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

Abstract

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 MSCs.

Homeostatic Immunity and the Microbiota

“…In vivo administration of NOD1 ligands to germ-free mice can also restore the numbers of hematopoietic stem cells and precursors to the levels displayed by specific pathogen-free animals. Mesenchymal stem cells can also sense NOD1 ligands, thereby expressing factors with known effects on hematopoiesis such as interleukin-7, Flt3L, stem cell factor, ThPO, and IL-6 (Iwamura et al, 2017). Such control may also occur in early life as antibiotic treatment of murine dams reduces their levels of IL-17 and G-CSF, events proposed to account for the reduced numbers of neutrophils and granulocyte/macrophage-restricted progenitor cells observed in neonates (Deshmukh et al, 2014).…”

Mesenchymal Stromal Cells and Toll-Like Receptor Priming: A Critical Review

“…LPS as a potent inducer of IL-6 favors myelopoiesis, whereas NOD1 ligand augments the numbers of all HSPCs (80). …”

Tuning of the Hematopoietic Stem Cell Compartment in its Inflammatory Environment

“…Interestingly, partial reconstitution of the microbiota fails to fully restore the size of LSK compartment suggesting the existence of specific qualitative and/or quantitative requirements for the microbiota to modulate the most immature hematopoietic fractions. These results were confirmed in more refined HSC compartment phenotypically defined as LSK Flk2 - CD34 - or LSK CD48 - CD150 + CD34 - Notably studies in GF mice and in mice treated with a broad-spectrum antibiotic cocktail show that disruption of the microbiota results in a two-to-three fold reduction in the number of HSCs [22••, 23•]. Complementation experiments through microbiota transfer in GF mice or interruption of the antibiotic treatment seems to confirm that the microbiota provides a dynamic and reversible regulation of HSC number.…”

“…It is well established that host interactions with pathogenic and commensal microbiota lead to the presence of immunogenic microbial compounds in the systemic circulation. Often referred as pathogen-associated molecular patterns (PAMPs), these molecules, which include lipopolysaccharide (LPS), RNA, and peptidoglycans, are present at low concentrations in healthy individuals [29, 22••]. As a normal part of the immune response, host cells recognize these molecules through numerous specialized pathogen-recognition receptors (PRRs) that include toll-like receptors (TLR), C-type lectin receptors, nucleotide-binding oligomerization domain-containing protein (NOD)-like receptors (NLR) and other RNA sensing-receptors.…”

“…While such discrepancies remain to be explained, it is tempting to speculate that they could reflect some subtle environmental differences in research animal facilities and therefore might testify to the importance of these pathways in adapting the HSC compartment to changes in microbiota and/or hygienic conditions. In addition to TLR signaling, a recent study describes a key role of NOD-like receptor Nod1 on the HSC homeostasis [22••]. The authors found that HSCs express Nod1 and that the Nod1-deficient mice displayed a reduction in the size of the hematopoietic primitive compartment that mimics the phenotype observed in GF condition.…”