Article

Rittie L, Stoll SW, Kang S et al.Hedgehog signaling maintains hair follicle stem cell phenotype in young and aged human skin. Aging Cell 8:738-751

Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
Aging cell (Impact Factor: 6.34). 12/2009; 8(6):738-51. DOI: 10.1111/j.1474-9726.2009.00526.x
Source: PubMed

ABSTRACT

Skin hair follicles (HF) contain bulge stem cells (SC) that regenerate HFs during hair cycles, and repair skin epithelia following injury. As natural aging is associated with decreased skin repair capacity in humans, we have investigated the impact of age on human scalp HF bulge cell number and function. Here, we isolated human bulge cells, characterized as CD200+/KRT15+/KRT19+ cells of the HF, by dissection-combined CD200 selection in young and aged human skin. Targeted transcriptional profiling indicates that KRT15, KRT19, Dkk3, Dkk4, Tcf3, S100A4, Gas1, EGFR and CTGF/CCN2 are also preferentially expressed by human bulge cells, compared to differentiated HF keratinocytes (KC). Our results demonstrate that aging does not alter expression or localization of these HF SC markers. In addition, we could not detect significant differences in HF density or bulge cell number between young and aged human scalp skin. Interestingly, hedgehog (Hh) signaling is activated in human bulge cells in vivo, and down-regulated in differentiated HF KCs, both in young and aged skin. In addition, activation of Hh signaling by lentivirus-mediated overexpression of transcription factor Gli1 induces transcription of HF SC markers KRT15, KRT19, and Gas1, in cultured KCs. Together with previously reported knock-out mouse results, these data suggest a role for Hh signaling in maintaining bulge cell phenotype in young and aged human skin.

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    • "Required in Sox9+ cells to establish eHFSC niche Ablation in Sox9+ cells results in failure of CD34+ cell emergence [52] Tcf3 ~ Heightened mRNA detected relative to differentiated keratinocytes [12] eHFSC marker [53] Tcf4 ? eHFSC marker [38] [53] ? "
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    • "Whether CCN3 similarly regulates keratinocyte growth in relation to gap junction status remains unknown. Our results clearly indicate that CCN2 is not expressed in interfollicular epidermal keratinocytes, which is in sharp contrast with CCN2 expression in human hair follicle keratinocytes (Rittié et al. 2009) and in agreement with mouse findings (Kapoor et al. 2008). Our data indicate that CCN2 is restricted to melanocytes in human epidermis in vivo. "
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    • "Human SHH protein shows a similarity of 92.4% in the amino acid sequence with its murine homolog (Marigo et al., 1995). It has been shown that the SHH protein plays key roles in controlling organogenesis and morphogenesis of a variety of tissues and organs and epithelial-mesenchymal interactions during the vertebrate embryonic development as well as in the regulation of adult stem/progenitor cell behavior (Cohen, 2003; Beachy et al., 2004; Palma and Ruiz i Altaba, 2004; Palma et al., 2005; Katoh and Katoh, 2006; Liu et al., 2006; Zhou et al., 2006; Lin et al., 2007; Shi et al., 2008; Varjosalo and Taipale, 2008; Amankulor et al., 2009; Rittié et al., 2009). "
    [Show abstract] [Hide abstract] ABSTRACT: The hedgehog (Hh)/glioma-associated oncogene (GLI) signaling network is among the most important and fascinating signal transduction systems that provide critical functions in the regulation of many developmental and physiological processes. The coordinated spatiotemporal interplay of the Hh ligands and other growth factors is necessary for the stringent control of the behavior of diverse types of tissue-resident stem/progenitor cells and their progenies. The activation of the Hh cascade might promote the tissue regeneration and repair after severe injury in numerous organs, insulin production in pancreatic beta-cells, and neovascularization. Consequently, the stimulation of the Hh pathway constitutes a potential therapeutic strategy to treat diverse human disorders, including severe tissue injuries; diabetes mellitus; and brain, skin, and cardiovascular disorders. In counterbalance, a deregulation of the Hh signaling network might lead to major tissular disorders and the development of a wide variety of aggressive and metastatic cancers. The target gene products induced through the persistent Hh activation can contribute to the self-renewal, survival, migration, and metastasis of cancer stem/progenitor cells and their progenies. Moreover, the pivotal role mediated through the Hh/GLI cascade during cancer progression also implicates the cooperation with other oncogenic products, such as mutated K-RAS and complex cross-talk with different growth factor pathways, including tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), Wnt/beta-catenin, and transforming growth factor-beta (TGF-beta)/TGF-beta receptors. Therefore, the molecular targeting of distinct deregulated gene products, including Hh and EGFR signaling components and other signaling elements that are frequently deregulated in highly tumorigenic cancer-initiating cells and their progenies, might constitute a potential therapeutic strategy to eradicate the total cancer cell mass. Of clinical interest is that these multitargeted approaches offer great promise as adjuvant treatments for improving the current antihormonal therapies, radiotherapies, and/or chemotherapies against locally advanced and metastatic cancers, thereby preventing disease relapse and the death of patients with cancer.
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