Epithelial tissue confinement inhibits cell growth and leads to volume-reducing divisions.
Epithelial tissue confinement inhibits cell growth and leads to volume-reducing divisions.
复制标题
上皮组织限制抑制细胞的生长并导致减少体积的分裂。
DOI：
10.1016/j.devcel.2023.05.018
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发表时间：
2023-08-21
影响因子：
11.8
通讯作者：
Gardel ML
中科院分区：
文献类型：
--
作者：
Devany J;Falk MJ;Holt LJ;Murugan A;Gardel ML
细胞增殖是组织发育、体内平衡和疾病的中心过程，然而在组织背景下增殖如何被调节仍然知之甚少。在这里，我们引入了一个定量的框架来阐明组织生长动力学如何调节细胞增殖。使用MDCK上皮细胞单层，我们表明，组织扩张的限制率产生限制，抑制细胞生长，但是，这种限制并不直接影响细胞周期。这导致上皮细胞生长和分裂速率之间的解偶联，从而减少细胞体积。分裂在最小的细胞体积下停止，这在体内不同的上皮细胞中是一致的。在这里，细胞核接近能够包装基因组的最小体积。细胞周期蛋白D1依赖的细胞体积调节的丧失导致异常高的核质体积比和DNA损伤。总体而言，我们证明了上皮细胞增殖是如何调节组织限制和细胞体积调节之间的相互作用。Devany等人表明，细胞生长和分裂对上皮细胞中的不同线索有反应。他们发现细胞生长速率受到组织生长速率的限制，生长停滞的细胞可以通过分裂继续减少体积，直到达到最小尺寸。
Cell proliferation is a central process in tissue development, homeostasis, and disease, yet how proliferation is regulated in the tissue context remains poorly understood. Here, we introduce a quantitative framework to elucidate how tissue growth dynamics regulate cell proliferation. Using MDCK epithelial monolayers, we show that a limiting rate of tissue expansion creates confinement that suppresses cell growth; however, this confinement does not directly affect the cell cycle. This leads to uncoupling between rates of cell growth and division in epithelia and, thereby, reduces cell volume. Division becomes arrested at a minimal cell volume, which is consistent across diverse epithelia in vivo. Here, the nucleus approaches the minimum volume capable of packaging the genome. Loss of cyclin D1-dependent cell-volume regulation results in an abnormally high nuclear-to-cytoplasmic volume ratio and DNA damage. Overall, we demonstrate how epithelial proliferation is regulated by the interplay between tissue confinement and cell-volume regulation. Devany et al. show that cell growth and division respond to different cues in epithelia. They find that cell growth rate is constrained by tissue growth rate and that growth-arrested cells can continue to reduce their volume by division until reaching a minimum size.
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