Kinetic analysis of minimal residual disease using 3-dimentinal computational models of human granulopoiesis and development of risk of relapse-stratified treatment of pediatric leukemia.

在2005年，我们试图开发一个独特的人类粒细胞生成的计算模型，以确定稳态造血的调控机制。一个计算方法与造血系统的螺旋模型已被应用于探索的原则，该系统的基础。模型需要易于访问，并高度期望集成细节和再现细胞的动态行为，但也要预测响应于各种模拟的特定细胞行为。我们已经成功地开发了一个新的横向计算模型，人类粒细胞生成使用三维细胞自动机（3D-CA），它结合了时空的概念来描述粒细胞生成过程中的有限空间的骨髓腔。我们强调该模型的独特性质如下：1）该模型不包含用于调节的控制方程或负反馈回路，以及2）人们可以在计算机屏幕上直接观察这种计算机模拟的粒细胞生成，其中HSC复制，分化，并将它们的后代分布在由130 × 130 × 130单位立方区域组成的分析空间中，其中结构对象假定为血管和骨小梁。该模型具体化了单个粒系造血细胞的局部相互作用产生的反馈回路导致系统全局动力学和稳定性的原理，并在2006年进一步应用该模型分析了化疗和造血干细胞移植条件下粒系造血的细胞动力学。模拟研究预测了G-CSF方案治疗药物诱导的中性粒细胞减少症的疗效和最低要求。造血干细胞归巢的细胞动力学特征解释了移植中不同来源干细胞移植后植入时间的差异。从计算血液学中学习细胞行为可以为恶性血液病的治疗提供新的策略。

In 2005, we attempted to develop a unique computational model of human granulopoiesis to identify the regulatory mechanisms for homeostatic hematopoiesis. A computational approach with mathematical-modeling of the hematopoietic system has been applied for exploring the principles that underlie the system. Models are required of easy access and highly expected to integrate details and reproduce the dynamic behaviors of the cells but also to predict the specific cellular behaviors in response to various simulations. We have successfully developed a new lateral computational modeling for human granulopoiesis using three-dimensional Cellular Automata (3D-CA), which incorporates a spatio-temporal concept to describe the granulopoietic process developing in the finite space of bone marrow cavity. We emphasize unique properties of this model as following ; 1)the model does not contain either governing equations or negative feedback loops assumed for regulation and 2)one can directly view this in silico granulopoiesis on the computer screen, in which HSCs replicate, differentiate, and distribute their offspring in an analytical space consisting of 130 x 130 x 130 unit cubic areas with structural objects assuming vessels and trabecular bones. The model reified the principle that local interaction of individual granulopoietic cells produced feedback circuits leading global dynamics and stability of the system.In 2006, we further applied this model to analyze cellular dynamics of granulopoiesis under chemotherapy and hematopoietic stem cell transplantation. Simulation studies predicted efficacy and minimal requirement of G-CSF scheduling for drug-induced neutropenia. Cellular dynamics of homing HSCs explained difference of engraftment periods observed in different utilization of stem cell sources in transplantation. Learning cellular behaviors from computational hematology could provide the novel strategies for the treatment of hematological malignancies.