Editors' ChoiceStem Cells

DIY Stem Cell Niche

See allHide authors and affiliations

Sci. Signal.  10 Dec 2013:
Vol. 6, Issue 305, pp. ec297
DOI: 10.1126/scisignal.2004976

Stem cell niches provide signals that maintain populations of self-renewing stem cells and prevent excessive proliferation. Without the regulatory influence of the niche, stem cells might proliferate too much, thus forming a tumor, or differentiate prematurely, thus depleting a tissue’s regenerative capacity. Wnts have been implicated in stem cell maintenance and hair growth, so Lim et al. investigated the role of Wnt signaling in the regulation of resident stem cells in mouse intrafollicular epidermis (IFE). (IFE lacks hair follicle stem cells, which may contribute to epidermal regeneration.) The basal layer of the IFE contained cells that expressed the Wnt target gene Axin2, and lineage-tracing experiments indicated that these cells gave rise to both self-renewing basal cells and various types of differentiated cells present in the suprabasal layers. These cells also participated in regeneration after wounding, consistent with these cells being epidermal stem cells. Disrupting Wnt signaling in the Axin2-expressing cells by conditionally inactivating the gene encoding the Wnt effector β-catenin or by adenovirus-mediated overexpression of the Wnt inhibitor Dkk1 yielded a thin epidermis in which these cells stopped proliferating and instead differentiated. The Axin2-expressing basal cells expressed Wnt4 and Wnt10a, and basal epidermal cells isolated from human skin also expressed Wnt4. Cultured human keratinocytes produce Wnts, and treating these cells with a small-molecule inhibitor of Wnt secretion inhibited proliferation and stimulated expression of a differentiation marker. The secreted Wnt inhibitors Dkk3 and WIF1 accumulate in suprabasal layers of human skin, and the authors demonstrated that transcripts encoding Dkk3 were present in Axin2-expressing basal cells in mouse IFE, but the Dkk3 protein accumulated in suprabasal layers, suggesting that Dkk3 was produced by and diffused away from the basal stem cells. These results define a model in which autocrine Wnt signaling promotes self-renewal and prevents differentiation in the basally located epidermal stem cells, whereas Wnt inhibitors secreted from these cells inhibit Wnt signaling in suprabasal cells, thus promoting differentiation of cells as they leave the basal layer. Thus, in this tissue, self-renewal depends on signals secreted from the stem cells themselves rather than on signals from neighboring niche cells. As noted in a Perspective by Frede and Jones, it is unclear how injury stimulates the proliferation of these stem cells and whether Wnt signaling plays a role in this process.

X. Lim, S. H. Tan, W. L. C. Koh, R. M. W. Chau, K. S. Yan, C. J. Kuo, R. van Amerongen, A. M. Klein, R. Nusse, Interfollicular epidermal stem cells self-renew via autocrine Wnt signaling. Science 342, 1226–1230 (2013). [Abstract] [Full Text]

J. Frede, P. H. Jones, Permission to proliferate. Science 342, 1183–1184 (2013). [Abstract] [Full Text]