Computing hematopoietic stem and progenitor cell plasticity in response to genetic mutations and environmental stimulations

Yuchen Wen, Hang He, Yunxi Ma, Lorie Chen Cai, Huaquan Wang, Yanmei Li, Baobing Zhao, Zhigang Cai
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Abstract

Cell plasticity (CP), describing a dynamic cell state, plays a crucial role in maintaining homeostasis during organ morphogenesis, regeneration and damage-to-repair biological process. Single-cell-omics datasets provide unprecedented resource to empowers analysis on CP. Hematopoiesis offers fertile opportunities to develop quantitative methods for understanding CP with rich supports from experimental ground-truths. In this study we generated high-quality lineage-negative (Lin) single-cell RNA-sequencing datasets under various conditions and introduced a working pipeline named Snapdragon to interrogate naïve and disturbed plasticity of hematopoietic stem and progenitor cells (HSPCs) with mutational or environmental challenges. Utilizing embedding methods UMAP or FA, a continuum of hematopoietic development is visually observed in wildtype where the pipeline confirms a very low Proportion of hybrid-cells (Phc, with bias range: 0.4-0.6) on a transition trajectory. Upon Tet2 mutation, a driver of leukemia, or treatment of DSS, an inducer of colitis, Phc is increased and plasticity of HSPCs was enhanced. Quantitative analysis indicates that Tet2 mutation enhances HSC self-renewal capability while DSS treatment results in an enhanced myeloid-skewing trajectory, suggesting their similar but different consequences. We prioritized several transcription factors (i.e the EGR family) and signaling pathways (i.e. receptors IL1R1 and ADRB, inflammation and sympathy-sensing respectively) which are responsible for Phc alterations. CellOracle-based simulation suggests that knocking-out EGR regulons or pathways of IL1R1 and ADRB partially reverses Phc promoted by Tet2 mutation and inflammation. In conclusion, the study provides high-quality datasets with single-cell transcriptomic matrices for diversified hematopoietic simulations and a computational pipeline Snapdragon for quantifying disturbed Phc and CP. (247 words)
计算造血干细胞和祖细胞在基因突变和环境刺激下的可塑性
细胞可塑性(CP)描述的是一种动态细胞状态,在器官形态发生、再生和损伤到修复的生物过程中对维持平衡起着至关重要的作用。单细胞组学数据集为分析细胞可塑性提供了前所未有的资源。造血系统为开发定量方法提供了肥沃的土壤,这些方法可以从实验真相中获得丰富的支持,从而理解造血干细胞。在这项研究中,我们在各种条件下生成了高质量的系阴性(Lin-)单细胞RNA测序数据集,并引入了一个名为Snapdragon的工作流水线,以研究造血干细胞和祖细胞(HSPCs)在突变或环境挑战下的幼稚和紊乱可塑性。利用嵌入方法 UMAP 或 FA,可直观地观察到野生型造血发育的连续性,该管道确认了过渡轨迹上极低的杂交细胞比例(Phc,偏倚范围:0.4-0.6)。在白血病驱动因子 Tet2 突变或结肠炎诱导因子 DSS 治疗后,Phc 增加,HSPC 的可塑性增强。定量分析显示,Tet2突变增强了造血干细胞的自我更新能力,而DSS处理则导致髓系偏移轨迹增强,这表明它们的后果相似但又不同。我们优先考虑了导致 Phc 改变的几个转录因子(即 EGR 家族)和信号通路(即 IL1R1 和 ADRB 受体,分别涉及炎症和同情感应)。基于CellOracle的模拟表明,敲除EGR调控子或IL1R1和ADRB的通路可部分逆转由Tet2突变和炎症促进的Phc。总之,该研究为多样化造血模拟提供了高质量的单细胞转录组矩阵数据集,并为量化受干扰的Phc和CP提供了计算管道Snapdragon。(247字)
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