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Nature Genetics Oct 2016We define the chromatin accessibility and transcriptional landscapes in 13 human primary blood cell types that span the hematopoietic hierarchy. Exploiting the finding...
We define the chromatin accessibility and transcriptional landscapes in 13 human primary blood cell types that span the hematopoietic hierarchy. Exploiting the finding that the enhancer landscape better reflects cell identity than mRNA levels, we enable 'enhancer cytometry' for enumeration of pure cell types from complex populations. We identify regulators governing hematopoietic differentiation and further show the lineage ontogeny of genetic elements linked to diverse human diseases. In acute myeloid leukemia (AML), chromatin accessibility uncovers unique regulatory evolution in cancer cells with a progressively increasing mutation burden. Single AML cells exhibit distinctive mixed regulome profiles corresponding to disparate developmental stages. A method to account for this regulatory heterogeneity identified cancer-specific deviations and implicated HOX factors as key regulators of preleukemic hematopoietic stem cell characteristics. Thus, regulome dynamics can provide diverse insights into hematopoietic development and disease.
Topics: Cell Lineage; Chromatin; Clone Cells; Enhancer Elements, Genetic; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Hematopoiesis; Humans; Leukemia, Myeloid, Acute; Myelopoiesis; Regulatory Sequences, Nucleic Acid; Sequence Analysis, DNA; Tumor Cells, Cultured
PubMed: 27526324
DOI: 10.1038/ng.3646 -
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 -
Mitochondrial pyruvate metabolism and glutaminolysis toggle steady-state and emergency myelopoiesis.The Journal of Experimental Medicine Sep 2023To define the metabolic requirements of hematopoiesis, we examined blood lineages in mice conditionally deficient in genes required for long-chain fatty acid oxidation...
To define the metabolic requirements of hematopoiesis, we examined blood lineages in mice conditionally deficient in genes required for long-chain fatty acid oxidation (Cpt2), glutaminolysis (Gls), or mitochondrial pyruvate import (Mpc2). Genetic ablation of Cpt2 or Gls minimally impacted most blood lineages. In contrast, deletion of Mpc2 led to a sharp decline in mature myeloid cells and a slower reduction in T cells, whereas other hematopoietic lineages were unaffected. Yet MPC2-deficient monocytes and neutrophils rapidly recovered due to a transient and specific increase in myeloid progenitor proliferation. Competitive bone marrow chimera and stable isotope tracing experiments demonstrated that this proliferative burst was progenitor intrinsic and accompanied by a metabolic switch to glutaminolysis. Myeloid recovery after loss of MPC2 or cyclophosphamide treatment was delayed in the absence of GLS. Reciprocally, MPC2 was not required for myeloid recovery after cyclophosphamide treatment. Thus, mitochondrial pyruvate metabolism maintains myelopoiesis under steady-state conditions, while glutaminolysis in progenitors promotes emergency myelopoiesis.
Topics: Mice; Animals; Myelopoiesis; Hematopoiesis; Bone Marrow; Cyclophosphamide; Pyruvates
PubMed: 37249600
DOI: 10.1084/jem.20221373 -
Cell Reports Mar 2023Inflammatory stimuli cause a state of emergency myelopoiesis leading to neutrophil-like monocyte expansion. However, their function, the committed precursors, or growth...
Inflammatory stimuli cause a state of emergency myelopoiesis leading to neutrophil-like monocyte expansion. However, their function, the committed precursors, or growth factors remain elusive. In this study we find that Ym1Ly6C monocytes, an immunoregulatory entity of neutrophil-like monocytes, arise from progenitors of neutrophil 1 (proNeu1). Granulocyte-colony stimulating factor (G-CSF) favors the production of neutrophil-like monocytes through previously unknown CD81CX3CR1 monocyte precursors. GFI1 promotes the differentiation of proNeu2 from proNeu1 at the cost of producing neutrophil-like monocytes. The human counterpart of neutrophil-like monocytes that also expands in response to G-CSF is found in CD14CD16 monocyte fraction. The human neutrophil-like monocytes are discriminated from CD14CD16 classical monocytes by CXCR1 expression and the capacity to suppress T cell proliferation. Collectively, our findings suggest that the aberrant expansion of neutrophil-like monocytes under inflammatory conditions is a process conserved between mouse and human, which may be beneficial for the resolution of inflammation.
Topics: Mice; Animals; Humans; Monocytes; Neutrophils; Myelopoiesis; Cell Differentiation; Granulocyte Colony-Stimulating Factor
PubMed: 36862552
DOI: 10.1016/j.celrep.2023.112165 -
Cells Dec 2020Fibronectin is a ubiquitous extracellular matrix protein that is produced by many cell types in the bone marrow and distributed throughout it. Cells of the stem cell... (Review)
Review
Fibronectin is a ubiquitous extracellular matrix protein that is produced by many cell types in the bone marrow and distributed throughout it. Cells of the stem cell niche produce the various isoforms of this protein. Fibronectin not only provides the cells a scaffold to bind to, but it also modulates their behavior by binding to receptors on the adjacent hematopoietic stem cells and stromal cells. These receptors, which include integrins such as α4β1, α9β1, α4β7, α5β1, αvβ3, Toll-like receptor-4 (TLR-4), and CD44, are found on the hematopoietic stem cell. Because the knockout of fibronectin is lethal during embryonal development and because fibronectin is produced by almost all cell types in mammals, the study of its role in hematopoiesis is difficult. Nevertheless, strong and direct evidence exists for its stimulation of myelopoiesis and thrombopoiesis using in vivo models. Other reviewed effects can be deduced from the study of fibronectin receptors, which showed their activation modifies the behavior of hematopoietic stem cells. Erythropoiesis was only stimulated under hemolytic stress, and mostly late stages of lymphocytic differentiation were modulated. Because fibronectin is ubiquitously expressed, these interactions in health and disease need to be taken into account whenever any molecule is evaluated in hematopoiesis.
Topics: Animals; Cell Differentiation; Cell Movement; Cell Proliferation; Erythropoiesis; Fibronectins; Hematopoiesis; Hematopoietic Stem Cells; Hemolysis; Humans; Hyaluronan Receptors; Integrins; Mice; Myelopoiesis; Receptors, Fibronectin; Stem Cell Niche; Stem Cells; Thrombopoiesis; Toll-Like Receptor 4
PubMed: 33353083
DOI: 10.3390/cells9122717 -
CCR1 and CCR5 mediate cancer-induced myelopoiesis and differentiation of myeloid cells in the tumor.Journal For Immunotherapy of Cancer Jan 2022Cancer-induced 'emergency' myelopoiesis plays a key role in tumor progression by inducing the accumulation of myeloid cells with a suppressive phenotype peripherally and...
BACKGROUND
Cancer-induced 'emergency' myelopoiesis plays a key role in tumor progression by inducing the accumulation of myeloid cells with a suppressive phenotype peripherally and in the tumor. Chemokine receptors (CCRs) and, in particular, CCR1, CCR2, CCR5, and CCR7 are emerging as key regulators of myeloid cell trafficking and function but their precise role has not been completely clarified yet because of the signal redundancy, integration, and promiscuity of chemokines and of the expression of these CCRs on other leukocyte subsets.
METHODS
We used the 4PD nanoparticle for the in vivo targeted silencing of CCR1, CCR2, CCR5, and/or CCR7 in the myeloid cells of tumor bearing mice to evaluate the effect of treatments on tumor growth, myeloid cell trafficking and polarization. We used flow and image cytometry and functional assays to monitor changes in the tumor microenvironment and depletion experiments and immune deficient mice to determine the role of Ly6Gcells during tumor progression. We further evaluated in vitro the impact of chemokine receptor inhibition and tumor derived factors on myeloid cell differentiation from mouse and human hematopoietic stem and precursors cells (HSPCs) using flow cytometry, transcriptome analysis, cytokines beads arrays, functional assays, and mice deficient for CCR1 or CCR5.
RESULTS
4PD-mediated in vivo silencing of CCR1 and CCR5 on myeloid cells and myeloid precursors was necessary and sufficient to inhibit tumor progression. Functional studies indicated that this antitumor effect was not mediated by alteration of myeloid cell chemotaxes but rather by the repolarization of polymorphonuclear myeloid-derived suppressor cells (MDSCs) into tumoricidal neutrophils. Transcriptome functional and cytokine analysis indicated that tumor derived factors induced CCL3 and CCL4 in HSPCs that, through the autocrine engagement of CCR1 and CCR5, induced HSPCs differentiation in MDSCs. These finding were confirmed across mice with different genetic backgrounds and using HSPCs from umbilical cord blood and peripheral blood of patients with cancer.
CONCLUSIONS
Our data support the notion that CCR1 and CCR5 and their ligands are a master immunological hub activated by several tumor derived factors. Activation of this pathway is necessary for the differentiation of MDSCs and protumoral macrophages.
Topics: Animals; Cell Differentiation; Humans; Immunomodulation; Mice; Myeloid-Derived Suppressor Cells; Myelopoiesis; Nanoparticles; Receptors, CCR1; Receptors, CCR5; Tumor Microenvironment
PubMed: 35064009
DOI: 10.1136/jitc-2021-003131 -
European Heart Journal Apr 2016Atherosclerosis, the major underlying cause of cardiovascular disease, is characterized by a lipid-driven infiltration of inflammatory cells in large and medium... (Review)
Review
Atherosclerosis, the major underlying cause of cardiovascular disease, is characterized by a lipid-driven infiltration of inflammatory cells in large and medium arteries. Increased production and activation of monocytes, neutrophils, and platelets, driven by hypercholesterolaemia and defective high-density lipoproteins-mediated cholesterol efflux, tissue necrosis and cytokine production after myocardial infarction, or metabolic abnormalities associated with diabetes, contribute to atherogenesis and athero-thrombosis. This suggests that in addition to traditional approaches of low-density lipoproteins lowering and anti-platelet drugs, therapies directed at abnormal haematopoiesis, including anti-inflammatory agents, drugs that suppress myelopoiesis, and excessive platelet production, rHDL infusions and anti-obesity and anti-diabetic agents, may help to prevent athero-thrombosis.
Topics: Atherosclerosis; Blood Platelets; Cholesterol; Hematopoiesis; Hematopoiesis, Extramedullary; Hematopoietic Stem Cells; Humans; Leukocytosis; Metabolic Diseases; Monocytes; Myelopoiesis; Myeloproliferative Disorders; Neutrophils; Risk Factors; Thrombopoiesis; Thrombosis
PubMed: 26869607
DOI: 10.1093/eurheartj/ehv718 -
Immunity Feb 2019Myelopoiesis ensures the steady state of the myeloid cell compartment. Technological advances in fate mapping and genetic engineering, as well as the advent of single... (Review)
Review
Myelopoiesis ensures the steady state of the myeloid cell compartment. Technological advances in fate mapping and genetic engineering, as well as the advent of single cell RNA-sequencing, have highlighted the heterogeneity of the hematopoietic system and revealed new concepts in myeloid cell ontogeny. These technologies are also shedding light on mechanisms of myelopoiesis at homeostasis and at different phases of infection and inflammation, illustrating important feedback loops between affected tissues and the bone marrow. We review these findings here and revisit principles in myelopoiesis in light of the evolving understanding of myeloid cell ontogeny and heterogeneity. We argue for the importance of system-wide evaluation of changes in myelopoiesis and discuss how even after the resolution of inflammation, long-lasting alterations in myelopoiesis may play a role in innate immune memory or trained immunity.
Topics: Animals; Bone Marrow; Homeostasis; Humans; Immunity, Innate; Infections; Inflammation; Models, Immunological; Myeloid Cells; Myeloid Progenitor Cells; Myelopoiesis
PubMed: 30784577
DOI: 10.1016/j.immuni.2019.01.019 -
Proceedings of the National Academy of... Oct 2021Trained immunity defines long-lasting adaptations of innate immunity based on transcriptional and epigenetic modifications of myeloid cells and their bone marrow...
Trained immunity defines long-lasting adaptations of innate immunity based on transcriptional and epigenetic modifications of myeloid cells and their bone marrow progenitors [M. Divangahi et al., 22, 2-6 (2021)]. Innate immune cells, however, do not exclusively differentiate between foreign and self but also react to host-derived molecules referred to as alarmins. Extracellular "labile" heme, released during infections, is a bona fide alarmin promoting myeloid cell activation [M. P. Soares, M. T. Bozza, 38, 94-100 (2016)]. Here, we report that labile heme is a previously unrecognized inducer of trained immunity that confers long-term regulation of lineage specification of hematopoietic stem cells and progenitor cells. In contrast to previous reports on trained immunity, essentially mediated by pathogen-associated molecular patterns, heme training depends on spleen tyrosine kinase signal transduction pathway acting upstream of c-Jun N-terminal kinases. Heme training promotes resistance to sepsis, is associated with the expansion of self-renewing hematopoetic stem cells primed toward myelopoiesis and to the occurrence of a specific myeloid cell population. This is potentially evoked by sustained activity of Nfix, Runx1, and Nfe2l2 and dissociation of the transcriptional repressor Bach2. Previously reported trained immunity inducers are, however, infrequently present in the host, whereas heme abundantly occurs during noninfectious and infectious disease. This difference might explain the vanishing protection exerted by heme training in sepsis over time with sustained long-term myeloid adaptations. Hence, we propose that trained immunity is an integral component of innate immunity with distinct functional differences on infectious disease outcome depending on its induction by pathogenic or endogenous molecules.
Topics: Animals; Epigenesis, Genetic; Heme; Humans; Immunity, Innate; Mice; Myelopoiesis
PubMed: 34663697
DOI: 10.1073/pnas.2102698118 -
Current Opinion in Lipidology Oct 2019Monocytes and macrophages are key players in the pathogenesis of atherosclerosis and dictate atherogenesis growth and stability. The heterogeneous nature of myeloid... (Review)
Review
PURPOSE OF REVIEW
Monocytes and macrophages are key players in the pathogenesis of atherosclerosis and dictate atherogenesis growth and stability. The heterogeneous nature of myeloid cells concerning their metabolic and phenotypic function is increasingly appreciated. This review summarizes the recent monocyte and macrophage literature and highlights how differing subsets contribute to atherogenesis.
RECENT FINDINGS
Monocytes are short-lived cells generated in the bone marrow and released to circulation where they can produce inflammatory cytokines and, importantly, differentiate into long-lived macrophages. In the context of cardiovascular disease, a myriad of subtypes, exist with each differentially contributing to plaque development. Herein we describe recent novel characterizations of monocyte and macrophage subtypes and summarize the recent literature on mediators of myelopoiesis.
SUMMARY
An increased understanding of monocyte and macrophage phenotype and their molecular regulators is likely to translate to the development of new therapeutic targets to either stem the growth of existing plaques or promote plaque stabilization.
Topics: Atherosclerosis; Bone Marrow Cells; Cell Differentiation; Cytokines; Humans; Macrophages; Monocytes; Myelopoiesis; Plaque, Atherosclerotic
PubMed: 31361625
DOI: 10.1097/MOL.0000000000000634