Hypoxia enhances the hair growth-promoting effects of embryonic stem cell-derived mesenchymal stem cells via NADPH oxidase 4.

Human embryonic stem cell (hES)-derived mesenchymal stem cells (-MSCs) are an unlimited source of MSCs. The hair growth-promoting effects of diverse MSCs have been reported, but not that of hES-MSCs. In the present study, we investigated the hair growth-promoting effects of hES-MSCs and their underlying mechanisms. hES-MSCs or conditioned medium of hES-MSCs exhibited hair-growth effects, which increased the length of mouse vibrissae and human hair follicles. hES-MSCs accelerated the telogen-to-anagen transition in C3H mice and were more effective than adipose-derived stem cells. We further examined whether hypoxia could enhance the hair-growth promoting effects of hES-MSCs. The injection of hES-MSCs or conditioned medium (Hyp-CM) cultured under hypoxia (2% O) enhanced the telogen-to-anagen transition in C3H mice. Additionally, Hyp-CM increased the length of mouse vibrissae, human hair follicles, and the proliferation of human dermal papilla and outer root sheath cells. Moreover, fibroblast growth factor 7, interleukin 12B, and teratocarcinoma-derived growth factor 1 were upregulated under hypoxia, and the co-treatment with these three proteins increased the hair length and induced telogen-to-anagen transition. Hypoxia increased reactive oxygen species (ROS) production, and ROS scavenging attenuated the secretion of growth factors. NADPH oxidase 4 was primarily expressed in hES-MSCs and generated ROS under hypoxia. Collectively, our results suggest that hES-MSCs exhibit hair-growth effects, which is enhanced by hypoxia.