Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):E2106-15. doi: 10.1073/pnas.1215935110. Epub 2013 May 20.
Regenerative cycling of hair follicles offers an unique opportunity to explore the role of circadian clock in physiological tissue regeneration. We focused on the role of circadian clock in actively proliferating transient amplifying cells, as opposed to quiescent stem cells. We identified two key sites of peripheral circadian clock activity specific to regenerating anagen hair follicles, namely epithelial matrix and mesenchymal dermal papilla. We showed that peripheral circadian clock in epithelial matrix cells generates prominent daily mitotic rhythm. As a consequence of this mitotic rhythmicity, hairs grow faster in the morning than in the evening. Because cells are the most susceptible to DNA damage during mitosis, this cycle leads to a remarkable time-of-day-dependent sensitivity of growing hair follicles to genotoxic stress. Same doses of γ-radiation caused dramatic hair loss in wild-type mice when administered in the morning, during mitotic peak, compared with the evening, when hair loss is minimal. This diurnal radioprotective effect becomes lost in circadian mutants, consistent with asynchronous mitoses in their hair follicles. Clock coordinates cell cycle progression with genotoxic stress responses by synchronizing Cdc2/Cyclin B-mediated G2/M checkpoint. Our results uncover diurnal mitotic gating as the essential protective mechanism in highly proliferative hair follicles and offer strategies for minimizing or maximizing cytotoxicity of radiation therapies.
毛囊的再生循环为探索生物钟在生理组织再生中的作用提供了独特的机会。我们专注于生物钟在活跃增殖的短暂扩增细胞（而非静止干细胞）中的作用。我们确定了两个特化于再生的生长期毛囊的外周生物钟活动的关键部位，即上皮基质和间质真皮乳头。我们表明，上皮基质细胞中的外周生物钟会产生明显的每日有丝分裂节律。由于这种有丝分裂节律性，毛发在早上的生长速度比晚上快。由于细胞在有丝分裂过程中最容易受到 DNA 损伤，因此这种周期导致正在生长的毛囊对遗传毒性应激的敏感性具有显著的时间依赖性。与晚上（此时脱发最少）相比，在有丝分裂高峰期的早上给予相同剂量的γ射线会导致野生型小鼠出现明显的脱发。这种昼夜保护作用在生物钟突变体中丧失，这与它们的毛囊中的有丝分裂不同步一致。生物钟通过同步 Cdc2/细胞周期蛋白 B 介导的 G2/M 检查点将细胞周期进程与遗传毒性应激反应协调起来。我们的研究结果揭示了有丝分裂门控作为高度增殖的毛囊中的基本保护机制，并为最小化或最大化放射疗法的细胞毒性提供了策略。
