Modeling of replicative senescence in hematopoietic development
Modeling of replicative senescence in hematopoietic development
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DOI：
10.18632/aging.100072
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发表时间：
2009-08-01
期刊：
影响因子：
5.2
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(HSC)在我们的一生中产生了大量的血细胞。相反，在体外培养条件下，它们在衰老之前的细胞分裂数量是有限的。在这里，我们考虑的问题是，HSC是否可以无限恢复活力，或者细胞分裂的数量是否受到限制。我们建立了一个基于常微分方程组的多室模型。该模型基于这样的假设，即在成熟的每个阶段，自我更新相对于分化的百分比由单一的外部反馈机制来调节。我们模拟了这个模型，假设造血分化在六个成熟阶段之前，细胞在50个分裂后最终停止增殖。我们的结果表明，如果HSC分裂速度慢，自我更新率高，那么在一生中维持造血是可能的。随着年龄的增长，反馈信号增加，从而增强自我更新，从而导致干细胞和祖细胞数量的增加。这项研究表明，复制性衰老与终身造血是相容的，模型预测与实验观察是一致的。因此，HSC可能不会无限期地分裂，具有潜在的重要临床意义。
Hematopoietic stem cells (HSC) give rise to an enormous number of blood cells throughout our life. In contrast their number of cell divisions preceding senescence is limited under in vitro culture conditions. Here we consider the question whether HSC can rejuvenate indefinitely or if the number of cell divisions is restricted. We have developed a multi-compartmental model for hematopoietic differentiation based on ordinary differential equations. The model is based on the hypothesis that in each step of maturation, the percentage of self-renewal versus differentiation is regulated by a single external feedback mechanism. We simulate the model under the assumption that hematopoietic differentiation precedes the six steps of maturation and the cells ultimately cease to proliferate after 50 divisions. Our results demonstrate that it is conceivable to maintain hematopoiesis over a life-time if HSC have a slow division rate and a high self-renewal rate. With age, the feedback signal increases and this enhances self-renewal, which results in the increase of the number of stem and progenitor cells. This study demonstrates that replicative senescence is compatible with life-long hematopoiesis and that model predictions are in line with experimental observations. Thus, HSC might not divide indefinitely with potentially important clinical implications.