背景:脱发影响患者的外观和心理。混合谱系激酶结构域样假激酶(MLKL)介导的坏死在各种皮肤病中起作用,但它对头发生长的影响尚不清楚。
目的:研究MLKL对头发生长的影响及其调节机制,并确定Necrosulonamide的潜在临床价值(NSA,MLKL靶向抑制剂)促进头发生长和抵消双氢睾酮(DHT)对头发生长的抑制作用。
方法:在雄激素性脱发(AGA)患者的头皮和小鼠的皮肤组织中检测MLKL的表达水平。敲低MLKL表达或使用NSA观察体内和体外毛发生长。
结果:在AGA患者中,MLKL表达在脱发区升高。在老鼠身上,MLKL在毛囊的外根鞘(ORS)细胞中显著表达,在cadagen阶段达到峰值。MLKL在小鼠皮肤中的敲低表达促进毛发生长。NSA通过Wnt信号增强毛发生长并防止毛囊退化。降低MLKL可促进ORS细胞增殖,而不会直接影响DPCs的生长。有趣的是,当与ORS细胞共培养时,NSA促进DPCs的增殖和诱导。此外,NSA在体内和体外减轻了DHT对毛发生长的抑制作用。
结论:NSA抑制ORS细胞中MLKL的激活,促进DPC细胞中Wnt信号的激活,并改善了DHT对头发生长的抑制作用,阐明了一种新的脱发机制,并有助于抗脱发药物的开发。
BACKGROUND: Alopecia affects patients\' appearance and psychology. Mixed-lineage kinase domain-like pseudokinase (MLKL)-mediated necroptosis plays a role in various skin diseases, but its effect on hair growth is unclear.
OBJECTIVE: To investigate the effects of MLKL on hair growth and its regulatory mechanisms and to determine the potential clinical value of Necrosulfonamide (NSA, a MLKL-targeting inhibitor) in promoting hair growth and counteracting dihydrotestosterone (DHT) inhibition of hair growth.
METHODS: The expression level of MLKL was detected in the scalp of androgenetic alopecia (AGA) patients and the skin tissues of mice. Knock down MLKL expression or use NSA to observe hair growth in vivo and in vitro.
RESULTS: In AGA patients, MLKL expression is elevated in the alopecia areas. In mice, MLKL is significantly expressed in the outer root sheath (ORS) cells of hair follicles, peaking during the catagen phase. Knockdown expression of MLKL in mice skin promoted hair growth. NSA enhanced hair growth and prevented hair follicle regression via the Wnt signaling. Reduced MLKL boosts ORS cell proliferation without directly impacting DPCs\' growth. Interestingly, NSA boosts DPCs\' proliferation and induction when co-cultured with ORS cells. Besides, NSA alleviated the inhibition of DHT on hair growth in vivo and vitro.
CONCLUSIONS: NSA inhibited the activation of MLKL in ORS cells, promoted the activation of Wnt signal in DPC cells, and improved the inhibition of hair growth by DHT, illuminating a new alopecia mechanism and aiding anti-alopecia drug development.