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Cell Regeneration (London, England) Jan 2023Myelopoiesis is the process in which the mature myeloid cells, including monocytes/macrophages and granulocytes, are developed. Irregular myelopoiesis may cause and... (Review)
Review
Myelopoiesis is the process in which the mature myeloid cells, including monocytes/macrophages and granulocytes, are developed. Irregular myelopoiesis may cause and deteriorate a variety of hematopoietic malignancies such as leukemia. Myeloid cells and their precursors are difficult to capture in circulation, let alone observe them in real time. For decades, researchers had to face these difficulties, particularly in in-vivo studies. As a unique animal model, zebrafish possesses numerous advantages like body transparency and convenient genetic manipulation, which is very suitable in myelopoiesis research. Here we review current knowledge on the origin and regulation of myeloid development and how zebrafish models were applied in these studies.
PubMed: 36595106
DOI: 10.1186/s13619-022-00139-2 -
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 -
Experimental Hematology May 2023Immunologic memory is a feature typically ascribed to the adaptive arm of the immune system. However, recent studies have demonstrated that hematopoietic stem cells... (Review)
Review
Immunologic memory is a feature typically ascribed to the adaptive arm of the immune system. However, recent studies have demonstrated that hematopoietic stem cells (HSCs) and innate immune cells such as monocytes and macrophages can gain epigenetic signatures to enhance their response in the context of reinfection. This suggests the presence of long-term memory, a phenomenon referred to as trained immunity. Trained immunity in HSCs can occur via changes in the epigenetic landscape and enhanced chromatin accessibility in lineage-specific genes, as well as through metabolic alterations. These changes can lead to a skewing in lineage bias, particularly enhanced myelopoiesis and the generation of epigenetically modified innate immune cells that provide better protection against pathogens on secondary infection. Here, we summarize recent advancements in trained immunity and epigenetic memory formation in HSCs and self-renewing alveolar macrophages, which was the focus of the Spring 2022 International Society for Experimental Hematology (ISEH) webinar.
Topics: Immunity, Innate; Trained Immunity; Epigenetic Memory; Macrophages; Immunologic Memory
PubMed: 36764598
DOI: 10.1016/j.exphem.2023.02.001 -
Nature Immunology Jan 2022Anemia is a major comorbidity in aging, chronic kidney and inflammatory diseases, and hematologic malignancies. However, the transcriptomic networks governing...
Anemia is a major comorbidity in aging, chronic kidney and inflammatory diseases, and hematologic malignancies. However, the transcriptomic networks governing hematopoietic differentiation in blood cell development remain incompletely defined. Here we report that the atypical kinase RIOK2 (right open reading frame kinase 2) is a master transcription factor (TF) that not only drives erythroid differentiation, but also simultaneously suppresses megakaryopoiesis and myelopoiesis in primary human stem and progenitor cells. Our study reveals the previously uncharacterized winged helix-turn-helix DNA-binding domain and two transactivation domains of RIOK2 that are critical to regulate key hematopoietic TFs GATA1, GATA2, SPI1, RUNX3 and KLF1. This establishes RIOK2 as an integral component of the transcriptional regulatory network governing human hematopoietic differentiation. Importantly, RIOK2 mRNA expression significantly correlates with these TFs and other hematopoietic genes in myelodysplastic syndromes, acute myeloid leukemia and chronic kidney disease. Further investigation of RIOK2-mediated transcriptional pathways should yield therapeutic approaches to correct defective hematopoiesis in hematologic disorders.
Topics: Amino Acid Sequence; Blood Cells; Cell Differentiation; Cell Line, Tumor; Cells, Cultured; Erythropoiesis; Gene Expression Regulation; HEK293 Cells; Hematopoietic Stem Cells; Humans; K562 Cells; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myelopoiesis; Protein Serine-Threonine Kinases; Transcription Factors; Transcription, Genetic
PubMed: 34937919
DOI: 10.1038/s41590-021-01079-w -
Current Osteoporosis Reports Feb 2020We reviewed recent progress on the role of sclerostin (SOST) and its effects on the immune system in order to summarize the current state of knowledge in... (Review)
Review
PURPOSE OF REVIEW
We reviewed recent progress on the role of sclerostin (SOST) and its effects on the immune system in order to summarize the current state of knowledge in osteoimmunology, in regard to hematopoiesis, lymphopoiesis, and inflammation.
RECENT FINDINGS
Changes in sclerostin levels affect distinct niches within the bone marrow that support hematopoietic stem cells and B cell development. Sclerostin's regulation of adipogenesis could also be important for immune cell maintenance with age. Surprisingly, B cell development in the bone marrow is influenced by Sost produced by mesenchymal stem cells and osteoblasts, but not by osteocytes. Additionally, extramedullary hematopoiesis in the spleen and increased pro-inflammatory cytokine levels in the bone marrow are observed in global Sost mice. In addition to changes in bone marrow density, sclerostin depletion affects B lymphopoiesis and myelopoiesis, as well as other changes within the bone marrow cavity that could affect hematopoiesis. It is therefore important to monitor for hematopoietic changes in patients receiving sclerostin-depleting therapies.
Topics: Adaptor Proteins, Signal Transducing; Adipogenesis; Animals; B-Lymphocytes; Bone Marrow; Cytokines; Hematopoiesis; Hematopoiesis, Extramedullary; Hematopoietic Stem Cells; Humans; Lymphopoiesis; Mesenchymal Stem Cells; Mice; Mice, Knockout; Myelopoiesis; Osteoblasts; Osteocytes
PubMed: 31970653
DOI: 10.1007/s11914-020-00563-w -
Frontiers in Immunology 2021The ability to remember a previous encounter with pathogens was long thought to be a key feature of the adaptive immune system enabling the host to mount a faster, more... (Review)
Review
The ability to remember a previous encounter with pathogens was long thought to be a key feature of the adaptive immune system enabling the host to mount a faster, more specific and more effective immune response upon the reencounter, reducing the severity of infectious diseases. Over the last 15 years, an increasing amount of evidence has accumulated showing that the innate immune system also has features of a memory. In contrast to the memory of adaptive immunity, innate immune memory is mediated by restructuration of the active chromatin landscape and imprinted by persisting adaptations of myelopoiesis. While originally described to occur in response to pathogen-associated molecular patterns, recent data indicate that host-derived damage-associated molecular patterns, alarmins, can also induce an innate immune memory. Potentially this is mediated by the same pattern recognition receptors and downstream signaling transduction pathways responsible for pathogen-associated innate immune training. Here, we summarize the available experimental data underlying innate immune memory in response to damage-associated molecular patterns. Further, we expound that trained immunity is a general component of innate immunity and outline several open questions for the rising field of pathogen-independent trained immunity.
Topics: Alarmins; Animals; Humans; Immunity, Innate; Immunologic Memory; Pathogen-Associated Molecular Pattern Molecules
PubMed: 34745089
DOI: 10.3389/fimmu.2021.699563 -
Hematology. American Society of... Dec 2023Leukocytosis is a common finding in pediatric patients, and the differential diagnosis can be broad, including benign reactive leukocytosis and malignant...
Leukocytosis is a common finding in pediatric patients, and the differential diagnosis can be broad, including benign reactive leukocytosis and malignant myeloproliferative disorders. Transient abnormal myelopoiesis is a myeloproliferative disorder that occurs in young infants with constitutional trisomy 21 and somatic GATA1 mutations. Most patients are observed, but outcomes span the spectrum from spontaneous resolution to life-threatening complications. Juvenile myelomonocytic leukemia is a highly aggressive myeloproliferative disorder associated with altered RAS-pathway signaling that occurs in infants and young children. Treatment typically involves hematopoietic stem cell transplantation, but certain patients can be observed. Early recognition of these and other myeloproliferative disorders is important and requires a clinician to be aware of these diagnoses and have a clear understanding of their presentations. This paper discusses the presentation and evaluation of leukocytosis when myeloproliferative disorders are part of the differential and reviews different concepts regarding treatment strategies.
Topics: Infant; Humans; Child; Child, Preschool; Leukemia, Myelomonocytic, Juvenile; Down Syndrome; Leukocytosis; Mutation; Myeloproliferative Disorders
PubMed: 38066851
DOI: 10.1182/hematology.2023000464 -
Clinical Journal of the American... Feb 2022Kidney homeostasis is highly dependent upon the correct functioning of myeloid cells. These cells form a distributed surveillance network throughout the kidney, where... (Review)
Review
Kidney homeostasis is highly dependent upon the correct functioning of myeloid cells. These cells form a distributed surveillance network throughout the kidney, where they play an integral role in the response to organ threat. Dysregulation of resident proinflammatory and profibrotic macrophages leads to kidney structural damage and scarring after kidney injury. Fibrosis throughout the kidney parenchyma contributes to the progressive functional decline observed in CKD, independent of the etiology. Circulating myeloid cells bearing intrinsic defects also affect the kidney substructures, such as neutrophils activated by autoantibodies that cause GN in ANCA-associated vasculitis. The kidney can also be affected by disorders of myelopoiesis, including myeloid leukemias (acute and chronic myeloid leukemias) and myelodysplastic syndromes. Clonal hematopoiesis of indeterminate potential is a common, newly recognized premalignant clinical entity characterized by clonal expansion of hyperinflammatory myeloid lineage cells that may have significant kidney sequelae. A number of existing therapies in CKD target myeloid cells and inflammation, including glucocorticoid receptor agonists and mineralocorticoid receptor antagonists. The therapeutic indications for these and other myeloid cell-targeted treatments is poised to expand as our understanding of the myeloid-kidney interface evolves.
Topics: Humans; Kidney; Kidney Diseases; Myeloid Cells
PubMed: 34507968
DOI: 10.2215/CJN.04120321 -
Frontiers in Cellular and Infection... 2021Periodontitis is a polymicrobial infectious disease characterized by alveolar bone loss. Systemic diseases or local infections, such as diabetes, postmenopausal... (Review)
Review
Periodontitis is a polymicrobial infectious disease characterized by alveolar bone loss. Systemic diseases or local infections, such as diabetes, postmenopausal osteoporosis, obesity, and inflammatory bowel disease, promote the development and progression of periodontitis. Accumulating evidences have revealed the pivotal effects of gut microbiota on bone health gut-alveolar-bone axis. Gut pathogens or metabolites may translocate to distant alveolar bone circulation and regulate bone homeostasis. In addition, gut pathogens can induce aberrant gut immune responses and subsequent homing of immunocytes to distant organs, contributing to pathological bone loss. Gut microbial translocation also enhances systemic inflammation and induces trained myelopoiesis in the bone marrow, which potentially aggravates periodontitis. Furthermore, gut microbiota possibly affects bone health regulating the production of hormone or hormone-like substances. In this review, we discussed the links between gut microbiota and periodontitis, with a particular focus on the underlying mechanisms of gut-bone axis by which systemic diseases or local infections contribute to the pathogenesis of periodontitis.
Topics: Alveolar Bone Loss; Gastrointestinal Microbiome; Humans; Inflammation; Obesity; Periodontitis
PubMed: 34869062
DOI: 10.3389/fcimb.2021.752708 -
Antioxidants & Redox Signaling Jul 2021Neutrophils are potent effector cells of innate immunity requiring precise regulation of their numbers and functions in blood and tissues. Macrophages have emerged as... (Review)
Review
Neutrophils are potent effector cells of innate immunity requiring precise regulation of their numbers and functions in blood and tissues. Macrophages have emerged as modulators of neutrophil properties. In inflammatory conditions, tissue macrophages modulate neutrophil trafficking and activation. Further, macrophages govern granulopoiesis in the bone marrow hematopoietic niche. Interactions of macrophages and neutrophils can be induced by cytokines and damage-associated molecular patterns, and they are also regulated by oxidative signaling. We review the impact of macrophages on neutrophil development and function, and its consequences in health and disease. Targeting the liaison between macrophages and neutrophils might provide an interesting therapeutic strategy to reduce tissue inflammation and promote immune tolerance. . 35, 182-191.
Topics: Animals; Bone Marrow; Cell Communication; Cell Differentiation; Cytokines; Hematopoietic Stem Cells; Homeostasis; Humans; Immunity, Innate; Inflammation Mediators; Macrophages; Myelopoiesis; Neutrophils; Oxidation-Reduction; Phagocytosis; Signal Transduction; Stem Cell Niche
PubMed: 33107319
DOI: 10.1089/ars.2020.8203