Hematopoietic stem and progenitor cells confer cross-protective trained immunity in mouse models.

Recent studies suggest that infection reprograms hematopoietic stem and progenitor cells (HSPCs) to enhance innate immune responses upon secondary infectious challenge, a process called "trained immunity." However, the specificity and cell types responsible for this response remain poorly defined. We established a model of trained immunity in mice in response to Mycobacterium avium infection. scRNA-seq analysis revealed that HSPCs activate interferon gamma-response genes heterogeneously upon primary challenge, while rare cell populations expand. Macrophages derived from trained HSPCs demonstrated enhanced bacterial killing and metabolism, and a single dose of recombinant interferon gamma exposure was sufficient to induce similar training. Mice transplanted with influenza-trained HSPCs displayed enhanced immunity against M. avium challenge and vice versa, demonstrating cross protection against antigenically distinct pathogens. Together, these results indicate that heterogeneous responses to infection by HSPCs can lead to long-term production of bone marrow derived macrophages with enhanced function and confer cross-protection against alternative pathogens.

FGD5 marks a subpopulation of hematopoietic stem and progenitor cells that resist interferon-γ-mediated differentiation.

Hematopoietic stem and progenitor cells (HSPCs) are responsible for the production of all immune and blood cells in both steady state and emergency settings. The rates at which HSPCs divide and differentiate vary widely in accordance with both cell intrinsic and cell extrinsic factors. However, the kinetics of these events remain poorly understood. In prior work, we determined that the inflammatory cytokine interferon-γ (IFN-γ) induces HSPC division and differentiation. Here, we report that a subset of hematopoietic stem cells (HSCs) that express Fgd5 do not divide or differentiate in response to IFN-γ. This suggests that FGD5 marks a subset of HSCs that remains unperturbed during emergency hematopoiesis and is potentially a mechanism of preservation of the HSC compartment.

Hematopoietic stem and progenitor cells improve survival from sepsis by boosting immunomodulatory cells.

New therapeutic strategies to reduce sepsis-related mortality are urgently needed, as sepsis accounts for one in five deaths worldwide. Since hematopoietic stem and progenitor cells (HSPCs) are responsible for producing blood and immune cells, including in response to immunological stress, we explored their potential for treating sepsis. In a mouse model of Group A Streptococcus (GAS)-induced sepsis, severe immunological stress was associated with significant depletion of bone marrow HSPCs and mortality within approximately 5-7 days. We hypothesized that the inflammatory environment of GAS infection drives rapid HSPC differentiation and depletion that can be rescued by infusion of donor HSPCs. Indeed, infusion of 10,000 naïve HSPCs into GAS-infected mice resulted in rapid myelopoiesis and a 50-60% increase in overall survival. Surprisingly, mice receiving donor HSPCs displayed a similar pathogen load compared to untreated mice. Flow cytometric analysis revealed a significantly increased number of myeloid-derived suppressor cells in HSPC-infused mice, which correlated with reduced inflammatory cytokine levels and restored HSPC levels. These findings suggest that HSPCs play an essential immunomodulatory role that may translate into new therapeutic strategies for sepsis.

Cigarette Smoke Exposure in Mice using a Whole-Body Inhalation System.

Close to 14% of adults in the United States were reported to smoke cigarettes in 2018. The effects of cigarette smoke (CS) on lungs and cardiovascular diseases have been widely studied, however, the impact of CS in other tissues and organs such as blood and bone marrow remain incompletely defined. Finding the appropriate system to study the effects of CS in rodents can be prohibitively expensive and require the purchase of commercially available systems. Thus, we set out to build an affordable, reliable, and versatile system to study the pathologic effects of CS in mice. This whole-body inhalation exposure system (WBIS) set-up mimics the breathing and puffing of cigarettes by alternating exposure to CS and clean air. Here we show that this do-it-yourself (DIY) system induces airway inflammation and lung emphysema in mice after 4-months of cigarette smoke exposure. The effects of whole-body inhalation (WBI) of CS on hematopoietic stem and progenitor cells (HSPCs) in the bone marrow using this apparatus are also shown.

The Role of Interferon-Gamma in Hematopoietic Stem Cell Development, Homeostasis, and Disease.

PURPOSE OF REVIEW: Interferon-gamma (IFN-γ) is a pro-inflammatory cytokine that participates in the regulation of hematopoietic stem cells (HSC) during development and under homeostatic conditions. IFN-γ also plays a key pathogenic role in several diseases that affect hematopoiesis including aplastic anemia, hemophagocytic lymphohistiocytosis, and cirrhosis of the liver. RECENT FINDINGS: Studies have shown that increased IFN-γ negatively affects HSC homeostasis, skewing HSC towards differentiation over self-renewal and eventually causing exhaustion of the HSC compartment. SUMMARY: Here, we explore the mechanisms by which IFN-γ regulates HSC in both normal and pathological conditions. We focus on the role of IFN-γ signaling in HSC fate decisions, and the transcriptional changes it elicits. Elucidating the mechanisms through which IFN-γ regulates HSCs may lead to new therapeutic options to prevent or treat adverse hematologic effects of the many diseases to which IFN-γ contributes.

A Maize Gene Regulatory Network for Phenolic Metabolism.

The translation of the genotype into phenotype, represented for example by the expression of genes encoding enzymes required for the biosynthesis of phytochemicals that are important for interaction of plants with the environment, is largely carried out by transcription factors (TFs) that recognize specific cis-regulatory elements in the genes that they control. TFs and their target genes are organized in gene regulatory networks (GRNs), and thus uncovering GRN architecture presents an important biological challenge necessary to explain gene regulation. Linking TFs to the genes they control, central to understanding GRNs, can be carried out using gene- or TF-centered approaches. In this study, we employed a gene-centered approach utilizing the yeast one-hybrid assay to generate a network of protein-DNA interactions that participate in the transcriptional control of genes involved in the biosynthesis of maize phenolic compounds including general phenylpropanoids, lignins, and flavonoids. We identified 1100 protein-DNA interactions involving 54 phenolic gene promoters and 568 TFs. A set of 11 TFs recognized 10 or more promoters, suggesting a role in coordinating pathway gene expression. The integration of the gene-centered network with information derived from TF-centered approaches provides a foundation for a phenolics GRN characterized by interlaced feed-forward loops that link developmental regulators with biosynthetic genes.