Decoding immunocompetence code that can reactivate aged hematopoietic stem cells

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Recent works show that not only adaptive immunity but also innate immunity is capable of memorizing previously-encountered pathogens to develop trained immunity. Accumulating evidences show that HSCs can develop immune memory after microbial infection, although the underlying mechanism still remains unclear. We have previously found that upon gut inflammation, Bacteroides species, one of gram negative bacteria in the gut, infiltrate into body and activate BM haematopoiesis in which hematopoietic progenitor (HPCs) are directed to gut-associated lymph node and generate anti-inflammatory myeloid cells for tissue repair (Hayashi et al., bioRxiv 2021). Thus, we hypothesize that Bacteroides might be able to epigenetically imprint an innate immune memory on HSCs and their derived innate immune cells that exert stronger immunocompetence. To test our hypothesis, we primarily challenged mice with Bacteroides and performed in vivo sepsis model as secondary challenge. Microbial prestimulation can provide cross-protective effect to improve host survival. To elucidate the underlying mechanism, we establish a novel bioinformatic pipeline to integrate single-cell sequencing data, and identified epigenetic priming in anti-inflammatory, innate immunity- and metabolism-related genes at 1-month post-stimulation. The Bacteroides also induced substantial changes in active histone modification in the primed HSCs. Our data suggest that understanding of formation, maintenance and abrogation of innate immune memory in HSCs might help to enforce immune-competent of aged hemato-immune system.