Involvement of DKK1 secreted from adipose‐derived stem cells in alopecia areata

Abstract

Adipose‐derived stem cells (ASCs) have shown efficacy in promoting hair growth, while DKK1 inhibits the WNT pathway, which is associated with hair loss. Our study focused on investigating the expression of DKK1 in alopecia areata (AA), a condition characterised by significant increases in the DKK1 levels in human and mouse ASCs. Treatment of interferon‐γ increased the expression of DKK1 via STAT3 phosphorylation in ASCs. Treatment with recombinant DKK1 resulted in a decrease of cell growth in outer root sheath cells, whereas the use of a DKK1 neutralising antibody promoted hair growth. These results indicate that ASCs secrete DKK1, playing a crucial role in the progression and development of AA. Consequently, we generated DKK1 knockout (KO) ASCs using the Crispr/Cas9 system and evaluated their hair growth‐promoting effects in an AA model. The DKK1 KO in ASCs led to enhanced cell motility and reduced cellular senescence by activating the WNT signalling pathway, while it reduced the expression of inflammatory cytokines by inactivating the NF‐kB pathway. As expected, the intravenous injection of DKK1‐KO‐ASCs in AA mice, and the treatment with a conditioned medium derived from DKK1‐KO‐ASCs in hair organ culture proved to be more effective compared with the use of naïve ASCs and their conditioned medium. Overall, these findings suggest that DKK1 represents a novel therapeutic target for treating AA, and cell therapy using DKK1‐KO‐ASCs demonstrates greater efficiency.

Abstract

IFNγ stimulates an increase in DKK1 levels in adipose‐derived stem cells (ASCs) through the activation of the STAT3 pathway. The secreted DKK1 promotes inflammation and inhibits follicular growth. However, when DKK1 is knocked out in ASCs, it deactivates the NF‐kB pathway, resulting in reduced cytokine levels and suppression of the inflammatory response. Moreover, DKK1 knockout ASCs (DKK1‐KO‐ASCs) activate the Wnt pathway, enhancing the growth and migration abilities of the DKK1‐KO‐ASCs and reducing cellular senescence. As a result, DKK1‐KO‐ASCs exhibit an inhibitory effect on alopecia areata.