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Cell Oct 2020A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic...
A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis (Mtb). We have shown that systemic administration of Bacille Calmette-Guérin (BCG) or β-glucan reprograms HSCs in the bone marrow (BM) via a type II interferon (IFN-II) or interleukin-1 (IL1) response, respectively, which confers protective trained immunity against Mtb. Here, we demonstrate that, unlike BCG or β-glucan, Mtb reprograms HSCs via an IFN-I response that suppresses myelopoiesis and impairs development of protective trained immunity to Mtb. Mechanistically, IFN-I signaling dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death specifically in myeloid progenitors. Additionally, activation of the IFN-I/iron axis in HSCs impairs trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the BM that controls the magnitude and intrinsic anti-microbial capacity of innate immunity to infection.
Topics: Animals; Bone Marrow Cells; Cell Proliferation; Disease Susceptibility; Hematopoietic Stem Cells; Homeostasis; Immunity; Interferon Type I; Iron; Kinetics; Lung; Macrophages; Mice, Inbred C57BL; Mycobacterium tuberculosis; Myeloid Cells; Myelopoiesis; Necrosis; Signal Transduction; Transcription, Genetic; Tuberculosis
PubMed: 33125891
DOI: 10.1016/j.cell.2020.09.062 -
Immunity Aug 2020Granulocyte-monocyte progenitors (GMPs) have been previously defined for their potential to generate various myeloid progenies such as neutrophils and monocytes....
Granulocyte-monocyte progenitors (GMPs) have been previously defined for their potential to generate various myeloid progenies such as neutrophils and monocytes. Although studies have proposed lineage heterogeneity within GMPs, it is unclear if committed progenitors already exist among these progenitors and how they may behave differently during inflammation. By combining single-cell transcriptomic and proteomic analyses, we identified the early committed progenitor within the GMPs responsible for the strict production of neutrophils, which we designate as proNeu1. Our dissection of the GMP hierarchy led us to further identify a previously unknown intermediate proNeu2 population. Similar populations could be detected in human samples. proNeu1s, but not proNeu2s, selectively expanded during the early phase of sepsis at the expense of monocytes. Collectively, our findings help shape the neutrophil maturation trajectory roadmap and challenge the current definition of GMPs.
Topics: Animals; Granulocyte Precursor Cells; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Myelopoiesis; Neutrophils; Single-Cell Analysis
PubMed: 32579887
DOI: 10.1016/j.immuni.2020.06.005 -
Cell Stem Cell May 2023Remote tumors disrupt the bone marrow (BM) ecosystem (BME), eliciting the overproduction of BM-derived immunosuppressive cells. However, the underlying mechanisms remain...
Remote tumors disrupt the bone marrow (BM) ecosystem (BME), eliciting the overproduction of BM-derived immunosuppressive cells. However, the underlying mechanisms remain poorly understood. Herein, we characterized breast and lung cancer-induced BME shifts pre- and post-tumor removal. Remote tumors progressively lead to osteoprogenitor (OP) expansion, hematopoietic stem cell dislocation, and CD41 granulocyte-monocyte progenitor (GMP) aggregation. The tumor-entrained BME is characterized by co-localization between CD41 GMPs and OPs. OP ablation abolishes this effect and diminishes abnormal myeloid overproduction. Mechanistically, HTRA1 carried by tumor-derived small extracellular vesicles upregulates MMP-13 in OPs, which in turn induces the alterations in the hematopoietic program. Importantly, these effects persist post-surgery and continue to impair anti-tumor immunity. Conditional knockout or inhibition of MMP-13 accelerates immune reinstatement and restores the efficacies of immunotherapies. Therefore, tumor-induced systemic effects are initiated by OP-GMP crosstalk that outlasts tumor burden, and additional treatment is required to reverse these effects for optimal therapeutic efficacy.
Topics: Humans; Matrix Metalloproteinase 13; Ecosystem; Myelopoiesis; Hematopoietic Stem Cells; Neoplasms; Immunosuppression Therapy; High-Temperature Requirement A Serine Peptidase 1
PubMed: 37146584
DOI: 10.1016/j.stem.2023.04.005 -
Acta Haematologica 2019Diagnosis and classification of acute myeloid leukaemia (AML) require cytogenetic and molecular genetic investigation. However, while these evaluations are pending,... (Review)
Review
Diagnosis and classification of acute myeloid leukaemia (AML) require cytogenetic and molecular genetic investigation. However, while these evaluations are pending, morphology supplemented by immunophenotyping can provide clues to the diagnosis of specific cytogenetic/genetic categories of AML. Most importantly, acute promyelocytic leukaemia can be diagnosed with a high degree of certainty. However, provisional identification of cases associated with t(8; 21), inv(16), t(1; 22), and NPM1 mutation may also be possible. In addition, transient abnormal myelopoiesis of Down's syndrome can generally be diagnosed morphologically.
Topics: Chromosome Inversion; Chromosomes, Human; Down Syndrome; Humans; Leukemia, Promyelocytic, Acute; Myelopoiesis; Neoplasm Proteins; Nuclear Proteins; Nucleophosmin; Translocation, Genetic; World Health Organization
PubMed: 30965338
DOI: 10.1159/000496097 -
Developmental and Comparative Immunology Sep 2023Macrophage-lineage cells are indispensable to immunity and physiology of all vertebrates. Amongst these, amphibians represent a key stage in vertebrate evolution and are... (Review)
Review
Macrophage-lineage cells are indispensable to immunity and physiology of all vertebrates. Amongst these, amphibians represent a key stage in vertebrate evolution and are facing decimating population declines and extinctions, in large part due to emerging infectious agents. While recent studies indicate that macrophages and related innate immune cells are critically involved during these infections, much remains unknown regarding the ontogeny and functional differentiation of these cell types in amphibians. Accordingly, in this review we coalesce what has been established to date about amphibian blood cell development (hematopoiesis), the development of key amphibian innate immune cells (myelopoiesis) and the differentiation of amphibian macrophage subsets (monopoiesis). We explore the current understanding of designated sites of larval and adult hematopoiesis across distinct amphibian species and consider what mechanisms may lend to these species-specific adaptations. We discern the identified molecular mechanisms governing the functional differentiation of disparate amphibian (chiefly Xenopus laevis) macrophage subsets and describe what is known about the roles of these subsets during amphibian infections with intracellular pathogens. Macrophage lineage cells are at the heart of so many vertebrate physiological processes. Thus, garnering greater understanding of the mechanisms responsible for the ontogeny and functionality of these cells in amphibians will lend to a more comprehensive view of vertebrate evolution.
Topics: Animals; Myelopoiesis; Amphibians; Macrophages; Cell Differentiation; Hematopoiesis; Xenopus laevis
PubMed: 37196852
DOI: 10.1016/j.dci.2023.104701 -
Cell Mar 2024Neonates are highly susceptible to inflammation and infection. Here, we investigate how late fetal liver (FL) mouse hematopoietic stem and progenitor cells (HSPCs)...
Neonates are highly susceptible to inflammation and infection. Here, we investigate how late fetal liver (FL) mouse hematopoietic stem and progenitor cells (HSPCs) respond to inflammation, testing the hypothesis that deficits in the engagement of emergency myelopoiesis (EM) pathways limit neutrophil output and contribute to perinatal neutropenia. We show that fetal HSPCs have limited production of myeloid cells at steady state and fail to activate a classical adult-like EM transcriptional program. Moreover, we find that fetal HSPCs can respond to EM-inducing inflammatory stimuli in vitro but are restricted by maternal anti-inflammatory factors, primarily interleukin-10 (IL-10), from activating EM pathways in utero. Accordingly, we demonstrate that the loss of maternal IL-10 restores EM activation in fetal HSPCs but at the cost of fetal demise. These results reveal the evolutionary trade-off inherent in maternal anti-inflammatory responses that maintain pregnancy but render the fetus unresponsive to EM activation signals and susceptible to infection.
Topics: Animals; Mice; Pregnancy; Fetus; Hematopoiesis; Hematopoietic Stem Cells; Inflammation; Interleukin-10; Myelopoiesis; Animals, Newborn; Female
PubMed: 38428422
DOI: 10.1016/j.cell.2024.02.002 -
Cell Stem Cell May 2020Hematopoietic stem cells (HSCs) maintain life-long production of immune cells and can directly respond to infection, but sustained effects on the immune response remain...
Hematopoietic stem cells (HSCs) maintain life-long production of immune cells and can directly respond to infection, but sustained effects on the immune response remain unclear. We show that acute immune stimulation with lipopolysaccharide (LPS) induced only transient changes in HSC abundance, composition, progeny, and gene expression, but persistent alterations in accessibility of specific myeloid lineage enhancers occurred, which increased responsiveness of associated immune genes to secondary stimulation. Functionally, this was associated with increased myelopoiesis of pre-exposed HSCs and improved innate immunity against the gram-negative bacterium P. aeruginosa. The accessible myeloid enhancers were enriched for C/EBPβ targets, and C/EBPβ deletion erased the long-term inscription of LPS-induced epigenetic marks and gene expression. Thus, short-term immune signaling can induce C/EBPβ-dependent chromatin accessibility, resulting in HSC-trained immunity, during secondary infection. This establishes a mechanism for how infection history can be epigenetically inscribed in HSCs as an integral memory function of innate immunity.
Topics: CCAAT-Enhancer-Binding Protein-beta; Epigenesis, Genetic; Epigenomics; Hematopoietic Stem Cells; Humans; Immunity, Innate; Myelopoiesis
PubMed: 32169166
DOI: 10.1016/j.stem.2020.01.017 -
Nature Feb 2021In contrast to nearly all other tissues, the anatomy of cell differentiation in the bone marrow remains unknown. This is owing to a lack of strategies for examining...
In contrast to nearly all other tissues, the anatomy of cell differentiation in the bone marrow remains unknown. This is owing to a lack of strategies for examining myelopoiesis-the differentiation of myeloid progenitors into a large variety of innate immune cells-in situ in the bone marrow. Such strategies are required to understand differentiation and lineage-commitment decisions, and to define how spatial organizing cues inform tissue function. Here we develop approaches for imaging myelopoiesis in mice, and generate atlases showing the differentiation of granulocytes, monocytes and dendritic cells. The generation of granulocytes and dendritic cells-monocytes localizes to different blood-vessel structures known as sinusoids, and displays lineage-specific spatial and clonal architectures. Acute systemic infection with Listeria monocytogenes induces lineage-specific progenitor clusters to undergo increased self-renewal of progenitors, but the different lineages remain spatially separated. Monocyte-dendritic cell progenitors (MDPs) map with nonclassical monocytes and conventional dendritic cells; these localize to a subset of blood vessels expressing a major regulator of myelopoiesis, colony-stimulating factor 1 (CSF1, also known as M-CSF). Specific deletion of Csf1 in endothelium disrupts the architecture around MDPs and their localization to sinusoids. Subsequently, there are fewer MDPs and their ability to differentiate is reduced, leading to a loss of nonclassical monocytes and dendritic cells during both homeostasis and infection. These data indicate that local cues produced by distinct blood vessels are responsible for the spatial organization of definitive blood cell differentiation.
Topics: Animals; Atlases as Topic; Blood Vessels; Cell Lineage; Cell Self Renewal; Cell Tracking; Dendritic Cells; Endothelium, Vascular; Female; Granulocytes; Listeria monocytogenes; Listeriosis; Macrophage Colony-Stimulating Factor; Male; Mice; Monocytes; Myeloid Cells; Myelopoiesis; Staining and Labeling
PubMed: 33568812
DOI: 10.1038/s41586-021-03201-2 -
Nature Immunology Oct 2022Traditionally viewed as poorly plastic, neutrophils are now recognized as functionally diverse; however, the extent and determinants of neutrophil heterogeneity in...
Traditionally viewed as poorly plastic, neutrophils are now recognized as functionally diverse; however, the extent and determinants of neutrophil heterogeneity in humans remain unclear. We performed a comprehensive immunophenotypic and transcriptome analysis, at a bulk and single-cell level, of neutrophils from healthy donors and patients undergoing stress myelopoiesis upon exposure to growth factors, transplantation of hematopoietic stem cells (HSC-T), development of pancreatic cancer and viral infection. We uncover an extreme diversity of human neutrophils in vivo, reflecting the rates of cell mobilization, differentiation and exposure to environmental signals. Integrated control of developmental and inducible transcriptional programs linked flexible granulopoietic outputs with elicitation of stimulus-specific functional responses. In this context, we detected an acute interferon (IFN) response in the blood of patients receiving HSC-T that was mirrored by marked upregulation of IFN-stimulated genes in neutrophils but not in monocytes. Systematic characterization of human neutrophil plasticity may uncover clinically relevant biomarkers and support the development of diagnostic and therapeutic tools.
Topics: Biomarkers; Humans; Interferons; Myelopoiesis; Neutrophils; Plastics
PubMed: 36138183
DOI: 10.1038/s41590-022-01311-1 -
Signal Transduction and Targeted Therapy Jul 2023Traumatic brain injury (TBI) accelerates fracture healing, but the underlying mechanism remains largely unknown. Accumulating evidence indicates that the central nervous...
Traumatic brain injury (TBI) accelerates fracture healing, but the underlying mechanism remains largely unknown. Accumulating evidence indicates that the central nervous system (CNS) plays a pivotal role in regulating immune system and skeletal homeostasis. However, the impact of CNS injury on hematopoiesis commitment was overlooked. Here, we found that the dramatically elevated sympathetic tone accompanied with TBI-accelerated fracture healing; chemical sympathectomy blocks TBI-induced fracture healing. TBI-induced hypersensitivity of adrenergic signaling promotes the proliferation of bone marrow hematopoietic stem cells (HSCs) and swiftly skews HSCs toward anti-inflammation myeloid cells within 14 days, which favor fracture healing. Knockout of β3- or β2-adrenergic receptor (AR) eliminate TBI-mediated anti-inflammation macrophage expansion and TBI-accelerated fracture healing. RNA sequencing of bone marrow cells revealed that Adrb2 and Adrb3 maintain proliferation and commitment of immune cells. Importantly, flow cytometry confirmed that deletion of β2-AR inhibits M2 polarization of macrophages at 7th day and 14th day; and TBI-induced HSCs proliferation was impaired in β3-AR knockout mice. Moreover, β3- and β2-AR agonists synergistically promote infiltration of M2 macrophages in callus and accelerate bone healing process. Thus, we conclude that TBI accelerates bone formation during early stage of fracture healing process by shaping the anti-inflammation environment in the bone marrow. These results implicate that the adrenergic signals could serve as potential targets for fracture management.
Topics: Mice; Animals; Fracture Healing; Bone Marrow; Myelopoiesis; Mice, Knockout; Brain Injuries, Traumatic; Adrenergic Agents
PubMed: 37402714
DOI: 10.1038/s41392-023-01457-w