Organ aging and susceptibility to cancer may be related to the geometry of the stem cell niche
Organ aging and susceptibility to cancer may be related to the geometry of the stem cell niche
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DOI：
10.1073/pnas.1106105108
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发表时间：
2011-11-29
影响因子：
11.1
通讯作者：
Blagoev, Krastan B.
中科院分区：
文献类型：
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作者：
Blagoev, Krastan B.
每次细胞复制时的端粒丢失限制了正常细胞（包括成体干细胞）的增殖能力。进入复制性衰老保护分裂细胞免受肿瘤转化，但也有助于组织老化。最近的实验表明，肠道小鼠干细胞是对称分裂的，随机决定是保持干细胞还是分化，并逐渐失去端粒DNA。细胞分化或保持干细胞的决定取决于局部细胞和化学环境，因此组织结构预计在细胞增殖动力学中发挥作用。考虑到干细胞生态位的结构决定其增殖潜能和对癌症的易感性，引入了一个理论模型，并对不同结构的生态位增殖潜能进行了量化。生态位增殖潜能与单个干细胞在不同结构类型的干细胞生态位中的增殖潜能有定量关系。处于生态位外围的干细胞承受着分裂和分化的压力，同时也要维持干细胞生态位边界，因此干细胞生态位的几何形状有望在决定干细胞分裂顺序和分化方面发挥作用。较小的表面体积比与较高的癌症易感性、较高的组织更新能力和较低的衰老率有关。讨论了几个可测试的实验预测，以及随机效应的存在。
Telomere loss at each cell replication limits the proliferative capacity of normal cells, including adult stem cells. Entering replicative senescence protects dividing cells from neoplastic transformation, but also contributes to aging of the tissue. Recent experiments have shown that intestinal mouse stem cells divide symmetrically, at random make decisions to remain stem cells or to differentiate, and gradually lose telomeric DNA. A cell's decision whether to differentiate or to remain a stem cell depends on the local cellular and chemical environment and thus tissue architecture is expected to play role in cell proliferation dynamics. To take into account the structure of the stem cell niche in determining its proliferative potential and susceptibility to cancer, a theoretical model is introduced and the niche proliferative potential is quantified for different architectures. The niche proliferative potential is quantitatively related to the proliferative potential of the individual stem cells for different structural classes of the stem cell niche. Stem cells at the periphery of a niche are under pressure to divide and to differentiate, as well as to maintain the stem cell niche boundary, and thus the geometry of the stem cell niche is expected to play a role in determining the stem cell division sequence and differentiation. Smaller surface-to-volume ratio is associated with higher susceptibility to cancer, higher tissue renewal capacity, and decreased aging rate. Several testable experimental predictions are discussed, as well the presence of stochastic effects.