Institute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
Center for Regenerative Medicine in Barcelona (CMRB), Bellvitge Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain.
Stem Cells. 2019 Jul;37(7):948-957. doi: 10.1002/stem.3005. Epub 2019 Apr 3.
The prevailing view on murine hematopoiesis and on hematopoietic stem cells (HSCs) in particular derives from experiments that are related to regeneration after irradiation and HSC transplantation. However, over the past years, different experimental techniques have been developed to investigate hematopoiesis under homeostatic conditions, thereby providing access to proliferation and differentiation rates of hematopoietic stem and progenitor cells in the unperturbed situation. Moreover, it has become clear that hematopoiesis undergoes distinct changes during aging with large effects on HSC abundance, lineage contribution, asymmetry of division, and self-renewal potential. However, it is currently not fully resolved how stem and progenitor cells interact to respond to varying demands and how this balance is altered by an aging-induced shift in HSC polarity. Aiming toward a conceptual understanding, we introduce a novel in silico model to investigate the dynamics of HSC response to varying demand. By introducing an internal feedback within a heterogeneous HSC population, the model is suited to consistently describe both hematopoietic homeostasis and regeneration, including the limited regulation of HSCs in the homeostatic situation. The model further explains the age-dependent increase in phenotypic HSCs as a consequence of the cells' inability to preserve divisional asymmetry. Our model suggests a dynamically regulated population of intrinsically asymmetrically dividing HSCs as suitable control mechanism that adheres with many qualitative and quantitative findings on hematopoietic recovery after stress and aging. The modeling approach thereby illustrates how a mathematical formalism can support both the conceptual and the quantitative understanding of regulatory principles in HSC biology.
目前关于鼠类造血以及造血干细胞（HSCs）的主流观点主要来源于与辐射后再生和 HSC 移植相关的实验。然而，在过去的几年中，已经开发出不同的实验技术来研究稳态下的造血，从而可以了解未受干扰情况下造血干细胞和祖细胞的增殖和分化率。此外，人们已经清楚地认识到，造血在衰老过程中会发生明显的变化，这对 HSC 的丰度、谱系贡献、分裂的不对称性和自我更新潜力有很大的影响。然而，目前尚不完全清楚干细胞和祖细胞如何相互作用以响应不同的需求，以及这种平衡如何因 HSC 极性的衰老诱导变化而改变。为了实现概念上的理解，我们引入了一种新的计算模型来研究 HSC 对不同需求的响应动态。通过在异质 HSC 群体中引入内部反馈，该模型适合于一致描述造血稳态和再生，包括在稳态下对 HSCs 的有限调节。该模型进一步解释了年龄依赖性表型 HSCs 的增加是由于细胞无法维持分裂的不对称性所致。我们的模型表明，具有内在不对称分裂的动态调节 HSC 群体是一种合适的控制机制，与应激和衰老后造血恢复的许多定性和定量发现一致。该建模方法说明了数学形式主义如何支持对 HSC 生物学中调节原理的概念和定量理解。
