NFATc1 balances quiescence and proliferation of skin stem cells
NFATc1 balances quiescence and proliferation of skin stem cells
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DOI：
10.1016/j.cell.2007.11.047
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发表时间：
2008-01-25
期刊：
影响因子：
64.5
通讯作者：
Fuchs, Elaine
中科院分区：
文献类型：
--
作者：
Horsley, Valerie;Aliprantis, Antonios O.;Fuchs, Elaine
静止的成体干细胞存在于特殊的微环境中，在组织稳态和损伤期间，它们在这些微环境中被激活从而增殖和分化。干细胞的静止是如何被调控的，人们对此知之甚少。我们在此报道，NFATc1在毛囊干细胞所处的微环境中由毛囊干细胞优先表达，其表达在上游由骨形态发生蛋白（BMP）信号激活，并在下游发挥作用，通过转录抑制细胞周期蛋白依赖性激酶4（CDK4）来维持干细胞的静止状态。当干细胞在毛发生长过程中被激活时，NFATc1被下调，解除对CDK4的抑制并激活增殖。当钙调神经磷酸酶/NFATc1信号通过药物手段或通过完全或条件性NFATc1基因敲除被抑制时，干细胞会过早激活，导致毛囊过早生长。我们的研究结果可能解释了为什么接受环孢素A进行免疫抑制治疗的患者会出现毛发过度生长的现象，并揭示了钙 - NFATc1 - CDK4通路在调控干细胞静止方面的功能作用。
Quiescent adult stem cells reside in specialized niches where they become activated to proliferate and differentiate during tissue homeostasis and injury. How stem cell quiescence is governed is poorly understood. We report here that NFATc1 is preferentially expressed by hair follicle stem cells in their niche, where its expression is activated by BMP signaling upstream and it acts downstream to transcriptionally repress CDK4 and maintain stem cell quiescence. As stem cells become activated during hair growth, NFATc1 is downregulated, relieving CDK4 repression and activating proliferation. When calcineurin/NFATc1 signaling is suppressed, pharmacologically or via complete or conditional NFATc1 gene ablation, stem cells are activated prematurely, resulting in precocious follicular growth. Our findings may explain why patients receiving cyclosporine A for immunosuppressive therapy display excessive hair growth, and unveil a functional role for calcium-NFATc1-CDK4 circuitry in governing stem cell quiescence.