of the integrin-induced signaling cascade. β1 integrin knock down reduced keratin 15 (K15) expression as well as the proliferation of outer root sheath keratinocytes (ORSKs). Embedding of HF epithelium into an ECM rich in β1 integrin ligands that mimic the HF mesenchyme significantly enhanced proliferation and migration of ORSKs, while K15 and CD200 gene and protein expression were inhibited. Employing ECM-embedded β1 integrin-activating or -inhibiting antibodies allowed to identify functionally distinct human ePC subpopulations in different compartments of the HF epithelium. The β1 integrin-inhibitory antibody reduced β1 integrin expression in situ and selectively enhanced proliferation of bulge ePCs, while the β1 integrin-stimulating antibody decreased hair matrix keratinocyte apoptosis and enhanced transferrin receptor (CD71) immunoreactivity, a marker of transit amplifying cells, but did not affect bulge ePC proliferation. That the putative ILK inhibitor QLT0267 significantly reduced ORSK migration and proliferation and induced massive ORSK apoptosis suggests a key role for ILK in mediating the ß1 integrin effects. Taken together, these findings demonstrate that ePCs in human HFs require β1 integrin-mediated signaling for survival, adhesion, and migration, and that different human HF ePC subpopulations differ in their response to β1 integrin signaling. These insights may be exploited for cell-based regenerative medicine strategies that employ human HF-derived ePCs.
    PLoS ONE 12/2013; 8(12):e84356. DOI:10.1371/journal.pone.0084356 · 3.23 Impact Factor
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    • "), and rabbit anti Egfl6 (a kind gift from Dr Fiona Watt (Fujiwara et al., 2011)). Confocal images were acquired with the Zeiss LSM 710 Confocal system (Carl Zeiss, Thornwood, NY). Whole-mount staining followed the online protocol as described before (Li and Mukouyama, 2011). "
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    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.Journal of Investigative Dermatology accepted article preview online, 4 April 2013; doi:10.1038/jid.2013.167.
    Journal of Investigative Dermatology 04/2013; 133(10). DOI:10.1038/jid.2013.167 · 7.22 Impact Factor
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