Figure 1: Immunofluorescent image of hair follicle stem cells (red) and melanocyte stem cells (green), which reside in the same niche. During the hair cycle, these two stem cells must be stimulated to differentiate coordinately in order for the melanin, produced by the differentiated melanocyte, to be transferred to the differentiated hair cells in the mature hair follicle. The timely production and transfer of melanin from melanocytes to hair cells is what makes the hair pigmented. Recently, the Fuchs' lab discovered a gene that, when mutated, uncouples this intricate communication circuitry. The work could have important implications for several disease and stress states in humans, where the coordinate behavior of these two stem cells is also disrupted.
Image provided by Elaine Fuchs. For more details, see Chang, C.Y., Pasolli, H.A., Giannopoulou, E.G., Guasch, G., Gronostajski, R.M., Elemento, O., and Fuchs, E. 2013. Nature 495:98-102.
Figure 2: Squamous cell carcinomas of the skin contain undifferentiated stem cells, which reside within the tumor-stroma interface. These cancer stem cells sustain long-term tumor growth and also differentiate into keratinized pearls at the tumor center. Here, keratin 5 (red) marks both undifferentiated cancer stem cells and their early progeny, while keratin 6 (green) is a well-established feature of aberrant tumor differentiation. Nuclear DNA is detected by DAPI (blue).
Image provided by Elaine Fuchs. For more details, see Schober, M., and Fuchs, E. 2011. Proceedings of the National Academy of Sciences USA 108:10544-10549.
Figure 3: Mice cloned from skin stem cells. The technology used, nuclear transfer, entails replacing a mouse oocyte with a skin stem cell nucleus. The hybrid cell is then cultured to form a tiny cluster of cells, which can be used either to generate mice or to make embryonic stem (ES) cells.
Image provided by Elaine Fuchs. See also Li, J., Greco, V., Guasch, G., Fuchs, E., and Mombaerts P. 2007. Proceedings of the National Academy of Sciences USA 104:2738–2743.
Figure 4: Embryonic mouse skin labeled with antibodies. Immunofluorescence image of embryonic mouse skin labeled with antibodies against Hes1, a nuclear factor encoded by a target gene activated by canonical Notch signaling (red). Skin sections are counterstained with DAPI (blue) to mark chromatin and with antibodies against β4 integrin (green) to mark the base of the epidermis.
From Blanpain, C., Lowry, W.E., Pasolli, H.A., and Fuchs, E. 2006. Genes & Development 20:3022–3035. © 2006 Cold Spring Harbor Laboratory Press.
Figure 5: Skin epithelium lacking the cell-cell adhesion protein α-catenin was grafted onto the back of a Nude (hairless) mouse. Forty days later, the skin showed signs of squamous cell carcinoma (shown). By 70 days, the tumor had become invasive.
From Kobielak, A., and Fuchs, E. 2006. Proceedings of the National Academy of Sciences USA 107:2322–23227. © 2006 by The National Academy of Sciences.
Figure 6: Uncontrolled release of cytokines. Without p120-catenin, epidermal cells cannot dampen the activity of NFκB, which controls expression of a number of proinflammatory cytokines. Epidermal release of cytokines is necessary in a normal wound response to fight off infection. When uncontrolled, it leads to a vicious proinflammatory response, resulting in hyperproliferation of the skin and thinning/loss of hair. WT, wild-type mouse; cKO, mouse lacking p120-catenin in the skin epithelial cells. Mice were photographed at 60 days of age.
From Perez-Moreno, M., Davis, M.A., Wong, E., Pasolli, H.A., Reynolds, A.B., and Fuchs, E. 2006. Cell 124:631–644. © 2006, with permission from Elsevier.
Figure 7: Controlling the balance between growth and differentiation by asymmetric divisions. As embryonic epidermis begins to stratify, epidermal cells reorient their cell divisions, from parallel to perpendicular relative to the skin surface. As a consequence, one daughter cell remains in the proliferative layer, next to the underlying basement membrane, rich in extracellular matrix and growth factors, while the other daughter is placed in the suprabasal layer, where it differentiates and makes the protective seal on the body surface. Embryonic day 15.5 skin was stained with an anti-tubulin antibody (green) and with propidium iodide (red).
Image: Terry Lechler and Elaine Fuchs. See also Lechler, T., and Fuchs, E. 2005. Nature 437:275–280.
Figure 8: Fluorescent labeling of stem cells in skin. In adult skin, each hair follicle possesses a reservoir of stem cells. On the premise that most adult stem cells are used sparingly and consequently divide only infrequently, the Fuchs lab developed a method to label stem cells specifically. Thus, if a green fluorescent histone is first expressed in all the epithelial cells of the skin, but then its expression is turned off, the more rapidly dividing progeny dilute out the label, and only the stem cells retain it. The fluorescent red labels the membrane boundaries of the hair follicle cells.
From Fuchs, E., Tumbar, T., and Guasch, G. 2004.Cell 116:769–778. © 2004, with permission from Elsevier.
Figure 9: Generation of hair follicles, sebaceous glands, and epidermis in nude mice. Progeny from a single skin stem cell can generate hair follicles, sebaceous glands, and epidermis in nude mice. To monitor skin stem cells, the Fuchs lab engineered a mouse that enabled them to fluorescently label the infrequently dividing stem cells. They used a fluorescence-activated cell sorter to isolate the stem cells, which they then placed in culture. Each stem cell produced a large colony of cells in vitro, which they then grafted onto the back of a nude mouse (defective in making hair follicles). The hairs (fluorescent under the appropriate lighting) growing on this mouse are particularly remarkable in that they are descendents of a single stem cell.
From Blanpain, C., Lowry, W.E., Geoghegan, A., Polak, L., and Fuchs, E. 2004.Cell 118:635–648. © 2004, with permission from Elsevier.
Figure 10: Mice expressing a green fluorescently tagged actin protein in the skin. These mice are used to understand how actin-based movements play a role in wound healing and in cancer.
From the Fuchs lab. See also Vaezi, A., Bauer, C., Vasioukhin, V., and Fuchs, E. 2002. Developmental Cell 3:367–381.
Figure 11: Specification of hair cell fate in the postnatal hair cycle. Nuclear β-catenin specifies hair cell fate in the postnatal hair cycle. Shown here is an early stage of the postnatal hair cycle during which stem cells give rise to new downgrowths that will eventually produce a new hair. Immunofluorescence analysis using antibodies directed against β-catenin (green) shows membrane-associated staining in all epidermal cells and nuclear β-catenin accumulation in a crescent of cells abutting the dermal papilla. Blocking β-catenin activity with expression of a ΔNlef1 transgene causes a transdifferentiation into oil-producing cells.
Cover image, Genes & Development, July 1, 2001. © 2001 Cold Spring Harbor Laboratory Press. See also Merrill, B.J., Gat, U., DasGupta, R., and Fuchs, E. 2001. Genes & Development 15:1688–1705.
Figure 12: Primary mouse keratinocytes grown under conditions that limit cell-cell adhesion. Confocal microscopy of cells labeled with antibodies against keratin 5 (green), DAPI (blue), and ACF7 (red). ACF7, an ortholog of the fly kakapo protein, is an unusual plakin that displays most prominent association with the peripheral ends of microtubules. It also binds to actin filaments but shows little or no association with the keratin cytoskeleton.
Cover image, Journal of Cell Biology, April 2000. © 2000 The Rockefeller University Press. See also Karakesisoglou, I., Yang, Y., and Fuchs, E. 2000. Journal of Cell Biology 149:195–208.
Figure 13: Extra-furry mouse genetically engineered to provide the skin with excess stimulus (a transactivating component of the LEF1 DNA-binding protein) for hair follicle formation.
Photo: Elaine Fuchs's laboratory
