Adult bone marrow (BM) had been long thought to be an immune-privileged organ where little immune reactions occur upon immunological challenges, and thus to form an advantageous environment to preserve long-lived hematopoietic and immune cells, e.g., hematopoietic stem cells (HSCs) that maintain lifelong hematopoiesis. They are mostly kept in quiescence, i.e., very slowly dividing within the steady state BM microenvironment, often referred to as niche, which consists of various type of non-hematopoietic cells such as endothelial cells, mesenchymal stromal cells1. In contrast, recent studies have suggested that a broad range of immunological and inflammatory responses occur in BM and largely influence HSC function2. Upon hematopoietic challenges, e.g., infection, inflammation, cancer, both HSCs and the surrounding niche cells can sense hematopoietic demand signals and integrate it to hematopoiesis via direct (HSC-mediated) and indirect (niche-mediated) sensing mechanisms. As a consequence, primitive HSC and their differentiated progenitors (HSPCs) migrate to inflamed organs, proliferate and differentiate into specific cell lineages that are locally consumed and to be replenished. Infection is one of hemato-immunological challenges that are highly conserved in evolution and relevant to pathogenesis of many diseases, e.g., cancer. Host defense against infection is initiated by rapid but relatively non-specific responses that involve innate immune effector cells, e.g., macrophages, granulocytes, and then is followed by slower but specific responses that involve acquired immunity. Recent studies have shown that not only immune cells but also HSPCs express innate immune sensors, such as Toll-like receptors (TLRs), and the ligation of receptors results in secretion of pro-inflammatory cytokines, cell migration, proliferation and differentiation into myeloid lineage cells (King, Nat Rev Immunol 2016). We have also shown that systemic infection of gram negative bacterial activates quiescent HSCs to proliferation through its cognate receptor, TLR4, and eventually impairs their hematopoietic repopulating ability3. More recently, we have found that intestinal tissue damage activates early hematopoiesis in BM via microbial signals and direct early HSPCs to inflamed lymph node to produce myeloid cells and promote tissue repair. Given the fact that innate immune cells are epigenetically programmed with innate immune memory upon sensitization ("training") infection to resist future infectious insults4, and that HSPCs are long-lived and immune-responsive, it has been demonstrated that upon exposure to pathogen, HSPCs also are able to memorize infection through metabolic and epigenetic changes, and build hemato-immune system with better protection to subsequent pathogen insults5. Taken together, these findings define the BM not as an immune-privileged reservoir, but rather as an organ of active immune reactions where immature HSPCs are capable of adapting the demand signal to hematopoiesis in response to hemato-immunological challenges, and of being trained by innate immune activation to reconstitute host defense with more resistance against future infection.
Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature. 2014 Jan 16;505(7483):327-34 Takizawa H, Boettcher S, Manz MG. Demand-adapted regulation of early hematopoiesis in infection and inflammation.Blood. 2012 Mar 29;119(13):2991-3002. Takizawa H, Fritsch K, Kovtonyuk LV, et al. Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness.Cell Stem Cell. 2017 Aug 3;21(2):225-240.e5. Netea MG, Joosten LA, Latz E, et al. Trained immunity: A program of innate immune memory in health and disease.Science. 2016 Apr 22;352(6284):aaf1098. Kopf M, Nielsen PJ. Training myeloid precursors with fungi, bacteria and chips. Nat Immunol. 2018 Apr;19(4):320-322.
Disclosures
No relevant conflicts of interest to declare.
In vivo administration of stem cell factor to mice increases the absolute number of pluripotent hematopoietic stem cells
