Single-cell mapping of stress-conditioned hematopoiesis reveals distinct molecular adaptation separating resilience from susceptibility 2267362

Abstract Introduction Chronic stress is a leading predictor of poor health, elevating risk for psychiatric, cardiovascular, neurodegenerative, and immune disorders. Stress-linked disease courses are marked by systemic inflammation, and both in humans with prolonged stress exposure and animal social-stress models show characteristic immunologic shifts (monocytosis, neutrophilia, lymphopenia). Yet how a psychological experience imprints durable biology and why genetically similar individuals diverge into resilience versus susceptibility, remains unclear. Methods We performed single-cell transcriptomics on HSPCs, progenitors, and mature lineages from control, resilient, and susceptible mice after chronic social defeat stress (CSDS; n = 3/group, 320K cells). Results two reproducible, opposing programs across the hematopoietic hierarchy. Resilient mice exhibit proteostasis/UPR buffering, orderly myeloid maturation, and a prompt negative-feedback module coupling AP-1 immediate-early genes to Dusp1, Zfp36, Btg2, and Nr4a1. In long-term HSCs, transcription-factor activity inference indicates preserved FOXO/Notch tone and fatty-acid oxidation–features of quiescence maintenance and rapid stimulus resolution. In contrast, susceptible mice display type-I interferon and viral-sensing signatures (Irf7/9, Oas1/3) together with mitotic/replication stress and mixed stemness/lineage-priming transcriptional states; TF activity highlights MYC/E2F engagement with one-carbon metabolism and glycolysis alongside strong AP-1 activation. Conclusion Together, our work motivate a conservative but innovative model: divergent outcomes arise from differences in AP-1 “dwell time” and the efficiency of NR4A-linked negative feedback. Our work suggests measurable enhancer kinetics as biomarkers and a route to rationally tune hematopoietic responses to stress. Funding Source n/a Topic Categories Hematopoiesis and Immune System Development (HEM)