Microbes prevent HSPCs from “NOD”-ing off

In this issue of Blood, Iwamura et al investigate the impact of microbes on the hematopoietic stem and precursor cell (HSPC) compartment. Using a mouse model and in vitro experiments, the authors demonstrate that the microbiota induces NOD1 in mesenchymal stem cells (MSCs), and that this, subsequently, induces proliferation within the HSPC compartment.¹ 

Mammals and microbes have coevolved for ∼200 million years, since the origin of mammals in the late Triassic period. This ancient relationship is largely believed to be mutualistic. Common parlance has favored referring to the majority of the microbes in the gut as “commensal,” which suggests that the microorganisms benefit from receiving nutrients in the human niche without affecting their host. However, a growing body of evidence suggests that the relationship is “symbiotic,” where both parties of the mutual relationship actively affect one another, most often in beneficial ways. A compelling argument in support of the symbiosis model is the finding that proper immunological development and competence are impaired in the absence of microbes. Although this phenomenon has been long acknowledged, the mechanisms underlying this relationship have been elusive.

Animals can be delivered and reared in so-called “germ-free” environments, where important microbiota niches such as the gastrointestinal system remain free of detectable microorganisms. Such germ-free animals have widespread deficits in immune development. These aberrancies, which are nicely reviewed by Round and Mazmanian,²  are most prominent in the intestinal immune compartment. One of the earliest specific examples of such a microbe-immune cell relationship was demonstrated by Littman and colleagues in 2009, where the introduction of segmented filamentous bacteria into germ-free mice induced the production of Th-17 cells.³ 

More recently, a phenomenon of hematopoietic cell compartment alterations has been noticed in these extensively studied germ-free animal models. Several immunologic cell types are impacted by exposure to microbes, including myeloid, natural killer T cells (NKTs), and monocytes. Myeloid cell progenitors in germ-free mice are lower in number and in differentiation potential. The finding of a lower number of myeloid cell progenitors in germ-free mice extends to those progenitors that derive from the yolk sac as well as the bone marrow. Microbially triggered granulopoiesis is at least partially mediated by interactions between microbial molecules such as lipopolysaccharides and toll-like receptors (TLRs), such as TLR4. These receptors, along with adapter molecules such as TRIF and Myd88, appear to be required for microbiota-driven myelopoiesis.⁴  A recent article in this journal, by Hergott et al, showed that intestinal microbes control neutrophil and monocyte turnover in a NOD1/NOD1L–dependent manner.⁵  NOD1, an intracellular pattern recognition receptor, when bound by the NOD1 ligand d-glutamyl-meso-diaminopimelic acid, activates the downstream transcription factor NF-κB to modulate both innate and adaptive arms of the immune system.

Consequences of depressed myeloid cell development in the germ-free setting include impaired innate immunity to gut pathogens, such as Listeria species. Although resistance against Listeria infection can be partially rescued by reintroduction of a balanced gut microbiota, it is possible that long-term defects of immunity persist even after a brief, early period of exposure to impaired immunity. The groups of Kasper and Blumberg found that early life exposure to microbes was critical for invariant NKT function. Invariant NKTs localized to the colonic lamina propria and lung in animals that were born germ free and thus were devoid of microbial exposures in the neonatal time period. Exposing these animals to microbes later in life was insufficient to drive redistribution of these invariant NKTs. Thus, it was concluded that there is an age dependence of microbially mediated immune “training.”⁶ 

Although there is strong evidence for tissue-level lymphoid and peripheral myeloid cell proliferation in response to microbial signals, predominantly through the TLR pathway, to date, there have been limited data on how microbes may impact the production and proliferation of hematopoietic progenitors. A significant conceptual step forward is made by the contribution of Iwamura et al in this issue. Building off the observation that naive Myd88 and TRIF–deficient mice have unaltered HSPC composition, the authors posit that alternative bacterial sensors may play a role in hematopoiesis. Using a germ-free mouse model, the authors demonstrate that hematopoietic stem cells are decreased in number compared with the amounts found in specific pathogen–free (SPF) mice. The administration of NOD1 ligand is sufficient to rescue HSPC numbers to levels found in SPF mice, and this effect is shown to be NOD1 dependent. Interestingly, although NOD1 is expressed in both HSPCs and MSCs, it is the NOD1 in MSCs that appears to be critical for effects on the HSPC compartment. The supernatant from NOD1L-treated MSCs is sufficient to recapitulate the effect on HSPCs, and specific MSC-secreted factors are suggested as potential mediators of this effect. Thus, the authors are able to show, for the first time, that MSCs mediate microbiota-induced effects on the HSPC compartment, and that this occurs in an MSC NOD1-dependent manner.

A growing body of literature now highlights the importance of the microbiota in mediating hematopoiesis and immunity. The studies noted here begin to elucidate critical mechanisms whereby microbes impact cellular programs that range from granulopoiesis to T-cell and NKT proliferation. The bacteria, viruses, and fungi that live within and on us play a role in nearly every aspect of hematopoiesis that has been investigated to date.⁷  Based on the findings of Iwamura et al, this impact extends to primitive progenitor compartments. As mysteries of the ancient and highly regulated relationship between microbes and their mammalian hosts are unraveled, we will likely learn of (1) novel microbial mediators of host modification, (2) additional positive and negative regulatory signaling pathways that are controlled by microbial mediators, and perhaps eventually (3) microbially targeted methods to modify hematopoietic cell regulation, differentiation, and modulation. Indeed, a paradigm of microbial “fine-tuning” of hematopoiesis and immune development may soon be firmly within the realm of reality. Such a paradigm shift may deeply impact how we consider managing hematopoiesis and hematological diseases by manipulating household and medical antimicrobial and promicrobial exposures in diseases that range from bone marrow failure to stem cell transplantation.