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Advanced Science (Weinheim,... Apr 2024Innate immune training involves myelopoiesis, dynamic gene modulation, and functional reprogramming of myeloid cells in response to secondary heterologous challenges....
Innate immune training involves myelopoiesis, dynamic gene modulation, and functional reprogramming of myeloid cells in response to secondary heterologous challenges. The present study evaluates whether systemic innate immune training can protect tissues from local injury. Systemic pretreatment of mice with β-glucan, a trained immunity agonist, reduces the mortality rate of mice with bleomycin-induced lung injury and fibrosis, as well as decreasing collagen deposition in the lungs. β-Glucan pretreatment induces neutrophil accumulation in the lungs and enhances efferocytosis. Training of mice with β-glucan results in histone modification in both alveolar macrophages (AMs) and neighboring lung epithelial cells. Training also increases the production of RvD1 and soluble mediators by AMs and efferocytes. Efferocytosis increases trained immunity in AMs by stimulating RvD1 release, thus inducing SIRT1 expression in neighboring lung epithelial cells. Elevated epithelial SIRT1 expression is associated with decreased epithelial cell apoptosis after lung injury, attenuating tissue damage. Further, neutrophil depletion dampens the effects of β-glucan on macrophage accumulation, epigenetic modification in lung macrophages, epithelial SIRT1 expression, and injury-mediated fibrosis in the lung. These findings provide mechanistic insights into innate immune training and clues to the potential ability of centrally trained immunity to protect peripheral organs against injury-mediated disorders.
Topics: Mice; Animals; Sirtuin 1; Efferocytosis; Lung Injury; beta-Glucans; Fibrosis
PubMed: 38279580
DOI: 10.1002/advs.202308978 -
Cancers Jan 2024Myeloproliferative neoplasms (MPNs) are hematopoietic diseases characterized by the clonal expansion of single or multiple lineages of differentiated myeloid cells that... (Review)
Review
Myeloproliferative neoplasms (MPNs) are hematopoietic diseases characterized by the clonal expansion of single or multiple lineages of differentiated myeloid cells that accumulate in the blood and bone marrow. MPNs are grouped into distinct categories based on key clinical presentations and distinctive mutational hallmarks. These include chronic myeloid leukemia (CML), which is strongly associated with the signature gene translocation, polycythemia vera (PV), essential thrombocythemia (ET), and primary (idiopathic) myelofibrosis (PMF), typically accompanied by molecular alterations in the , , or genes. There are also rarer forms such as chronic neutrophilic leukemia (CNL), which involves mutations in the gene. However, rather than focusing on the differences between these alternate disease categories, this review aims to present a unifying molecular etiology in which these overlapping diseases are best understood as disruptions of normal hematopoietic signaling: specifically, the chronic activation of signaling pathways, particularly involving signal transducer and activator of transcription (STAT) transcription factors, most notably STAT5B, leading to the sustained stimulation of myelopoiesis, which underpins the various disease sequalae.
PubMed: 38254802
DOI: 10.3390/cancers16020313 -
Proceedings of the National Academy of... Jan 2024The hierarchical model of hematopoiesis posits that self-renewing, multipotent hematopoietic stem cells (HSCs) give rise to all blood cell lineages. While this model...
The hierarchical model of hematopoiesis posits that self-renewing, multipotent hematopoietic stem cells (HSCs) give rise to all blood cell lineages. While this model accounts for hematopoiesis in transplant settings, its applicability to steady-state hematopoiesis remains to be clarified. Here, we used inducible clonal DNA barcoding of endogenous adult HSCs to trace their contribution to major hematopoietic cell lineages in unmanipulated animals. While the majority of barcodes were unique to a single lineage, we also observed frequent barcode sharing between multiple lineages, specifically between lymphocytes and myeloid cells. These results suggest that both single-lineage and multilineage contributions by HSCs collectively drive continuous hematopoiesis, and highlight a close relationship of myeloid and lymphoid development.
Topics: Animals; Cell Differentiation; Hematopoietic Stem Cells; Hematopoiesis; Adult Stem Cells; Cell Lineage
PubMed: 38227649
DOI: 10.1073/pnas.2317929121 -
Stem Cell Reports Feb 2024Emergency myelopoiesis (EM) is essential in immune defense against pathogens for rapid replenishing of mature myeloid cells. During the EM process, a rapid cell-cycle...
Emergency myelopoiesis (EM) is essential in immune defense against pathogens for rapid replenishing of mature myeloid cells. During the EM process, a rapid cell-cycle switch from the quiescent hematopoietic stem cells (HSCs) to highly proliferative myeloid progenitors (MPs) is critical. How the rapid proliferation of MPs during EM is regulated remains poorly understood. Here, we reveal that ATG7, a critical autophagy factor, is essential for the rapid proliferation of MPs during human myelopoiesis. Peripheral blood (PB)-mobilized hematopoietic stem/progenitor cells (HSPCs) with ATG7 knockdown or HSPCs derived from ATG7 human embryonic stem cells (hESCs) exhibit severe defect in proliferation during fate transition from HSPCs to MPs. Mechanistically, we show that ATG7 deficiency reduces p53 localization in lysosome for a potential autophagy-mediated degradation. Together, we reveal a previously unrecognized role of autophagy to regulate p53 for a rapid proliferation of MPs in human myelopoiesis.
Topics: Humans; Myelopoiesis; Tumor Suppressor Protein p53; Hematopoietic Stem Cells; Myeloid Cells; Autophagy
PubMed: 38215759
DOI: 10.1016/j.stemcr.2023.12.005 -
International Journal of Molecular... Dec 2023T-box genes encode transcription factors, which control developmental processes and promote cancer if deregulated. Recently, we described the lymphoid TBX-code, which...
T-box genes encode transcription factors, which control developmental processes and promote cancer if deregulated. Recently, we described the lymphoid TBX-code, which collates T-box gene activities in normal lymphopoiesis, enabling identification of members deregulated in lymphoid malignancies. Here, we have extended this analysis to cover myelopoiesis, compiling the myeloid TBX-code and, thus, highlighting which of these genes might be deregulated in myeloid tumor types. We analyzed public T-box gene expression datasets bioinformatically for normal and malignant cells. Candidate T-box-gene-expressing model cell lines were identified and examined by RQ-PCR, Western Blotting, genomic profiling, and siRNA-mediated knockdown combined with RNA-seq analysis and live-cell imaging. The established myeloid TBX-code comprised 10 T-box genes, including progenitor-cell-restricted TBX1. Accordingly, we detected aberrant expression of TBX1 in 10% of stem/progenitor-cell-derived chronic myeloid leukemia (CML) patients. The classic CML cell line K-562 expressed TBX1 at high levels and served as a model to identify TBX1 activators, including transcription factor GATA1 and genomic amplification of the TBX1 locus at 22q11; inhibitors, including BCR::ABL1 fusion and downregulated GNAI2, as well as BMP, FGF2, and WNT signaling; and the target genes CDKN1A, MIR17HG, NAV1, and TMEM38A. The establishment of the myeloid TBX-code permitted identification of aberrant TBX1 expression in subsets of CML patients and cell lines. TBX1 forms an integral part of an oncogenic regulatory network impacting proliferation, survival, and differentiation. Thus, the data spotlight novel diagnostic markers and potential therapeutic targets for this malignancy.
Topics: Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Genes, cdc; Blotting, Western; Cell Line, Tumor; T-Box Domain Proteins
PubMed: 38203204
DOI: 10.3390/ijms25010032 -
Stem Cell Reports Jan 2024CCAAT/enhancer-binding protein beta (C/EBPβ) induces primary v-Abl immortalized mouse B cells to transdifferentiate (BT, B cell transdifferentiation) into...
CCAAT/enhancer-binding protein beta (C/EBPβ) induces primary v-Abl immortalized mouse B cells to transdifferentiate (BT, B cell transdifferentiation) into granulocyte-macrophage progenitor-like cells (GMPBTs). GMPBTs maintain cytokine-independent self-renewal, lineage choice, and multilineage differentiation. Single-cell transcriptomics demonstrated that GMPBTs comprise a continuum of myelomonopoietic differentiation states that seamlessly fit into state-to-fate maps of normal granulocyte-macrophage progenitors (GMPs). Inactivating v-Abl kinase revealed the dependence on activated CSF2-JAK2-STAT5 signaling. Deleting IRF8 diminished monopoiesis and enhanced granulopoiesis while removing C/EBPβ-abrogated self-renewal and granulopoiesis but permitted macrophage differentiation. The GMPBT culture system is easily scalable to explore the basics of GMP biology and lineage commitment and largely reduces ethically and legislatively debatable, labor-intensive, and costly animal experiments.
Topics: Mice; Animals; Granulocytes; Monocytes; Cell Transdifferentiation; Hematopoiesis; Cell Differentiation; Biology
PubMed: 38157851
DOI: 10.1016/j.stemcr.2023.11.011 -
The Malaysian Journal of Pathology Dec 2023No abstract available.
The circulating cells with blast-like morphology in transient abnormal myelopoiesis of Down syndrome are unique and deserve a specific name: Would the term "megakaryogones" serve this purpose?
No abstract available.
Topics: Humans; Down Syndrome; Leukemoid Reaction
PubMed: 38155389
DOI: No ID Found -
Cureus Nov 2023Hematological disorders pose a diagnostic challenge due to overlapping clinical features, as demonstrated by the difficulty in differentiating between aplastic anemia...
Hematological disorders pose a diagnostic challenge due to overlapping clinical features, as demonstrated by the difficulty in differentiating between aplastic anemia (AA) and primary myelofibrosis (PM). Myeloproliferative disorders, characterized by aberrant proliferation of bone marrow stem cells, present complexities in diagnosis, often requiring a comprehensive evaluation to distinguish between disorders with similar manifestations. The distinctions between myelofibrosis and AA lie not only in clinical presentations but also in genetic and molecular markers, necessitating a nuanced diagnostic approach. We present a case of a 37-year-old male initially diagnosed with myelofibrosis based on a history of pancytopenia, warm submandibular and submental swelling, and negative BCR-ABL and JAK2 mutations. Further examination revealed empty fragmented cells, hypoplastic bone marrow, and suppressed erythropoiesis and myelopoiesis. Subsequent core biopsy showed increased megakaryocytes, prompting a revised diagnosis of AA. This case underscores the importance of a meticulous diagnostic journey, incorporating physical examination, genetic testing, and advanced imaging to unravel the complexities of hematological disorders. The intricacies of this case prompt a reevaluation of diagnostic paradigms, highlighting the limitations of relying solely on specific mutations for diagnosis. The absence of BCR-ABL and JAK2 mutations in AA raises questions about its genetic landscape, necessitating further exploration. Immunological considerations, given the immune-mediated nature of AA, provide a foundation for future research into immune dysregulation and potential therapeutic interventions. The clinical management challenges posed by AA underscore the need for personalized treatment strategies, guided by a deeper understanding of its underlying pathophysiology. Advanced imaging techniques, in conjunction with traditional diagnostic methods, emerge as crucial tools for enhancing diagnostic accuracy in hematological disorders. This case serves as a paradigm for ongoing medical education, multidisciplinary collaboration, and innovative approaches in the evolving landscape of hematology, emphasizing the imperative for continuous refinement in diagnostic strategies and patient care.
PubMed: 38149134
DOI: 10.7759/cureus.49445 -
Clinical and Translational Medicine Dec 2023Whereas most infants infected with respiratory syncytial virus (RSV) show no or only mild symptoms, an estimated 3 million children under five are hospitalized annually...
Whereas most infants infected with respiratory syncytial virus (RSV) show no or only mild symptoms, an estimated 3 million children under five are hospitalized annually due to RSV disease. This study aimed to investigate biological mechanisms and associated biomarkers underlying RSV disease heterogeneity in young infants, enabling the potential to objectively categorize RSV-infected infants according to their medical needs. Immunophenotypic and functional profiling demonstrated the emergence of immature and progenitor-like neutrophils, proliferative monocytes (HLA-DR , Ki67+), impaired antigen-presenting function, downregulation of T cell response and low abundance of HLA-DR B cells in severe RSV disease. HLA-DR monocytes were found as a hallmark of RSV-infected infants requiring hospitalization. Complementary transcriptomics identified genes associated with disease severity and pointed to the emergency myelopoiesis response. These results shed new light on mechanisms underlying the pathogenesis and development of severe RSV disease and identified potential new candidate biomarkers for patient stratification.
Topics: Infant; Child; Humans; Myelopoiesis; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; HLA-DR Antigens; Biomarkers
PubMed: 38115705
DOI: 10.1002/ctm2.1507 -
Comparative Medicine Oct 2023MISTRG is an immunodeficient mouse strain that expresses multiple human cytokines that support hematopoietic stem cell maintenance and myelopoiesis. While establishing a...
MISTRG is an immunodeficient mouse strain that expresses multiple human cytokines that support hematopoietic stem cell maintenance and myelopoiesis. While establishing a breeding colony of MISTRG mice in a dedicated barrier room, 6 cases of death or disease occurred in pregnant or postpartum mice. Clinically, this manifested as hunched posture, dyspnea, and 1 case of emaciation with ataxia. Pathologic analysis of 7 mice revealed multisystemic necrosuppurative inflammation variably affecting the uterus and placenta, joints, meninges, inner and middle ears, kidneys, and small intestine. Bacteria cultured from the blood of septic mice were identified with 89% probability by the Vitek 2 identification system as with atypical biochemical parameters; the API 20E/NE system fully differentiated the isolates as a novel species. MALDI Biotyper-based mass spectrometry also indicated that the phenotype represented a novel spp. Sequencing revealed that the full-length 16S rRNA gene identity was below 97% with known species, including the 2 closest species and . We propose the name spp. nov to our novel isolates. All male mice in this colony remained healthy despite their association with diseased female mice. Overall, 19% of the colony carried the novel in their oral cavity, but it could not be detected in feces. The organism was sensitive to amoxicillin, which was administered via drinking water throughout pregnancy and weaning to establish a colony of pathogen-negative future breeders. The colony remained disease-free and culture-negative for spp. nov after treatment with amoxicillin. We suspect that oral colonization of MISTRG mice with the novel species and its associated unique pathology in periparturient mice is potentially the principal cause of loss of this strain at several institutions. Therefore, screening the oral cavity for α-hemolytic streptococci followed by targeted antibiotic treatment may be necessary when establishing MISTRG and allied immunodeficient mouse strains.
Topics: Pregnancy; Male; Female; Humans; Animals; Mice; Streptococcal Infections; RNA, Ribosomal, 16S; Streptococcus; Amoxicillin; Mouth
PubMed: 38087407
DOI: 10.30802/AALAS-CM-23-000020