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ELife Jun 2023Polycomb repressive complex (PRC) 1 regulates stem cell fate by mediating mono-ubiquitination of histone H2A at lysine 119. While canonical PRC1 is critical for...
Polycomb repressive complex (PRC) 1 regulates stem cell fate by mediating mono-ubiquitination of histone H2A at lysine 119. While canonical PRC1 is critical for hematopoietic stem and progenitor cell (HSPC) maintenance, the role of non-canonical PRC1 in hematopoiesis remains elusive. PRC1.1, a non-canonical PRC1, consists of PCGF1, RING1B, KDM2B, and BCOR. We recently showed that PRC1.1 insufficiency induced by the loss of PCGF1 or BCOR causes myeloid-biased hematopoiesis and promotes transformation of hematopoietic cells in mice. Here we show that PRC1.1 serves as an epigenetic switch that coordinates homeostatic and emergency hematopoiesis. PRC1.1 maintains balanced output of steady-state hematopoiesis by restricting C/EBPα-dependent precocious myeloid differentiation of HSPCs and the HOXA9- and β-catenin-driven self-renewing network in myeloid progenitors. Upon regeneration, PRC1.1 is transiently inhibited to facilitate formation of granulocyte-macrophage progenitor (GMP) clusters, thereby promoting emergency myelopoiesis. Moreover, constitutive inactivation of PRC1.1 results in unchecked expansion of GMPs and eventual transformation. Collectively, our results define PRC1.1 as a novel critical regulator of emergency myelopoiesis, dysregulation of which leads to myeloid transformation.
Topics: Animals; Mice; Polycomb Repressive Complex 1; Myelopoiesis; Histones; Cell Differentiation; Hematopoietic Stem Cells
PubMed: 37266576
DOI: 10.7554/eLife.83004 -
Trends in Molecular Medicine May 2019In contrast to traditional immune cell-centered viewpoints, recent studies suggest that tissues are not passive recipients of immunity but have a 'regulatory say' over... (Review)
Review
In contrast to traditional immune cell-centered viewpoints, recent studies suggest that tissues are not passive recipients of immunity but have a 'regulatory say' over the host inflammatory response. Identification of tissue-derived homeostatic molecules regulating immune plasticity is seminal for understanding the inherent regulatory potential of different organs in the immune response. DEL-1 (developmental endothelial locus-1) is a secreted multidomain protein interacting with integrins and phospholipids and regulates, depending on its expression location, distinct stages of the host inflammatory response (from myelopoiesis over leukocyte recruitment to efferocytosis and resolution of inflammation). Here we synthesize recent evidence of DEL-1 as an exemplar local regulatory factor in the context of tissue immune plasticity and inflammatory disorders (such as periodontitis, multiple sclerosis, and pulmonary disorders), and discuss its potential as a therapeutic agent.
Topics: Animals; Calcium-Binding Proteins; Cell Adhesion Molecules; Cell Plasticity; Chemotaxis, Leukocyte; Disease Susceptibility; Homeostasis; Humans; Immunomodulation; Inflammation; Myelopoiesis; Neutrophils; Organ Specificity; Phagocytosis; Protein Binding; Signal Transduction; Structure-Activity Relationship
PubMed: 30885428
DOI: 10.1016/j.molmed.2019.02.010 -
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 -
Journal of Leukocyte Biology Nov 2016The gut microbiota is a complex and dynamic microbial ecosystem that plays a fundamental role in host physiology. Locally, the gut commensal microbes/host symbiotic... (Review)
Review
The gut microbiota is a complex and dynamic microbial ecosystem that plays a fundamental role in host physiology. Locally, the gut commensal microbes/host symbiotic relationship is vital for barrier fortification, nutrient absorption, resistance against intestinal pathogens, and the development and maintenance of the mucosal immune system. It is now clear that the effects of the indigenous intestinal flora extend beyond the gut, ranging from shaping systemic immune responses to metabolic and behavioral functions. However, the underlying mechanisms of the gut microbiota/systemic immune system interactions remain largely unknown. Myeloid cells respond to microbial signals, including those derived from commensals, and initiate innate and adaptive immune responses. In this review, we focus on the impact of the gut microbiota on myeloid cells at extraintestinal sites. In particular, we discuss how commensal-derived signals affect steady-state myelopoiesis and cellular function and how that influences the response to infection and cancer therapy.
Topics: Adaptive Immunity; Animals; Cytokines; Dysbiosis; Gastrointestinal Microbiome; Homeostasis; Humans; Immunity, Innate; Infections; Inflammation; Models, Immunological; Myeloid Cells; Myelopoiesis; Neoplasms; Neutrophils; Symbiosis; Vaccine Potency
PubMed: 27605211
DOI: 10.1189/jlb.3RI0516-222R -
Current Opinion in Hematology Jan 2018The purpose of this review is to describe recent findings in the context of previous work regarding dysregulated myelopoiesis and hematopoietic function following an... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to describe recent findings in the context of previous work regarding dysregulated myelopoiesis and hematopoietic function following an acute physiologic insult, focusing on the expansion and persistence of myeloid-deriver suppressor cells, the deterioration of lymphocyte number and function, and the inadequacy of stress erythropoiesis.
RECENT FINDINGS
Persistent myeloid-derived suppressor cell (MDSC) expansion among critically ill septic patients is associated with T-cell suppression, vulnerability to nosocomial infection, chronic critical illness, and poor long-term functional status. Multiple approaches targeting MDSC expansion and suppressor cell activity may serve as a primary or adjunctive therapeutic intervention. Traumatic injury and the neuroendocrine stress response suppress bone marrow erythropoietin receptor expression in a process that may be reversed by nonselective beta-adrenergic receptor blockade. Hepcidin-mediated iron-restricted anemia of critical illness requires further investigation of novel approaches involving erythropoiesis-stimulating agents, iron administration, and hepcidin modulation.
SUMMARY
Emergency myelopoiesis is a dynamic process with unique phenotypes for different physiologic insults and host factors. Following an acute physiologic insult, critically ill patients are subject to persistent MDSC expansion, deterioration of lymphocyte number and function, and inadequate stress erythropoiesis. Better strategies are required to identify patients who are most likely to benefit from targeted therapies.
Topics: Animals; Hematopoiesis; Humans; Lymphocytes; Myelopoiesis
PubMed: 29035909
DOI: 10.1097/MOH.0000000000000395 -
Pharmacological Research Jul 2021Recruitment of innate immune cells and their accumulation in the arterial wall and infarcted myocardium has been recognized as a central feature of atherosclerosis and... (Review)
Review
Recruitment of innate immune cells and their accumulation in the arterial wall and infarcted myocardium has been recognized as a central feature of atherosclerosis and cardiac ischemic injury, respectively. In both, steady state and under pathological conditions, majority of these cells have a finite life span and are continuously replenished from haematopoietic stem/progenitor cell pool residing in the bone marrow and extramedullary sites. While having a crucial role in the cardiovascular disease development, proliferation and differentiation of innate immune cells within haematopoietic compartments is greatly affected by the ongoing cardiovascular pathology. In the current review, we summarize key cells, processes and tissue compartments that are involved in myelopoiesis under the steady state, during atherosclerosis development and in myocardial infarction.
Topics: Animals; Atherosclerosis; Bone Marrow; Cardiovascular Diseases; Hematopoiesis, Extramedullary; Humans; Myeloid Cells; Myelopoiesis
PubMed: 33979688
DOI: 10.1016/j.phrs.2021.105663 -
Cells Apr 2021Our understanding of the relationship between the immune system and cancers has undergone significant discovery recently. Immunotherapy with T cell therapies and... (Review)
Review
Our understanding of the relationship between the immune system and cancers has undergone significant discovery recently. Immunotherapy with T cell therapies and checkpoint blockade has meaningfully changed the oncology landscape. While remarkable clinical advances in adaptive immunity are occurring, modulation of innate immunity has proven more difficult. The myeloid compartment, including macrophages, neutrophils, and dendritic cells, has a significant impact on the persistence or elimination of tumors. Myeloid cells, specifically in the tumor microenvironment, have direct contact with tumor tissue and coordinate with tumor-reactive T cells to either stimulate or antagonize cancer immunity. However, the myeloid compartment comprises a broad array of cells in various stages of development. In addition, hematopoietic stem and progenitor cells at various stages of myelopoiesis in distant sites undergo significant modulation by tumors. Understanding how tumors exert their influence on myeloid progenitors is critical to making clinically meaningful improvements in these pathways. Therefore, this review will cover recent developments in our understanding of how solid tumors modulate myelopoiesis to promote the formation of pro-tumor immature myeloid cells. Then, it will cover some of the potential avenues for capitalizing on these mechanisms to generate antitumor immunity.
Topics: Animals; Hematopoietic Stem Cells; Humans; Immunologic Factors; Immunotherapy; Myeloid Cells; Myelopoiesis; Neoplasms; Tumor Microenvironment
PubMed: 33919157
DOI: 10.3390/cells10050968 -
Journal of Leukocyte Biology Dec 2015Myeloid-derived suppressor cells are a heterogeneous group of pathologically activated immature cells that play a major role in the negative regulation of the immune... (Review)
Review
Myeloid-derived suppressor cells are a heterogeneous group of pathologically activated immature cells that play a major role in the negative regulation of the immune response in cancer, autoimmunity, many chronic infections, and inflammatory conditions, as well as in the regulation of tumor angiogenesis, tumor cell invasion, and metastases. Accumulation of myeloid-derived suppressor cells is governed by a network of transcriptional regulators that could be combined into 2 partially overlapping groups: factors promoting myelopoiesis and preventing differentiation of mature myeloid cells and factors promoting pathologic activation of myeloid-derived suppressor cells. In this review, we discuss the specific nature of these factors and their impact on myeloid-derived suppressor cell development.
Topics: Animals; Humans; Myeloid Cells; Myelopoiesis; Neoplasm Invasiveness; Neoplasms; Neovascularization, Pathologic; Transcription Factors; Transcription, Genetic
PubMed: 26337512
DOI: 10.1189/jlb.4RI0515-204R -
Nature Communications Sep 2023Telomerase RNA (TERC) has a noncanonical function in myelopoiesis binding to a consensus DNA binding sequence and attracting RNA polymerase II (RNA Pol II), thus...
Telomerase RNA (TERC) has a noncanonical function in myelopoiesis binding to a consensus DNA binding sequence and attracting RNA polymerase II (RNA Pol II), thus facilitating myeloid gene expression. The CR4/CR5 domain of TERC is known to play this role, since a mutation of this domain found in dyskeratosis congenita (DC) patients decreases its affinity for RNA Pol II, impairing its myelopoietic activity as a result. In this study, we report that two aptamers, short single-stranded oligonucleotides, based on the CR4/CR5 domain were able to increase myelopoiesis without affecting erythropoiesis in zebrafish. Mechanistically, the aptamers functioned as full terc; that is, they increased the expression of master myeloid genes, independently of endogenous terc, by interacting with RNA Pol II and with the terc-binding sequences of the regulatory regions of such genes, enforcing their transcription. Importantly, aptamers harboring the CR4/CR5 mutation that was found in DC patients failed to perform all these functions. The therapeutic potential of the aptamers for treating neutropenia was demonstrated in several preclinical models. The findings of this study have identified two potential therapeutic agents for DC and other neutropenic patients.
Topics: Humans; Animals; Aptamers, Nucleotide; Myelopoiesis; RNA Polymerase II; Syndrome; Zebrafish; Dyskeratosis Congenita
PubMed: 37737237
DOI: 10.1038/s41467-023-41472-7 -
Current Opinion in Hematology Jul 2015Hematopoietic stem cells can self-renew and also give rise to the entire repertoire of hematopoietic cells. During acute infectious and inflammatory stresses, the... (Review)
Review
PURPOSE OF REVIEW
Hematopoietic stem cells can self-renew and also give rise to the entire repertoire of hematopoietic cells. During acute infectious and inflammatory stresses, the hematopoietic system can quickly adapt to demand by increasing output of innate immune cells many-fold, often at the expense of lymphopoiesis and erythropoiesis. We review recent advances in understanding the regulation of stress-induced hematopoiesis with a specific focus on the direct effects of inflammatory signaling on hematopoietic stem and progenitor cells (HSPCs).
RECENT FINDINGS
Recent studies have highlighted several areas of exciting new developments in the field, including the complex interaction and crosstalk within HSPCs and between bone marrow mesenchymal stem cells and endothelial cells needed to achieve regulated myelopoiesis, identification of increased number of inflammatory and infectious molecules with direct effects on HSPCs, the critical role of inflammatory signaling on embryonic specification of hematopoietic stem cells, and the ability of cytokines to instruct lineage choice at the HSPC level.
SUMMARY
These exciting new findings will shape our fundamental understanding of how inflammatory signaling regulates hematopoiesis in health and disease, and facilitate the development of potential interventions to treat hematologic diseases associated with altered inflammatory signaling.
Topics: Adaptation, Physiological; Cell Communication; Cell Differentiation; Cell Lineage; Cytokines; Erythropoiesis; Gene Expression Regulation; Hematologic Diseases; Hematopoietic Stem Cells; Humans; Lymphopoiesis; Myelopoiesis; Signal Transduction; Stress, Physiological; Toll-Like Receptors
PubMed: 26049748
DOI: 10.1097/MOH.0000000000000149