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在人类毛囊中激活综合应激反应
Derek Pye1, Rachel Scholey2, Sin Ung1
1Division Musculoskeletal and Dermatological Sciences, Centre for Dermatology Research, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biosciences, The University of Manchester, Manchester, United Kingdom.
PloS one
|June 20, 2024
概括
针对人体毛囊中的线粒体酸盐载体 (MPC),通过触发代谢应激和综合应激反应 (ISR) 来阻止头发的生长. 抑制ISR可以逆转这种效果,为脱发治疗提供新的途径.
科学领域:
- 细胞生物学 细胞生物学
- 代谢过程中的代谢.
- 皮肤病学 皮肤病学
背景情况:
- 线粒体的酸盐载体 (MPC) 将酸盐导入线粒体,支持TCA循环.
- 以前的研究表明,MPC抑制通过乳酸生产激活了小鼠毛囊干细胞.
- 了解人类毛囊代谢对于解决脱发障碍至关重要.
研究的目的:
- 研究MPC抑制对人类毛囊表皮的作用.
- 阐明综合应激反应 (ISR) 在代谢应激诱导的毛囊停止中的作用.
- 为了确定脱发的潜在治疗点.
主要方法:
- 人类毛囊被培养出活体,并用MPC抑制剂UK-5099.9治疗.
- 进行了转录组分析,以评估基因表达变化.
- 使用RNAScope在现场确认蛋白质和基因表达.
- 用ISR抑制剂ISRIB来评估其对MPC抑制诱导变化的影响.
主要成果:
- 抑制MPC导致人类毛囊表皮质的增殖停止,包括素15+干细胞.
- 转录学揭示了信号通路 (FGF,IGF,TGFβ,WNT) 的破坏,线粒体功能障碍和ISR激活.
- 在现场证实了ATF4及其目标基因ADM2的升级.
- 通过ISRIB治疗可以逆转ADM2上调和增殖阻断.
结论:
- 抑制MPC诱导代谢压力并激活人体毛囊中的ISR,导致细胞循环停止.
- 通过ATF4调解的ISR在这种反应中发挥着关键作用.
- 针对ISR是一个潜在的治疗策略来控制脱发.
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