Laboratory of Mammalian Cell Biology and Development and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065.
Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):E4950-9. doi: 10.1073/pnas.1320301110. Epub 2013 Nov 26.
Hair production is fueled by stem cells (SCs), which transition between cyclical bouts of rest and activity. Here, we explore why hair growth wanes with age. We show that aged hair follicle SCs (HFSCs) in mice exhibit enhanced resting and abbreviated growth phases and are delayed in response to tissue-regenerating cues. Aged HFSCs are poor at initiating proliferation and show diminished self-renewing capacity upon extensive use. Only modestly restored by parabiosis, these features are rooted in elevated cell-intrinsic sensitivity and local elevation in bone morphogenic protein (BMP) signaling. Transcriptional profiling presents differences consistent with defects in aged HFSC activation. Notably, BMP-/calcium-regulated, nuclear factor of activated T-cell c1 (NFATc1) in HFSCs becomes recalcitrant to its normal down-regulating cues, and NFATc1 ChIP-sequencing analyses reveal a marked enrichment of NFATc1 target genes within the age-related signature. Moreover, aged HFSCs display more youthful levels of hair regeneration when BMP and/or NFATc1 are inhibited. These results provide unique insights into how skin SCs age.
毛发的生成依赖于干细胞（SCs），SCs 会在周期性的静止和活跃状态之间转换。在这里，我们探讨了为什么毛发的生长会随着年龄的增长而衰退。我们发现，衰老的毛囊干细胞（HFSCs）在小鼠中表现出增强的静止和缩短的生长阶段，并且对组织再生信号的反应延迟。衰老的 HFSCs 很难启动增殖，并且在广泛使用后自我更新能力下降。仅通过并系动物稍有恢复，这些特征源于细胞内在敏感性的升高和局部骨形态发生蛋白（BMP）信号的升高。转录谱分析呈现出与衰老 HFSC 激活缺陷一致的差异。值得注意的是，HFSCs 中的 BMP/钙调节的激活 T 细胞核因子 c1（NFATc1）对其正常下调信号变得顽固，并且 NFATc1 ChIP-seq 分析显示 NFATc1 靶基因在与年龄相关的特征内明显富集。此外，当抑制 BMP 和/或 NFATc1 时，衰老的 HFSCs 表现出更年轻的毛发再生水平。这些结果为我们提供了独特的见解，了解皮肤干细胞如何衰老。
