Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany.
Pflugers Arch. 2022 Sep;474(9):1021-1035. doi: 10.1007/s00424-022-02709-4. Epub 2022 Jun 1.
Polyunsaturated fatty acids (PUFAs) are used as traditional remedies to treat hair loss, but the mechanisms underlying their beneficial effects are not well understood. Here, we explored the role of PUFA metabolites generated by the cytochrome P450/soluble epoxide hydrolase (sEH) pathway in the regulation of the hair follicle cycle. Histological analysis of the skin from wild-type and sEH mice revealed that sEH deletion delayed telogen to anagen transition, and the associated activation of hair follicle stem cells. Interestingly, EdU labeling during the late anagen stage revealed that hair matrix cells from sEH mice proliferated at a greater rate which translated into increased hair growth. Similar effects were observed in in vitro studies using hair follicle explants, where a sEH inhibitor was also able to augment whisker growth in follicles from wild-type mice. sEH activity in the dorsal skin was not constant but altered with the cell cycle, having the most prominent effects on levels of the linoleic acid derivatives 12,13-epoxyoctadecenoic acid (12,13-EpOME), and 12,13-dihydroxyoctadecenoic acid (12,13-DiHOME). Fitting with this, the sEH substrate 12,13-EpOME significantly increased hair shaft growth in isolated anagen stage hair follicles, while its diol; 12,13-DiHOME, had no effect. RNA sequencing of isolated hair matrix cells implicated altered Wnt signaling in the changes associated with sEH deletion. Taken together, our data indicate that the activity of the sEH in hair follicle changes during the hair follicle cycle and impacts on two stem cell populations, i.e., hair follicle stem cells and matrix cells to affect telogen to anagen transition and hair growth.
多不饱和脂肪酸 (PUFAs) 被用作治疗脱发的传统药物，但人们对其有益作用的机制还了解甚少。在这里，我们探讨了细胞色素 P450/可溶性环氧化物水解酶 (sEH) 途径生成的 PUFAs 代谢物在调控毛囊周期中的作用。对野生型和 sEH 小鼠皮肤的组织学分析表明，sEH 缺失延迟了休止期向生长期的转变，并伴随着毛囊干细胞的激活。有趣的是，在晚期生长期进行 EdU 标记时发现，sEH 小鼠的毛囊基质细胞增殖速度更快，这导致了毛发生长的增加。在使用毛囊外植体的体外研究中也观察到了类似的效果，其中 sEH 抑制剂也能够增强野生型小鼠毛囊中的胡须生长。背部皮肤中的 sEH 活性不是恒定的，而是随着细胞周期而变化，对亚油酸衍生物 12,13-环氧十八碳烯酸 (12,13-EpOME) 和 12,13-二羟基十八碳烯酸 (12,13-DiHOME) 的水平有最显著的影响。这与 sEH 底物 12,13-EpOME 显著增加分离的生长期毛囊中的毛干生长的结果一致，而其二醇 12,13-DiHOME 则没有效果。分离的毛基质细胞的 RNA 测序表明，Wnt 信号通路的改变与 sEH 缺失相关。综上所述，我们的数据表明，sEH 在毛囊周期中在毛囊中的活性发生变化，并影响两种干细胞群体，即毛囊干细胞和基质细胞，以影响休止期向生长期的转变和毛发生长。
