Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
Dept. of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
PLoS One. 2019 Mar 1;14(3):e0212502. doi: 10.1371/journal.pone.0212502. eCollection 2019.
Hematopoietic stem cells (HSCs) play an important physiological role as regulators of all blood and immune cell populations, and are of clinical importance for bone marrow transplants. Regulating HSC biology in vitro for clinical applications requires improved understanding of biological inducers of HSC lineage specification. A significant challenge for controlled HSC expansion and differentiation is the complex network of molecular crosstalk between multiple bone marrow niche components influencing HSC biology. We describe a biology-driven computational approach to model cell kinetics in vitro to gain new insight regarding culture conditions and intercellular signaling networks. We further investigate the balance between self-renewal and differentiation that drives early and late hematopoietic progenitor populations. We demonstrate that changing the feedback driven by cell-secreted biomolecules alters lineage specification in early progenitor populations. Using a first order deterministic model, we are able to predict the impact of media change frequency on cell kinetics, as well as distinctions between primitive long-term HSCs and differentiated myeloid progenitors. Integrating the computational model and sensitivity analyses we identify critical culture parameters for regulating HSC proliferation and myeloid lineage specification. Our analysis suggests that accurately modeling the kinetics of hematopoietic sub-populations in vitro requires direct contributions from early progenitor differentiation along with the more traditionally considered intermediary oligopotent progenitors. While consistent with recent in vivo results, this work suggests the need to revise our perspective on HSC lineage engineering in vitro for expansion of discrete hematopoietic populations.
造血干细胞 (HSCs) 在调节所有血液和免疫细胞群体方面发挥着重要的生理作用，并且对于骨髓移植具有重要的临床意义。为了临床应用，需要更好地了解诱导 HSC 谱系特化的生物学诱导剂，从而调节体外 HSC 生物学。控制 HSC 扩增和分化的一个重大挑战是影响 HSC 生物学的多个骨髓龛成分之间复杂的分子串扰网络。我们描述了一种生物学驱动的计算方法，用于模拟体外细胞动力学，以深入了解培养条件和细胞间信号网络。我们进一步研究了驱动早期和晚期造血祖细胞群体的自我更新和分化之间的平衡。我们证明，改变由细胞分泌的生物分子驱动的反馈会改变早期祖细胞群体的谱系特化。使用一阶确定性模型，我们能够预测培养基变化频率对细胞动力学的影响，以及原始长期 HSCs 和分化的髓系祖细胞之间的区别。整合计算模型和敏感性分析，我们确定了调节 HSC 增殖和髓系谱系特化的关键培养参数。我们的分析表明，准确模拟体外造血亚群的动力学需要早期祖细胞分化的直接贡献，以及更传统的考虑中间多能祖细胞。虽然与最近的体内结果一致，但这项工作表明，有必要重新考虑我们在体外进行 HSC 谱系工程以扩增离散造血群体的观点。
