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 ( , with bias range: 0.4∼0.6) on a transition trajectory. Upon mutation, a driver of leukemia, or treatment of DSS, an inducer of colitis, is increased and plasticity of hematopoietic stem and progenitor cells was enhanced. We prioritized several transcription factors and signaling pathways, which are responsible for alterations. In silico perturbation suggests knocking out EGR regulons or pathways of IL-1R1 and β-adrenoreceptor partially reverses promoted by mutation and inflammation.