2017 - MICROBIAL SIGNAL INSTRUCTS EARLY HEMATOPOIESIS UPON INTESTINAL TISSUE DAMAGE

Abstract

Hematopoietic stem cells (HSCs) slowly self-renew and differentiate in adult bone marrow (BM) to sustain lifelong hematopoiesis, and can be activated to self-renew or differentiate when hematopoietic need increases. However, it remains unclear how HSC and progenitor cells (HSPCs) integrate the peripheral organ-derived demand signal to hematopoietic production and what the biological consequence of HSPCs activation is on their cell fate decision. We have previously shown that systemic challenge of gram negative bacteria directly activates dormant HSCs to proliferation and impairs their competitive fitness via Toll like receptor (TLR)-4 signaling (Cell Stem Cell 2017). These findings let us hypothesize that commensal bacteria, often referred to as microbiota, might also impact on early hematopoiesis upon intestinal barrier damage. Here, we employed inflammatory bowel disease (IBD) model to induce gut inflammation. Acute IBD induced expansion of HSPCs such as multipotent progenitors (MPPs) in primary BM followed by their localization in mesenteric lymph node (MLN), a local inflammatory site. Myeloid compartment, especially neutrophils and monocytes dominantly increased and suppressed IBD-induced colitis as shown by antibody-based cell depletion study, indicating possible contribution of MPP in tissue damage and repair. Genetic and pharmacological studies revealed that the HSPC expansion and their directed migration depend on a TLR/IL-1 receptor signaling and specific type of microbiota, suggesting that microbial signal generated in the distal organs regulates early hematopoietic cell proliferation and localization. Uncovering the underlying mechanism for gut associated inflammation will help to understand inflammatory feedback signals through cross-organ communications that orchestrate hematopoiesis, and might be relevant to ageing-associated chronic disorders.