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Sensing of the microbiota by NOD1 in mesenchymal stromal cells regulates murine hematopoiesis

Chiaki Iwamura, Nicolas Bouladoux, Yasmine Belkaid, Alan Sher and Dragana Jankovic

Key points

  • NOD1 ligand administration restores hematopoietic precursor pools in germ free mice to the levels seen in specific pathogen free animals.

  • NOD1 ligand-NOD1 signaling promotes steady state hematopoiesis indirectly through the induction of cytokines by mesenchymal stromal cells.

Abstract

The microbiota are known to influence the generation of hematopoietic progenitors although the pathways underlying this process are still poorly understood. NOD1 and NOD2 are intracellular sensors for both Gram-positive and negative bacteria, but their role in steady-state hematopoiesis has never been characterized. We observed that stimulation with NOD1 or NOD2 ligand had no effect on the survival/proliferation of hematopoietic precursors. Nonetheless, NOD1 but not NOD2 ligand induced expression of multiple hematopoietic cytokines (IL-7, Flt3L, SCF, ThPO and IL-6) from bone marrow mesenchymal stromal cells (MSC) in vitro. Moreover, in vivo administration of NOD1 ligand to germ-free mice restored the numbers of hematopoietic stem cells and precursors in bone marrow as well as serum concentrations of IL-7, Flt3L, SCF and ThPO to the levels displayed by specific pathogen free control animals. Based on these findings we propose that NOD1 signaling in MSC serves as an important pathway underlying the requirement for microbiota in the maintenance of steady-state hematopoiesis. This function is distinct from that triggered by lipopolysaccharide in both its broad effects on multiple progenitors and specific targeting of MSC as cytokine producing intermediates.

  • Submitted June 22, 2016.
  • Accepted October 27, 2016.