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  • Based on our findings and the recent literature we

    2018-10-20

    Based on our findings and the recent literature, we propose the following model of sebocyte differentiation (Figure 7). First, subsets of LGR6- and LRIG1-expressing enos inhibitor residing in the upper HF and periphery of the SG constitute the bona fide stem cells of the sebocyte lineage (Page et al., 2013; Snippert et al., 2010). This is in line with the observation that the SG can be maintained independently of the HF lineages (Ghazizadeh and Taichman, 2001). We do not rule out the existence of other SG stem cell compartments, and indeed, we believe this is likely, given the diversity of stem cells elsewhere in the epidermis (Kretzschmar and Watt, 2014). Second, we propose that MYC plays a role in proliferation of cells that are committed to undergo terminal differentiation. Third, upregulation of BLIMP1 promotes terminal differentiation by repressing c-Myc and inhibiting proliferation (Figure 7) (Berta et al., 2010; Cottle et al., 2013). Our revised model suggests that Blimp1 cKO mice exhibit SG hyperplasia directly because of derepression of c-Myc, as reported previously (Horsley et al., 2006), and indirectly by causing a barrier defect in the IFE (Chiang et al., 2013), which activates stem cells within the HF infundibulum/junctional zone and SG periphery to proliferate (Page et al., 2013).
    Experimental Procedures
    Acknowledgments We thank E. Magnúsdóttir, K.B. Jensen, B. Trappmann, and all F.M.W. lab members for suggestions and advice, especially S. Broad, R.R. Driskell, E. Heath, and E.J. MacRae. We acknowledge the expert technical assistance of J. Harris, P. Humphreys, B. Mansfield, M. McLeish, H. Skelton, R. Walker, and the biofacilities at the Cambridge Stem Cell Institute and the Guy’s Campus of King’s College London, as well as the flow cytometry core facility at the NIHR GSTT/KCL Biomedical Research Centre London. We thank H. Clevers and R. Toftgård for generously providing the Lgr6 KI line and K.B. Jensen for generating the Lrig1 KI line. This work was supported by the MRC, the Wellcome Trust, Cancer Research UK, and the European Union Framework 7 programme. We also gratefully acknowledge support from the University of Cambridge and Hutchison Whampoa. K.K. is the recipient of an MRC Ph.D. studentship.
    Introduction The primitive trachea and two distal lung buds emerge from the anterior foregut endoderm around embryonic day 9.5 (E9.5) (Kimura and Deutsch, 2007). Already at stage E10.5, the trachea comprises epithelial cells expressing the basal cell marker P63, and they increase in number until stage E15.5 (Que et al., 2007, 2009). Branching morphogenesis, characterized by SOX9 expression in the distal lung epithelium, gives rise to the conducting airway and the gas exchange regions throughout the prenatal period (Alanis et al., 2014). Before E15.0, the proximal branches downregulate SOX9, activate SOX2, and undergo conducting airway differentiation (ending at E17.0) (Alanis et al., 2014). ASCL1-expressing neuroendocrine cells become detectable at E12.5 (Li and Linnoila, 2012). The ciliated (Foxj1, β-tubulin+) and club cell (SCGB1A1+) markers are expressed around E14.5–E16.5 (Rawlins et al., enos inhibitor 2007, 2009b). In addition, the heterogeneous club cell population expresses early markers (Scgb3a2, Cyp2f2, and others) and region-specific transcripts (Reg3g, Gabrp, Hp, Upk3a, and others) (Guha et al., 2014). After the specification of the bronchioalveolar duct junctions at stage E17.0, alveolar type 1 (AT1) and 2 (AT2) cells differentiate during the sacculation process and mature into functional alveoli in the distal lung (Alanis et al., 2014; Desai et al., 2014; Treutlein et al., 2014). Branching morphogenesis and alveolar differentiation are oppositely regulated by KRAS, SOX9, and others (Chang et al., 2013). Mature basal cells are found postnatally (P63+, KRT14+, KRT5+, BS-I-B4+) (Daniely et al., 2004). Shortly after birth, submucosal glands emerge underneath the proximal airway epithelium, with acini comprised of secretory cells (e.g., mucous and serous cells) and myoepithelial basal cells connected to the surface by ducts made up of basal and ciliated cells (Wansleeben et al., 2013, 2014). The submucosal glands share expression of several markers with surface epithelium (e.g., P63, KRT5, MUC5AC, LTF, and others) but distinctively comprise P63+ KRT5+ SMA+ myoepithelial basal cells (Wansleeben et al., 2014).