Age-related dysfunction in mechanotransduction impairs differentiation of human mammary epithelial progenitors.
Age-related dysfunction in mechanotransduction impairs differentiation of human mammary epithelial progenitors.
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DOI：
10.1016/j.celrep.2014.05.021
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发表时间：
2014-06-26
期刊：
影响因子：
8.8
通讯作者：
LaBarge MA
中科院分区：
文献类型：
--
作者：
Pelissier FA;Garbe JC;Ananthanarayanan B;Miyano M;Lin C;Jokela T;Kumar S;Stampfer MR;Lorens JB;LaBarge MA
在人类乳腺上皮细胞老化的过程中，具有获得性基本细胞特性的功能障碍的祖细胞和腔细胞积累，原因尚不清楚。来自30岁女性的多能祖细胞暴露在与生理相关的基质弹性模数范围内，刚性增加导致对肌上皮细胞的分化偏向，同时减少腔细胞的产生和祖细胞的维持。55岁女性祖先的血统表现不受生理模数变化的影响。年轻祖细胞的模数依赖性肌上皮/基础偏向需要有效地激活河马通路转导系统YAP和TAZ。在较年长的祖细胞中，YAP/TAZ只有在受到外部生理刚性基质的压力时才被激活，这使分化偏向于管腔样表型。YAP主要活跃在年轻乳腺组织的肌上皮细胞中，但腔细胞中的活性随着年龄的增长而增加。因此，乳腺上皮细胞的衰老表型可能部分是因为HIPPO通路激活的改变影响了祖细胞分化和谱系特异性的过程。
Dysfunctional progenitor and luminal cells with acquired basal cell properties accumulate during human mammary epithelia aging for reasons not understood. Multipotent progenitors from women aged <30 years were exposed to a physiologically relevant range of matrix elastic modulus, and increased rigidity caused a differentiation bias towards myoepithelial cells while reducing production of luminal cells and progenitor maintenance. Lineage representation in progenitors from women >55 years was unaffected by physiological modulus changes. Efficient activation of Hippo pathway transducers YAP and TAZ was required for the modulus-dependent myoepithelial/basal-bias in younger progenitors. In older progenitors YAP/TAZ were only activated when stressed by extra-physiologically rigid matrices, which biased differentiation towards luminal-like phenotypes. YAP was primarily active in myoepithelia of younger breast tissues, but activity increased in luminal cells with age. Thus aging phenotypes of mammary epithelia may arise partly because alterations in Hippo pathway activation affect the processes of progenitor differentiation and lineage specificity.
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