Cell lineages and the logic of proliferative control.
Cell lineages and the logic of proliferative control.
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DOI：
10.1371/journal.pbio.1000015
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发表时间：
2009-01-20
期刊：
影响因子：
9.8
通讯作者：
Calof, Anne L.
中科院分区：
文献类型：
--
作者：
Lander, Arthur D.;Gokoffski, Kimberly K.;Wan, Frederic Y. M.;Nie, Qing;Calof, Anne L.
人们普遍认为，组织和器官的生长和再生受到严格控制。虽然实验研究开始揭示这种控制的分子机制，但对控制策略本身仍然知之甚少。在这里，我们考虑如何分泌的负反馈因子（"查隆"）可用于控制输出的多级细胞谱系，作为例证的GDF11和激活素在自我更新的神经组织，哺乳动物嗅上皮（OE）的行动。我们开始通过指定性能目标-什么，确切地说，是被控制，到什么程度-并继续计算如何以及不同类型的反馈配置，反馈灵敏度，和组织架构实现控制。最终，我们表明，许多功能的OE反馈回路的数量，反馈的细胞过程，甚至祖细胞的位置内的组织适合与期望的最佳控制。这样做，我们也表明，通常绘制细胞和分子之间的某些区别，如是否一个细胞是干细胞或transit-amplifying细胞，或是否一个分子是生长抑制剂或刺激可能是控制的后果，而不是在细胞或分子特性的内在差异的反映。许多组织和器官生长到精确的大小，当受伤时，准确而迅速地再生。在这里，我们要问的是，细胞组织成谱系，以及谱系内发生的反馈相互作用，是否是使这种行为成为可能的控制策略的必要元素。利用数学建模和小鼠嗅上皮的实验操作结果，我们表明，性能目标，如强大的大小规格，从各种初始条件下快速再生，以及维持高比例的分化与未分化细胞，可以同时通过谱系结构，信号传导机制，以及与在许多生长和再生组织中观察到的相对应的细胞类型的空间分布。成功控制的关键是当终末分化细胞分泌降低祖细胞复制与分化的可能性的分子时实施的积分反馈机制。有趣的是，这一机制也解释了干细胞和"过渡扩增"细胞群体的独特增殖行为如何作为反馈效应的结果而出现，而不是细胞类型的内在编程。在组织生长和再生的定量控制中是否使用了常见的通用策略？对多级谱系中反馈效应的研究表明，它们确实如此。
It is widely accepted that the growth and regeneration of tissues and organs is tightly controlled. Although experimental studies are beginning to reveal molecular mechanisms underlying such control, there is still very little known about the control strategies themselves. Here, we consider how secreted negative feedback factors (“chalones”) may be used to control the output of multistage cell lineages, as exemplified by the actions of GDF11 and activin in a self-renewing neural tissue, the mammalian olfactory epithelium (OE). We begin by specifying performance objectives—what, precisely, is being controlled, and to what degree—and go on to calculate how well different types of feedback configurations, feedback sensitivities, and tissue architectures achieve control. Ultimately, we show that many features of the OE—the number of feedback loops, the cellular processes targeted by feedback, even the location of progenitor cells within the tissue—fit with expectations for the best possible control. In so doing, we also show that certain distinctions that are commonly drawn among cells and molecules—such as whether a cell is a stem cell or transit-amplifying cell, or whether a molecule is a growth inhibitor or stimulator—may be the consequences of control, and not a reflection of intrinsic differences in cellular or molecular character. Many tissues and organs grow to precise sizes and, when injured, regenerate accurately and rapidly. Here, we ask whether the organization of cells into lineages, and the feedback interactions that occur within lineages, are necessary elements of control strategies that make such behavior possible. Drawing on mathematical modeling and the results of experimental manipulation of the mouse olfactory epithelium, we show that performance objectives, such as robust size specification, fast regeneration from a variety of initial conditions, and maintenance of high ratios of differentiated to undifferentiated cells, can be simultaneously achieved through a combination of lineage structures, signaling mechanisms, and spatial distributions of cell types that correspond well with what is observed in many growing and regenerating tissues. Key to successful control is an integral-feedback mechanism that is implemented when terminally differentiated cells secrete molecules that lower the probability that progenitor cells replicate versus differentiate. Interestingly, this mechanism also explains how the distinctive proliferative behaviors of stem cell and “transit-amplifying” cell populations can emerge as a consequence of feedback effects, rather than intrinsic programming of cell types. Are common, generic strategies used in the quantitative control of tissue growth and regeneration? An investigation of feedback effects in multistage lineages suggests they are.
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