Hybrid mathematical model of cardiomyocyte turnover in the adult human heart.
Hybrid mathematical model of cardiomyocyte turnover in the adult human heart.
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DOI：
10.1371/journal.pone.0051683
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Margulies KB
中科院分区：
文献类型：
--
作者：
Elser JA;Margulies KB
健康成年人心脏中心肌细胞再生的能力与心肌稳态和心肌病治疗两者基本上相关。然而，心肌细胞周转率的估计值存在很大的冲突，一项采用C14脉冲追踪方法的研究得出结论，随着年龄的增长，年轻人的年周转率从1%下降到0.5%，另一项使用细胞群体动力学的研究表明，随着年龄的增长，周转率大幅增加（4%增加到20%）。创建一个混合数学模型，以严格检查来自替代方法的心肌细胞周转率。单独检查时，细胞群分析对干细胞扩增指数（20%的变化导致2倍周转率变化）和细胞凋亡率表现出严重的敏感性。同样，脉冲追逐模型是急性敏感的假设瞬时纳入大气中的C14到体内（4倍的影响，营业额在年轻的科目），而数值限制排除了其他可行的解决方案。考虑到主要变量的敏感性和有争议的模型假设，一个无偏的数值求解器确定了一个显着的，年龄增加的周转率（4 - 6%增加到15 - 22%随着年龄的增长），这是与两项研究的数据兼容的情况下，连续几代心肌细胞经历了比前辈更高的损耗率。在细胞群体模型中，将组织学观察到的干/祖细胞分配为离散的再生表型强烈影响了周转动力学，而无需直接测试。另外，C14贩运假设和脉冲追踪模型中的限制性模型人为地排除了高周转率解决方案。然而，最近的细胞周转率估计之间的差异可以解释和调和。本文提供的混合数学模型允许进一步检查这些和即将到来的数据集。
The capacity for cardiomyocyte regeneration in the healthy adult human heart is fundamentally relevant for both myocardial homeostasis and cardiomyopathy therapeutics. However, estimates of cardiomyocyte turnover rates conflict greatly, with a study employing C14 pulse-chase methodology concluding 1% annual turnover in youth declining to 0.5% with aging and another using cell population dynamics indicating substantial, age-increasing turnover (4% increasing to 20%). Create a hybrid mathematical model to critically examine rates of cardiomyocyte turnover derived from alternative methodologies. Examined in isolation, the cell population analysis exhibited severe sensitivity to a stem cell expansion exponent (20% variation causing 2-fold turnover change) and apoptosis rate. Similarly, the pulse-chase model was acutely sensitive to assumptions of instantaneous incorporation of atmospheric C14 into the body (4-fold impact on turnover in young subjects) while numerical restrictions precluded otherwise viable solutions. Incorporating considerations of primary variable sensitivity and controversial model assumptions, an unbiased numerical solver identified a scenario of significant, age-increasing turnover (4–6% increasing to 15–22% with age) that was compatible with data from both studies, provided that successive generations of cardiomyocytes experienced higher attrition rates than predecessors. Assignment of histologically-observed stem/progenitor cells into discrete regenerative phenotypes in the cell population model strongly influenced turnover dynamics without being directly testable. Alternatively, C14 trafficking assumptions and restrictive models in the pulse-chase model artificially eliminated high-turnover solutions. Nevertheless, discrepancies among recent cell turnover estimates can be explained and reconciled. The hybrid mathematical model provided herein permits further examination of these and forthcoming datasets.
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影响因子：
20.1
作者：
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