Androgens induce sebaceous differentiation in sebocyte cells expressing a stable functional androgen receptor

• We established a stable human sebocyte cell line expressing androgen receptor.
• Androgen treatment of these cells modulates known androgen-sensitive genes.
• Androgens decrease stem cell and hair markers and induce sebocyte markers.
• Androgens induce lipid synthesis and storage, increase cell size, and apoptosis.
• Androgens alone can engage sebocytes in a clear sebaceous differentiation program.

Androgens act through non-genomic and androgen receptor (AR)-dependent genomic mechanisms. AR is expressed in the sebaceous gland and the importance of androgens in the sebaceous function is well established. However, the in vitro models used to date have failed to evidence a clear genomic effect (e.g., modification of gene expression profile) of androgens on human sebocyte cells. In order to study the impact of active androgens in sebocytes, we constructed a stable human sebocyte cell line derived from SEBO662 [17] constitutively expressing a fully functional AR. In these SEBO662 AR+ cells, dihydrotestosterone (DHT) induced AR nuclear translocation and the strong modulation of a set of transcripts (RASD1, GREB1…) known to be androgen-sensitive in other androgenic cells and tissues. Moreover, we observed that DHT precociously down-regulated markers for immature follicular cells (KRT15, TNC) and for hair lineage (KRT75, FST) and up-regulated the expression of genes potentially related to sebocyte differentiation (MUC1/EMA, AQP3, FADS2). These effects were fully confirmed at the protein level. In addition, DHT-stimulated SEBO662 AR+, cultured in a low-calcium defined keratinocyte medium without serum or any complement, neosynthesize lipids, including sebum lipids, and store increased amounts of triglycerides in lipid droplets. DHT also induces morphological changes, increases cell size, and treatments over 7 days lead to a time-dependent increase in the population of apoptotic DNA-fragmented cells.Taken together, these results show for the first time that active androgens alone can engage immature sebocytes in a clear lipogenic differentiation process (). These effects depend on the expression of a functional AR in these cells. This model should be of interest for revisiting the mechanisms of the sebaceous function in vitro and for the design of relevant pharmacological models for drug or compound testing.

Schematic representation of the main characteristics of sebocyte differentiation (black) and listing of the related effects of DHT in the SEBO662 AR+ cells evidenced in this paper (red).Figure optionsDownload as PowerPoint slide