-
Cancer Discovery Oct 2022Transgenic knockin mice expressing a common loss-of-function mutation in human TET2 exhibit aging-related accelerated myeloid leukemia development and skewing of...
Transgenic knockin mice expressing a common loss-of-function mutation in human TET2 exhibit aging-related accelerated myeloid leukemia development and skewing of myelopoiesis toward the production of proinflammatory MHC-IIhi monocytes that may contribute to disease. See related article by Yeaton et al., p. 2392 (2).
Topics: Animals; Carcinogenesis; DNA-Binding Proteins; Dioxygenases; Humans; Inflammation; Leukemia; Mice; Monocytes; Mutation; Neoplasms; Proto-Oncogene Proteins
PubMed: 36196576
DOI: 10.1158/2159-8290.CD-22-0846 -
Redox Biology Oct 2020Psychosocial stress has a profound impact on well-being and health. The response to stress is associated mainly with the amygdala, a crucial structure of the... (Review)
Review
Psychosocial stress has a profound impact on well-being and health. The response to stress is associated mainly with the amygdala, a crucial structure of the fear-defense system, essential for social cognition and emotion regulation. Recent neuroimaging-studies demonstrated how an increased metabolic activity of the amygdala enhances inflammation, and leads to cardiometabolic disease. The development of therapeutic strategies depends on our understanding of both which factors activate the fear-defense system and the subsequent molecular mechanisms that translate emotional stress into cell damage. Fear of emotions as an aftermath of attachment trauma is the most important trigger of the maladaptive activation of the fear-defense system. The central molecular pathways are enhanced myelopoiesis and upregulated proinflammatory gene expression, glucocorticoid and insulin resistance, and oxidative stress. Therapeutic strategies may benefit from holistic approaches. Psychotherapy can reduce the maladaptively increased activation of the fear-defense system. Biological interventions can buffer the detrimental effects of oxidative stress in the organism.
Topics: Amygdala; Emotions; Fear; Humans; Oxidative Stress
PubMed: 32739155
DOI: 10.1016/j.redox.2020.101588 -
EMBO Molecular Medicine Nov 2023Therapies reconstituting autologous antiviral immunocompetence may represent an important prophylaxis and treatment for immunosuppressed individuals. Following...
Therapies reconstituting autologous antiviral immunocompetence may represent an important prophylaxis and treatment for immunosuppressed individuals. Following hematopoietic cell transplantation (HCT), patients are susceptible to Herpesviridae including cytomegalovirus (CMV). We show in a murine model of HCT that macrophage colony-stimulating factor (M-CSF) promoted rapid antiviral activity and protection from viremia caused by murine CMV. M-CSF given at transplantation stimulated sequential myeloid and natural killer (NK) cell differentiation culminating in increased NK cell numbers, production of granzyme B and interferon-γ. This depended upon M-CSF-induced myelopoiesis leading to IL15Rα-mediated presentation of IL-15 on monocytes, augmented by type I interferons from plasmacytoid dendritic cells. Demonstrating relevance to human HCT, M-CSF induced myelomonocytic IL15Rα expression and numbers of functional NK cells in G-CSF-mobilized hematopoietic stem and progenitor cells. Together, M-CSF-induced myelopoiesis triggered an integrated differentiation of myeloid and NK cells to protect HCT recipients from CMV. Thus, our results identify a rationale for the therapeutic use of M-CSF to rapidly reconstitute antiviral activity in immunocompromised individuals, which may provide a general paradigm to boost innate antiviral immunocompetence using host-directed therapies.
Topics: Humans; Mice; Animals; Cytomegalovirus; Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Cytomegalovirus Infections; Hematopoiesis; Antiviral Agents; Cell Differentiation
PubMed: 37635627
DOI: 10.15252/emmm.202317694 -
Journal of Molecular and Cellular... Feb 2024Of all the different risk factors known to cause cardiovascular disease (CVD), age and sex are considered to play a crucial role. Aging follows a continuum from birth to... (Review)
Review
Of all the different risk factors known to cause cardiovascular disease (CVD), age and sex are considered to play a crucial role. Aging follows a continuum from birth to death, and therefore it inevitably acts as a risk for CVD. Along with age, sex differences have also been shown to demonstrate variations in immune system responses to pathological insults. It has been widely perceived that females are protected against myocardial infarction (MI) and the protection is quite apparent in young vs. old women. Acute MI leads to changes in the population of myeloid and lymphoid cells at the injury site with myeloid bias being observed in the initial inflammation and the lymphoid in the late-resolution phases of the pathology. Multiple evidence demonstrates that aging enhances damage to various cellular processes through inflamm-aging, an inflammatory process identified to increase pro-inflammatory markers in circulation and tissues. Following MI, marked changes were observed in different sub-sets of major myeloid cell types viz., neutrophils, monocytes, and macrophages. There is a paucity of information regarding the tissue and site-specific functions of these sub-sets. In this review, we highlight the importance of age and sex as crucial risk factors by discussing their role during MI-induced myelopoiesis while emphasizing the current status of myeloid cell sub-sets. We further put forth the need for designing and executing age and sex interaction studies aimed to determine the appropriate age and sex to develop personalized therapeutic strategies post-MI.
Topics: Female; Humans; Male; Myelopoiesis; Myocardial Infarction; Monocytes; Macrophages; Inflammation
PubMed: 38163742
DOI: 10.1016/j.yjmcc.2023.11.011 -
Journal of Leukocyte Biology Aug 2020Discussion on how CXXC5 alters hematopoiesis by regulating the differentiation of hematopoietic stem and progenitor cells toward monocyte development.
Discussion on how CXXC5 alters hematopoiesis by regulating the differentiation of hematopoietic stem and progenitor cells toward monocyte development.
Topics: Animals; Cell Cycle; Cell Differentiation; DNA-Binding Proteins; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Intracellular Signaling Peptides and Proteins; Mice; Myelopoiesis; Transcription Factors
PubMed: 32745327
DOI: 10.1002/JLB.1CE0420-106R -
Hematology/oncology Clinics of North... Apr 2020Myelodysplastic syndromes are disorders of clonal myelopoiesis having a range of clinical manifestations, from benign and indolent to aggressive with very poor... (Review)
Review
Myelodysplastic syndromes are disorders of clonal myelopoiesis having a range of clinical manifestations, from benign and indolent to aggressive with very poor prognosis. Classifying the likely trajectory of disease within a patient largely guides therapeutic decision making and therefore survival. Traditional methods of risk-stratification systems rely on clinical features: simple blood tests, peripheral smears, bone marrow biopsies, and cytogenetics, but do not adequately predict disease severity for a substantial proportion of patients. This article reviews the state of stratification at use in the clinic, describes emerging systems that leverage large-scale genomic data, and summarizes efforts toward truly personalized prediction models.
Topics: Computational Biology; DNA Methylation; Disease Management; Disease Susceptibility; Genetic Heterogeneity; Humans; Models, Biological; Mutation; Myelodysplastic Syndromes; Prognosis; Risk Assessment; Treatment Outcome
PubMed: 32089216
DOI: 10.1016/j.hoc.2019.10.001 -
International Immunology May 2023The microbiota engages in the development and maintenance of the host immune system. The microbiota affects not only mucosal tissues where it localizes but also the... (Review)
Review
The microbiota engages in the development and maintenance of the host immune system. The microbiota affects not only mucosal tissues where it localizes but also the distal organs. Myeloid cells are essential for host defense as first responders of the host immune system. Their generation, called myelopoiesis, is regulated by environmental signals, including commensal microbiota. Hematopoietic stem and progenitor cells in bone marrow can directly or indirectly sense microbiota-derived signals, thereby giving rise to myeloid cell lineages at steady-state and during inflammation. In this review, we discuss the role of commensal microorganisms in the homeostatic regulation of myelopoiesis in the bone marrow. We also outline the effects of microbial signals on myelopoiesis during inflammation and infection, with a particular focus on the development of innate immune memory. Studying the relationship between the microbiota and myelopoiesis will help us understand how the microbiota regulates immune responses at a systemic level beyond the local mucosa.
Topics: Humans; Myelopoiesis; Inflammation; Bone Marrow; Microbiota; Homeostasis
PubMed: 36694400
DOI: 10.1093/intimm/dxad002 -
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 -
The Journal of Experimental Medicine Aug 2023Hematopoietic stem cells (HSC) and downstream lineage-biased multipotent progenitors (MPP) tailor blood production and control myelopoiesis on demand. Recent lineage...
Hematopoietic stem cells (HSC) and downstream lineage-biased multipotent progenitors (MPP) tailor blood production and control myelopoiesis on demand. Recent lineage tracing analyses revealed MPPs to be major functional contributors to steady-state hematopoiesis. However, we still lack a precise resolution of myeloid differentiation trajectories and cellular heterogeneity in the MPP compartment. Here, we found that myeloid-biased MPP3 are functionally and molecularly heterogeneous, with a distinct subset of myeloid-primed secretory cells with high endoplasmic reticulum (ER) volume and FcγR expression. We show that FcγR+/ERhigh MPP3 are a transitional population serving as a reservoir for rapid production of granulocyte/macrophage progenitors (GMP), which directly amplify myelopoiesis through inflammation-triggered secretion of cytokines in the local bone marrow (BM) microenvironment. Our results identify a novel regulatory function for a secretory MPP3 subset that controls myeloid differentiation through lineage-priming and cytokine production and acts as a self-reinforcing amplification compartment in inflammatory stress and disease conditions.
Topics: Cell Differentiation; Cell Lineage; Hematopoiesis; Myeloid Cells; Receptors, IgG; Guanylate Kinases; Membrane Proteins
PubMed: 37115584
DOI: 10.1084/jem.20230088 -
Molecular Immunology May 2020Myeloid cells and their progenitors have historically been characterized based on their expression of a well-defined set of surface proteins, transcription factors and... (Review)
Review
Myeloid cells and their progenitors have historically been characterized based on their expression of a well-defined set of surface proteins, transcription factors and cytokines they depend on. These traditional analyses on "bulk" myeloid cell populations led to valuable early insights into the ontogeny of dendritic cells, granulocytes, monocytes and macrophages - a process called myelopoiesis. However, bulk approaches have limitations: they are unable to discern the individual stages and functions of progenitors and may be compromised by contaminating cells of non-myeloid lineages with similar or overlapping phenotypes. In recent years the emergence of high dimensional technologies to interrogate single cells at the molecular level, including single-cell mRNA sequencing and mass cytometry, has revolutionised our understanding of immune cell development and differentiation. Here, we highlight how the use of single-cell technologies has advanced our understanding of myelopoiesis and the emerging opportunities for it to continue to do so.
PubMed: 32388073
DOI: 10.1016/j.molimm.2020.04.020