Graded regulation of cellular quiescence depth between proliferation and senescence by a lysosomal dimmer switch
Graded regulation of cellular quiescence depth between proliferation and senescence by a lysosomal dimmer switch
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DOI：
10.1073/pnas.1915905116
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发表时间：
2019-11-05
影响因子：
11.1
通讯作者：
Yao, Guang
中科院分区：
文献类型：
--
作者：
Fujimaki, Kotaro;Li, Ruoyan;Yao, Guang
静止细胞的再活化以增殖是体内组织修复和稳态的基础。然而，通常被称为GO状态的静止不是均匀的状态，而是具有梯度深度。浅静止细胞比深静止细胞表现出更高的恢复增殖的倾向，而深静止细胞在生理条件下仍然是完全可逆的，与衰老细胞不同。静止深度的控制和静止与衰老之间的联系的细胞机制的特征很差，代表了我们对组织稳态和再生的理解中缺失的环节。在这里，我们测量了大鼠胚胎成纤维细胞在没有生长信号的情况下随着时间从浅静止移动到深静止时的转录组变化。我们发现，溶酶体基因的表达显着上调，在深度静止，并部分补偿逐渐减少的自噬通量。降低溶酶体功能使细胞逐渐进入更深的静止状态，并最终进入衰老样不可逆的停滞状态;通过降低氧化应激，增加溶酶体功能，使细胞逐渐进入更浅的静止状态。也就是说，溶酶体功能作为调光开关调节增殖和衰老之间的分级静止深度。最后，我们发现，通过比较成纤维细胞中的深和浅静止而开发的基因表达特征可以正确地在体外和体内对多种衰老和衰老细胞类型进行分类，这表明虽然静止通常被认为是保护细胞免受衰老的不可逆停滞，但静止加深可能代表了从细胞增殖到衰老的共同过渡路径，与衰老有关。
The reactivation of quiescent cells to proliferate is fundamental to tissue repair and homeostasis in the body. Often referred to as the GO state, quiescence is, however, not a uniform state but with graded depth. Shallow quiescent cells exhibit a higher tendency to revert to proliferation than deep quiescent cells, while deep quiescent cells are still fully reversible under physiological conditions, distinct from senescent cells. Cellular mechanisms underlying the control of quiescence depth and the connection between quiescence and senescence are poorly characterized, representing a missing link in our understanding of tissue homeostasis and regeneration. Here we measured transcriptome changes as rat embryonic fibroblasts moved from shallow to deep quiescence over time in the absence of growth signals. We found that lysosomal gene expression was significantly up-regulated in deep quiescence, and partially compensated for gradually reduced autophagy flux. Reducing lysosomal function drove cells progressively deeper into quiescence and eventually into a senescence-like irreversibly arrested state; increasing lysosomal function, by lowering oxidative stress, progressively pushed cells into shallower quiescence. That is, lysosomal function modulates graded quiescence depth between proliferation and senescence as a dimmer switch. Finally, we found that a gene-expression signature developed by comparing deep and shallow quiescence in fibroblasts can correctly classify a wide array of senescent and aging cell types in vitro and in vivo, suggesting that while quiescence is generally considered to protect cells from irreversible arrest of senescence, quiescence deepening likely represents a common transition path from cell proliferation to senescence, related to aging.