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首页> 外文期刊>Journal of Theoretical Biology >Mathematical modelling of the hematopoietic stem cell-niche system: Clonal dominance based on stem cell fitness
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Mathematical modelling of the hematopoietic stem cell-niche system: Clonal dominance based on stem cell fitness

机译：造血干细胞 - 利基系统的数学建模：基于干细胞健身的克隆优势

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Human blood cell production is maintained by hematopoietic stem cells (HSC) which give rise to all types of mature blood cells. Experimental observation of HSC in their physiologic bone-marrow microenvironment, the so-called stem cell niche, is challenging. Therefore, the details of HSC dynamics and the cellular interactions in the stem cell niche remain elusive. Mutations that lead to a competitive advantage are the cause of clinical challenges when treating HSC-derived malignancies such as acute myeloid leukemia or the myeloproliferative neoplasms (MPNs). To investigate the significance of the interaction between the HSC and the stem cell niche in these malignancies, we propose and analyse a mechanism-based mathematical model of HSC dynamics within the bone-marrow microenvironment. The model is based on the central hypothesis that HSC self-renewal depends on the niche. In the model, the interaction of HSC with specific niches located in the bone marrow are key to the indefinite HSC renewal necessary for long-term maintenance of blood cell production. We formulate a general model of n distinct clones that differ with respect to cell properties. We identify an attractive trapping region and compute and classify all steady states. A concept of HSC fitness naturally arises from the model analysis. HSC fitness is found to determine the asymptotic behaviour of the model, as the HSC clone with the highest fitness is related to the unique locally stable steady state. Based on biological assumptions about HSC, we propose two reduced models of different complexity. A thorough mathematical analysis reveals that both reduced models have the same asymptotic behaviour as the full model. We compare the simpler of the two models, a logistic equation of the disease burden, to clinical data of MPN-patients. The reduced model is found to agree well with data and suggests a simple interpretation and possible prediction of patient prognosis. The proposed mathematical model and the reduced forms have the potential to provide insights into the regulation of HSC dynamics and blood cell formation, and ultimately for future advances in treatment of hematologic malignancies. (C) 2021 Elsevier Ltd. All rights reserved.
机译：人类的血细胞生产是由造血干细胞（HSC）维持的，HSC产生各种类型的成熟血细胞。HSC在其生理性骨髓微环境（所谓的干细胞生态位）中的实验观察具有挑战性。因此，HSC动力学和干细胞生态位中的细胞相互作用的细节仍然难以捉摸。在治疗HSC衍生的恶性肿瘤，如急性髓系白血病或骨髓增生性肿瘤（MPN）时，导致竞争优势的突变是临床挑战的原因。为了研究HSC和干细胞生态位之间的相互作用在这些恶性肿瘤中的意义，我们提出并分析了骨髓微环境中HSC动力学的基于机制的数学模型。该模型基于HSC自我更新依赖于生态位的中心假设。在该模型中，HSC与骨髓中特定生态位的相互作用是长期维持血细胞生成所需的无限期HSC更新的关键。我们建立了n个不同克隆的通用模型，这些克隆在细胞特性方面有所不同。我们确定了一个吸引陷阱区域，并计算和分类了所有稳态。HSC适应度的概念自然产生于模型分析。发现HSC适应度可确定模型的渐近行为，因为具有最高适应度的HSC克隆与唯一的局部稳定稳态有关。基于对HSC的生物学假设，我们提出了两种不同复杂度的简化模型。深入的数学分析表明，两个简化模型与完整模型具有相同的渐近行为。我们将两个模型中比较简单的一个，即疾病负担的logistic方程，与MPN患者的临床数据进行比较。我们发现简化模型与数据吻合良好，并建议对患者预后进行简单解释和可能的预测。提出的数学模型和简化形式有可能为HSC动力学和血细胞形成的调节提供见解，并最终为血液系统恶性肿瘤治疗的未来进展提供帮助。（c）2021爱思唯尔有限公司保留所有权利。

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