Computing hematopoiesis plasticity in response to genetic mutations and environmental stimulations

Cell plasticity (CP), describing a dynamic cell state, plays a crucial role in maintaining homeostasis during organ morphogenesis, regeneration, and trauma-to-repair biological process. Single-cell-omics datasets provide an unprecedented resource to empower CP analysis. Hematopoiesis offers fertile opportunities to develop quantitative methods for understanding CP. In this study, we generated high-quality lineage-negative single-cell RNA-sequencing datasets under various conditions and introduced a working pipeline named scPlasticity to interrogate naïve and disturbed plasticity of hematopoietic stem and progenitor cells with mutational or environmental challenges. Using embedding methods UMAP or FA, a continuum of hematopoietic development is visually observed in wild type where the pipeline confirms a low <i>proportion of hybrid cells</i> ( <i><b>P</b></i> _{<i><b>hc</b></i>} , with bias range: 0.4∼0.6) on a transition trajectory. Upon <i>Tet2</i> mutation, a driver of leukemia, or treatment of DSS, an inducer of colitis, <i><b>P</b></i> _{<i><b>hc</b></i>} is increased and plasticity of hematopoietic stem and progenitor cells was enhanced. We prioritized several transcription factors and signaling pathways, which are responsible for <i><b>P</b></i> _{<i><b>hc</b></i>} alterations. In silico perturbation suggests knocking out EGR regulons or pathways of IL-1R1 and β-adrenoreceptor partially reverses <i><b>P</b></i> _{<i><b>hc</b></i>} promoted by <i>Tet2</i> mutation and inflammation.