Glutamate transporter Slc1a3 mediates inter‐niche stem cell activation during skin growth

Abstract

Tissues contain distinct stem cell niches, but whether cell turnover is coordinated between niches during growth is unknown. Here, we report that in mouse skin, hair growth is accompanied by sebaceous gland and interfollicular epidermis expansion. During hair growth, cells in the bulge and outer root sheath temporarily upregulate the glutamate transporter SLC1A3, and the number of SLC1A3 basal cells in interfollicular epidermis and sebaceous gland increases. Fate mapping of SLC1A3 cells in mice revealed transient expression in proliferating stem/progenitor cells in all three niches. Deletion of delays hair follicle anagen entry, uncouples interfollicular epidermis and sebaceous gland expansion from the hair cycle, and leads to reduced fur density in aged mice, indicating a role of SLC1A3 in stem/progenitor cell activation. Modulation of metabotropic glutamate receptor 5 activity mimics the effects of SLC1A3 deletion or inhibition. These data reveal that stem/progenitor cell activation is synchronized over distinct niches during growth and identify SLC1A3 as a general marker and effector of activated epithelial stem/progenitor cells throughout the skin.

The molecular anatomy of mouse skin during hair growth and rest

“…In anagen, most of the induced genes (compared to telogen) were involved in metabolic processes, including intermediate metabolism (Oat,Pkm,Tpi1,Dbi1), energy metabolism (Ndufa4l2, Ucp2), mitochondrial function (mt--Cytb), and protein synthesis. This more active cell state in anagen was further supported by observing a higher fraction of proliferating cells in the IFE and the upper HF in anagen skin in line with recent work (Reichenbach et al, 2018)…”

Past stem cells and finally in transit: SLC 1A3 instructs skin niche coupling

“…This is in line with results by Roy et al () showing that IFE clone size increases during anagen and that slow‐cycling IFE cells are less likely to be in proximity of hair follicles (Roy et al , ). The study by Reichenbach et al () implies, as reported before, that at least in the dorsal IFE (tail skin was not examined here), activity of progenitors cannot be dissociated from hair follicle cycling. It may also explain the heterogeneity observed in proliferation, as cells expressing SLC1A3 become transiently more proliferative (Fig ).…”

“…In this issue, Reichenbach et al () report a unifying mechanism that specifies proliferating stem and progenitor cell subsets in three different skin compartments—hair follicle, interfollicular epidermis as well as sebaceous gland—from other progenitors. They show through lineage tracing that the glutamate transporter SLC1A3 is transiently expressed upon progenitor and stem cell activation during anagen.…”

“… During postnatal growth of the skin and homeostatic hair cycling, different proliferative compartments contribute to tissue expansion and establishment of a functional epidermis. A new study by Reichenbach et al () reports coordinated proliferation of three distinct epithelial stem cell niches and a role for glutamate transporter Slc1a3 in synchronisation of activated stem and progenitor cells. …”

“…During postnatal growth of the skin and homeostatic hair cycling, different proliferative compartments contribute to tissue expansion and establishment of a functional epidermis. A new study by Reichenbach et al (2018) reports coordinated proliferation of three distinct epithelial stem cell niches and a role for glutamate transporter Slc1a3 in synchronisation of activated stem and progenitor cells. The EMBO Journal (2018) 37: e99393 See also: B Reichenbach et al (May 2018) T he past three decades gave us considerable progress in our understanding of epidermal stem cells (Blanpain & Fuchs, 2009).…”