Mathematical modeling of individual clone dynamics for genetically modified stem cells within the hematopoietic system

由于其长期的重建潜力，组织干细胞被用于基因治疗环境中，在这种环境中，基因工程细胞必须植入并长期重建特定的组织。然而，最近的观察表明，将基因转移到造血干细胞(HSC)中可能会改变它们的竞争行为，并可能导致遗传毒性。目前，很难理解细胞特性的微小差异如何成为克隆竞争的重要影响因素，以及干预措施可以在多大程度上影响克隆的波动。这个项目的目标是应用、改进和验证先前开发的数学模型来描述HSC系统中的个体克隆动力学，最终目的是预测体内克隆的贡献和持久性。将考虑小鼠、灵长类动物和人类造血的几种实验和临床情况，以得出经过验证的参考模型。通过计算机模拟，我们将分析克隆数量和大小分布的动态变化以及不同细胞功能对干细胞克隆竞争潜力的影响。这些结果将被用来优化克隆跟踪策略，并预测新的转基因和移植方案的潜在影响。

Due to their long-term reconstitution potential, tissue stem cells are used in gene therapeutic settings, where genetically engineered cells have to engraft and to long-term reconstitute specific tissues. However, recent observations demonstrate that gene transfer into hematopoietic stem cells (HSC) is potentially altering their competitive behavior and might induce genotoxicity. Currently, it is difficult to understand how small differences in cellular properties can become important effectors of clonal competition and to what extent clonal fluctuations can be influenced by interventions. The objective of this project is the application, refinement and validation of a previously developed mathematical model to describe individual clone dynamics in the HSC system with the ultimate aim to predict clonal contribution and persistence in vivo. Several experimental and clinical situations of murine, primate, and human hematopoiesis will be considered to derive validated reference models. Using computer simulations we will analyze the dynamic changes of clone number and size distributions and the influence of different cellular functions on the competitive potential of stem cell clones. These results will be used to optimize clone tracking strategies and to predict potential effects of new transfection and transplantation protocols.