Feedback mechanisms control coexistence in a stem cell model of acute myeloid leukaemia.
Feedback mechanisms control coexistence in a stem cell model of acute myeloid leukaemia.
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DOI：
10.1016/j.jtbi.2016.04.002
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发表时间：
2016-07-21
影响因子：
2
通讯作者：
Stumpf MP
中科院分区：
文献类型：
--
作者：
Crowell HL;MacLean AL;Stumpf MP
造血干细胞动力学调节健康血细胞的产生，并在白血病期间被破坏。细胞物种的竞争模型有助于阐明骨髓微环境（或生态位）中的干细胞动力学，并确定这些动力学如何影响白血病进展。在这里，我们开发了两种针对急性髓性白血病的模型，特别关注通过反馈信号控制增殖的机制。在允许共存的参数空间区域内，竞争的影响最微妙，临床结果最不确定。稳态和线性稳定性分析确定允许共存发生的参数区域，并允许我们在临界点附近观察行为。当解析表达式不再提供信息时，我们在共存区域上进行统计和采样参数空间。我们发现，健康祖细胞的增殖和分化率发挥关键控制共存。我们还表明，包括一个监管反馈到祖细胞促进健康的造血在白血病的代价，而且-有点矛盾-在共存区域内的反馈增加了系统的敏感性，一个血统的优势超过另一个。细胞群体之间的竞争模型可以描述急性髓性白血病的进展。我们确定的共存区域中，白血病和健康的造血物种可以共存的利基。祖细胞的动态发挥关键控制物种共存。调节反馈的引入可以促进健康的造血并抑制白血病。
Haematopoietic stem cell dynamics regulate healthy blood cell production and are disrupted during leukaemia. Competition models of cellular species help to elucidate stem cell dynamics in the bone marrow microenvironment (or niche), and to determine how these dynamics impact leukaemia progression. Here we develop two models that target acute myeloid leukaemia with particular focus on the mechanisms that control proliferation via feedback signalling. It is within regions of parameter space permissive of coexistence that the effects of competition are most subtle and the clinical outcome least certain. Steady state and linear stability analyses identify parameter regions that allow for coexistence to occur, and allow us to characterise behaviour near critical points. Where analytical expressions are no longer informative, we proceed statistically and sample parameter space over a coexistence region. We find that the rates of proliferation and differentiation of healthy progenitors exert key control over coexistence. We also show that inclusion of a regulatory feedback onto progenitor cells promotes healthy haematopoiesis at the expense of leukaemia, and that – somewhat paradoxically – within the coexistence region feedback increases the sensitivity of the system to dominance by one lineage over another. Models of competition between cell populations can describe the progression of acute myeloid leukaemia. We identify regions of coexistence in which leukaemia and healthy haematopoietic species can coexist in the niche. The dynamics of progenitor cells exert key control over species coexistence. The introduction of regulatory feedback can promote healthy haematopoiesis and suppress leukaemia.