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: 33.12). 02/2011; 144(4):577-89. DOI: 10.1016/j.cell.2011.01.014
Source: PubMed

ABSTRACT 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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    • "), 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 · 6.37 Impact Factor
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    • "Strikingly, in skin wounds or tumors the pericellular integrin distribution, including then also í µí»¼6í µí»½4, largely expands into suprabasal layers, which reflects a severe reduction in cell and tissue polarity [63] [64] [65]. Last not least, particular properties or microheterogeneity of BMs is supposed to contribute to the niche of tissue-specific stem or progenitor cells [66] [67] [68] [69] [70] [71] [72] "
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    ABSTRACT: The epidermis functions in skin as first defense line or barrier against environmental impacts, resting on extracellular matrix (ECM) of the dermis underneath. Both compartments are connected by the basement membrane (BM), composed of a set of distinct glycoproteins and proteoglycans. Herein we are reviewing molecular aspects of BM structure, composition, and function regarding not only (i) the dermoepidermal interface but also (ii) the resident microvasculature, primarily focusing on the per se nonscaffold forming components perlecan and nidogen-1 and nidogen-2. Depletion or functional deficiencies of any BM component are lethal at some stage of development or around birth, though BM defects vary between organs and tissues. Lethality problems were overcome by developmental stage- and skin-specific gene targeting or by cell grafting and organotypic (3D) cocultures of normal or defective cells, which allows recapitulating BM formation de novo. Thus, evidence is accumulating that BM assembly and turnover rely on mechanical properties and composition of the adjacent ECM and the dynamics of molecular assembly, including further "minor" local components, nidogens largely functioning as catalysts or molecular adaptors and perlecan as bridging stabilizer. Collectively, orchestration of BM assembly, remodeling, and the role of individual players herein are determined by the developmental, tissue-specific, or functional context.
    03/2013; 2013:179784. DOI:10.1155/2013/179784
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    • "To determine the cellular mechanisms leading to the absence of adult CD34 bulge SCs in Brca1-deficient epidermis , we excluded ectopic differentiation (Supplemental Fig. 2A) and performed a detailed temporal analysis of proliferation and apoptosis in the prospective bulge region of Brca1 cKO mice during HF morphogenesis (Fig. 5H–J; Supplemental Fig. 2B). To delineate the prospective bulge area, we used nephronectin (NPNT), an extracellular matrix protein expressed in the restricted region of the upper part of the lower outer root sheath cells that includes the prospective bulge SCs from early postnatal days (Supplemental Fig. 2C; Fujiwara et al. 2011). As shown in Figure 5H, the prospective bulge SCs in Brca1 cKO mice exhibited a fivefold to 10-fold higher rate of BrdU incorporation compared with their wild-type lit- Figure 5. Absence of quiescent adult HF SCs in BRCA1-de- ficient epidermis. "
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    ABSTRACT: The accurate maintenance of genomic integrity is essential for tissue homeostasis. Deregulation of this process leads to cancer and aging. BRCA1 is a critical mediator of this process. Here, we performed conditional deletion of Brca1 during epidermal development and found that BRCA1 is specifically required for hair follicle (HF) formation and for development of adult HF stem cells (SCs). Mice deficient for Brca1 in the epidermis are hairless and display a reduced number of HFs that degenerate progressively. Surprisingly, the interfollicular epidermis and the sebaceous glands remain unaffected by Brca1 deletion. Interestingly, HF matrix transient amplifying progenitors present increased DNA damage, p53 stabilization, and caspase-dependent apoptosis compared with the interfollicular and sebaceous progenitors, leading to hyperproliferation, apoptosis, and subsequent depletion of the prospective adult HF SCs. Concomitant deletion of p53 and Brca1 rescues the defect of HF morphogenesis and loss of HF SCs. During adult homeostasis, BRCA1 is dispensable for quiescent bulge SCs, but upon their activation during HF regeneration, Brca1 deletion causes apoptosis and depletion of Brca1-deficient bulge SCs. Our data reveal a major difference in the requirement of BRCA1 between different types of epidermal SCs and progenitors and during the different activation stages of adult HF SCs.
    Genes & development 12/2012; DOI:10.1101/gad.206573.112 · 12.64 Impact Factor
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