Haematopoietic stem cells can sense tissue damage in the gut

In the late-breaking oral session, Dr Hitoshi Takizawa (Kumamoto University, Japan) presented their study investigating how intestinal damage results in bone marrow haematopoiesis induction of haematopoietic stem cell (HSC) expansion followed by directional multipotent progenitor (MPP) migration to inflamed lymphoid tissues and generation of myeloid cells specialised for intestinal tissue repair [1].

Haematopoietic stem cells (HSCs) sustain lifelong haematopoiesis, while lineage-restricted progenitors actively divide and mainly contribute to daily haematopoiesis. Haematopoietic challenges such as inflammation or infection activate HSCs to self-renew. Systemic challenge of gram-negative bacteria directly activates dormant HSCs to proliferate and impairs their competitive fitness via Toll-like receptor (TLR)-4 signalling [2]. To test their hypothesis that progenitor cells (HSPCs) can sense tissue damage signals derived from distal organs such as the gut, and translate that to haematopoietic production, Dr Takizawa’s team induced inflammatory bowel disease (IBD) in mice by adding dextran sodium sulfate (DSS) to their drinking water.

Inducing inflammatory bowel disease in the mice enhanced proliferation and expansion of HSPCs such as MPP and myeloid-restricted progenitors in bone marrow, while simultaneously reducing lymphoid-restricted progenitors, as measured by flow cytometry, microscopy, in vivo pharmacological treatment, and in vivo serial transplantation. Proliferating MPPs were localised adjacent to endothelial cells within the gut-associated mesenteric lymph node (MLN) but not in other lymph nodes, suggesting a specific haematopoietic response to gut inflammation, which the researchers demonstrated to be dependent on TLR signalling. Mice were then pre-treated with either a single or a mixture of antibiotics to deplete specific types of bacteria to determine what might trigger the TLR signalling. Pre-treatment with gram-positive directed antibiotics like vancomycin and ampicillin, completely abrogated haematopoietic responses to IBD, whereas neomycin and metronidazole, directed against gram-negative bacteria, enhanced haematopoietic response. Genome profiling and bacterial lysate injection identified that gram-negative bacterial species prompt MPP migration to the MLN through TLR-related signals. Following the MPP recruitment, myeloid cells including eosinophils and monocytes rapidly increased in MLN and their cell depletion by neutralising antibody worsened IBD-induced colitis.

This data suggests that in response to intestinal damage, bone marrow haematopoietic PCs sense microbiota via innate immune receptor and induce HSPC expansion followed by directional MPP migration to inflamed lymphoid tissues and generation of myeloid cells specialised for intestinal tissue repair (see Figure).

Figure: Schematic of the working hypothesis presented by Dr Takizawa et al [1]

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   1. Takizawa H, et al. Abstract LB2604, 24th Congress of the EHA, 13-16 June 2019, Amsterdam, the Netherlands.
   2. Takizawa H, et al. Cell Stem Cell. 2017 Aug 3;21(2):225-240.e5

Posted on 9 August, 20198 April, 2024