Modeling of Asymmetric Cell Division in Hematopoietic Stem Cells-Regulation of Self-Renewal Is Essential for Efficient Repopulation
Modeling of Asymmetric Cell Division in Hematopoietic Stem Cells-Regulation of Self-Renewal Is Essential for Efficient Repopulation
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DOI：
10.1089/scd.2008.0143
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发表时间：
2009-04-01
影响因子：
4
通讯作者：
Wagner, Wolfgang
中科院分区：
文献类型：
--
作者：
Marciniak-Czochra, Anna;Stiehl, Thomas;Wagner, Wolfgang
造血干细胞(HSCs)具有自我更新、补充干细胞库和向成熟细胞分化的能力。祖细胞的后续阶段也分享了一些这种双重能力。目前尚不清楚外部信号是否调节增殖速度，或者更确切地说，是调节自我更新的比例。我们提出了三种依赖于单一外部反馈机制的多室模型。在模型1中，信号促进增殖，而所有隔室的自我更新率是固定的。在模型2中，信号调节自我更新的速度，而增殖率不变。在模型3中，该信号同时调节增殖和自我更新速率。研究表明，只有通过调节自更新速率才能实现唯一的严格正稳定稳定状态。此外，它需要较少的有效细胞倍增次数。为了维持干细胞库，HSC的自我更新比率必须为>；=50%，并且必须高于所有下游隔室的自我更新比率。有趣的是，成熟细胞的平衡水平仅取决于HSC的自我更新参数，而与所有上游隔室的动力学参数无关。该模型与HSC移植后白细胞数量的增加相适应。这项研究表明，在造血过程中，对HSC自我更新率的外在调节是最重要的。
Hematopoietic stem cells (HSCs) are characterized by their ability of self-renewal to replenish the stem cell pool and differentiation to more mature cells. The subsequent stages of progenitor cells also share some of this dual ability. It is yet unknown whether external signals modulate proliferation rate or rather the fraction of self-renewal. We propose three multicompartment models, which rely on a single external feedback mechanism. In Model 1 the signal enhances proliferation, whereas the self-renewal rates in all compartments are fixed. In Model 2 the signal regulates the rate of self-renewal, whereas the proliferation rate is unchanged. In Model 3, the signal regulates both proliferation and self-renewal rates. This study demonstrates that a unique strictly positive stable steady state can only be achieved by regulation of the rate of self-renewal. Furthermore, it requires a lower number of effective cell doublings. In order to maintain the stem cell pool, the self-renewal ratio of the HSC has to be >= 50% and it has to be higher than the self-renewal ratios of all downstream compartments. Interestingly, the equilibrium level of mature cells depends only on the parameters of self-renewal of HSC and it is independent of the parameters of dynamics of all upstream compartments. The model is compatible with the increase of leukocyte numbers following HSC transplantation. This study demonstrates that extrinsic regulation of the self-renewal rate of HSC is most essential in the process of hematopoiesis.