Functional decline of aged organisms is associated to tissue-specific stem cell impairment, which leads to homeostasis alterations. Dermal stem cells (DSC) lose regenerative capacity with age. The DSC pool includes Schwann cell precursors and perivascular cells, their stemness being mediated by Sox2 expression levels. We hypothesized that DSC activity may decrease during the skin ageing process as a consequence of Sox2+ cell population impairment. To test this hypothesis, we characterized in vitro and in vivo the DSC niches in young (2 month) vs aged (>18 month) Sox2GFP mice (heterozygous for Sox2). As expected, cutaneous microvessel and nerve terminal density decreased with age, concomitant with impaired proliferation and differentiation capacities of aged-DSC. Moreover, Sox2GFP+ cell number decreased with age. Based on EGFP intensity, three Sox2+ cell subpopulations were defined: Sox2 high (Sox2hi), medium (Sox2med) and low (Sox2lo). Interestingly, in aged-DSC Sox2hi cells were depleted and Sox2lo cell population enriched, indicating that Sox2 expression levels reduced with age. This reduction in aged-DSC resulted in loss in stemness capacities of Sox2+ cells, as measured by neural differentiation potential. Additionally, Sox2 heterozygosity resulted in adipogenic gene upregulation already in the young, and increased thickness of dermal white adipose tissue in old mice. Furthermore, histological analyses revealed impaired dermal extracellular matrix organization and composition. Altogether our results suggest that dermal homeostasis is compromised due to changes in aged DSC fate via modulation of Sox2 expression levels.

Characterization of aged dermal stem cell phenotype: implications for skin homeostasis