Local circadian clock gates cell cycle progression of transient amplifying cells during regenerative hair cycling
Local circadian clock gates cell cycle progression of transient amplifying cells during regenerative hair cycling
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DOI：
10.1073/pnas.1215935110
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发表时间：
2013-06-04
影响因子：
11.1
通讯作者：
Chuong, Cheng-Ming
中科院分区：
文献类型：
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作者：
Plikus, Maksim V.;Vollmers, Christopher;Chuong, Cheng-Ming
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一个独特的机会。我们专注于生物钟在活跃增殖的瞬时放大细胞中的作用，而不是静止的干细胞。我们确定了再生生发毛囊的外周生物钟活动的两个关键部位，即上皮基质和间充质毛乳头。我们发现，上皮基质细胞的外周生物钟产生了显著的每日有丝分裂节律。这种有丝分裂节律性的结果是，毛发在早上比晚上生长得更快。由于细胞在有丝分裂过程中最容易受到DNA损伤，这一周期导致生长的毛囊对遗传毒性压力具有显著的时间依赖性敏感性。与晚上脱发最少的时候相比，同样剂量的伽马辐射在有丝分裂高峰期的早晨给野生型小鼠造成了戏剧性的脱发。这种昼夜辐射防护作用在昼夜节律突变中消失，与毛囊中的异步性有丝分裂一致。Clock通过同步CDc2/Cyclin B介导的G(2)/M检查点来协调细胞周期进程和遗传毒性应激反应。我们的结果揭示了在高度增殖的毛囊中，白天有丝分裂门控是基本的保护机制，并为最小化或最大化放射治疗的细胞毒性提供了策略。
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 gamma-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 G(2)/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.