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Developmental Cell Mar 2023Mammalian hematopoietic stem cells (HSCs) colonize the bone marrow during late fetal development, and this becomes the major site of hematopoiesis after birth. However,...
Mammalian hematopoietic stem cells (HSCs) colonize the bone marrow during late fetal development, and this becomes the major site of hematopoiesis after birth. However, little is known about the early postnatal bone marrow niche. We performed single-cell RNA sequencing of mouse bone marrow stromal cells at 4 days, 14 days, and 8 weeks after birth. Leptin-receptor-expressing (LepR) stromal cells and endothelial cells increased in frequency during this period and changed their properties. At all postnatal stages, LepR cells and endothelial cells expressed the highest stem cell factor (Scf) levels in the bone marrow. LepR cells expressed the highest Cxcl12 levels. In early postnatal bone marrow, SCF from LepR/Prx1 stromal cells promoted myeloid and erythroid progenitor maintenance, while SCF from endothelial cells promoted HSC maintenance. Membrane-bound SCF in endothelial cells contributed to HSC maintenance. LepR cells and endothelial cells are thus important niche components in early postnatal bone marrow.
Topics: Animals; Mice; Bone Marrow; Bone Marrow Cells; Endothelial Cells; Hematopoiesis; Hematopoietic Stem Cells; Mammals; Receptors, Leptin; Stem Cell Factor; Stem Cell Niche
PubMed: 36868235
DOI: 10.1016/j.devcel.2023.02.003 -
Journal of Hematology & Oncology Jul 2023Tumor-associated myeloid cells (TAMCs) are among the most important immune cell populations in the tumor microenvironment, and play a significant role on the efficacy of... (Review)
Review
Tumor-associated myeloid cells (TAMCs) are among the most important immune cell populations in the tumor microenvironment, and play a significant role on the efficacy of immune checkpoint blockade. Understanding the origin of TAMCs was found to be the essential to determining their functional heterogeneity and, developing cancer immunotherapy strategies. While myeloid-biased differentiation in the bone marrow has been traditionally considered as the primary source of TAMCs, the abnormal differentiation of splenic hematopoietic stem and progenitor cells, erythroid progenitor cells, and B precursor cells in the spleen, as well as embryo-derived TAMCs, have been depicted as important origins of TAMCs. This review article provides an overview of the literature with a focus on the recent research progress evaluating the heterogeneity of TAMCs origins. Moreover, this review summarizes the major therapeutic strategies targeting TAMCs with heterogeneous sources, shedding light on their implications for cancer antitumor immunotherapies.
Topics: Humans; Neoplasms; Myeloid Cells; Immunotherapy; Bone Marrow; Hematopoietic Stem Cells; Tumor Microenvironment
PubMed: 37415162
DOI: 10.1186/s13045-023-01473-x -
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 -
Cell Nov 2020Ebola virus (EBOV) causes epidemics with high mortality yet remains understudied due to the challenge of experimentation in high-containment and outbreak settings. Here,...
Ebola virus (EBOV) causes epidemics with high mortality yet remains understudied due to the challenge of experimentation in high-containment and outbreak settings. Here, we used single-cell transcriptomics and CyTOF-based single-cell protein quantification to characterize peripheral immune cells during EBOV infection in rhesus monkeys. We obtained 100,000 transcriptomes and 15,000,000 protein profiles, finding that immature, proliferative monocyte-lineage cells with reduced antigen-presentation capacity replace conventional monocyte subsets, while lymphocytes upregulate apoptosis genes and decline in abundance. By quantifying intracellular viral RNA, we identify molecular determinants of tropism among circulating immune cells and examine temporal dynamics in viral and host gene expression. Within infected cells, EBOV downregulates STAT1 mRNA and interferon signaling, and it upregulates putative pro-viral genes (e.g., DYNLL1 and HSPA5), nominating pathways the virus manipulates for its replication. This study sheds light on EBOV tropism, replication dynamics, and elicited immune response and provides a framework for characterizing host-virus interactions under maximum containment.
Topics: Animals; Antigens, CD; Biomarkers; Bystander Effect; Cell Differentiation; Cell Proliferation; Cytokines; Ebolavirus; Endoplasmic Reticulum Chaperone BiP; Gene Expression Profiling; Gene Expression Regulation; Gene Expression Regulation, Viral; Hemorrhagic Fever, Ebola; Histocompatibility Antigens Class II; Host-Pathogen Interactions; Interferons; Macaca mulatta; Macrophages; Monocytes; Myelopoiesis; RNA, Messenger; Single-Cell Analysis; Time Factors; Transcriptome
PubMed: 33159858
DOI: 10.1016/j.cell.2020.10.002 -
International Journal of Molecular... Jun 2023Hematopoietic stem cells (HSCs) are defined based on their capacity to replenish themselves (self-renewal) and give rise to all mature hematopoietic cell types... (Review)
Review
Hematopoietic stem cells (HSCs) are defined based on their capacity to replenish themselves (self-renewal) and give rise to all mature hematopoietic cell types (multi-lineage differentiation) over their lifetime. HSCs are mainly distributed in the bone marrow during adult life, harboring HSC populations and a hierarchy of different kinds of cells contributing to the "niche" that supports HSC regulation, myelopoiesis, and lymphopoiesis. In addition, HSC-like progenitors, innate immune cell precursors such as macrophages, mast cells, natural killer cells, innate lymphoid cells, and megakaryocytes and erythrocyte progenitor cells are connected by a series of complex ontogenic relationships. The first source of mast cells is the extraembryonic yolk sac, on embryonic day 7. Mast cell progenitors circulate and enter peripheral tissues where they complete their differentiation. Embryonic mast cell populations are gradually replaced by definitive stem cell-derived progenitor cells. Thereafter, mast cells originate from the bone marrow, developing from the hematopoietic stem cells via multipotent progenitors, common myeloid progenitors, and granulocyte/monocyte progenitors. In this review article, we summarize the knowledge on mast cell sources, particularly focusing on the complex and multifaceted mechanisms intervening between the hematopoietic process and the development of mast cells.
Topics: Mast Cells; Immunity, Innate; Lymphocytes; Cell Differentiation; Hematopoiesis; Hematopoietic Stem Cells; Cell Lineage
PubMed: 37445862
DOI: 10.3390/ijms241310679 -
Clinics in Laboratory Medicine Sep 2021Infant acute leukemia is a rare but aggressive disease. Although infant acute leukemia is cytologically and histologically similar to acute leukemia seen in older... (Review)
Review
Infant acute leukemia is a rare but aggressive disease. Although infant acute leukemia is cytologically and histologically similar to acute leukemia seen in older children and adults, it displays unique and characteristic clinical and genetic characteristics. The features, as well as the extremely young age of the patients, present multiple challenges for treatment. This review focuses on the unique pathology of acute leukemia of infancy, including the genetic characteristics that are specific for these diseases.
Topics: Acute Disease; Adult; Child; Down Syndrome; Humans; Infant; Leukemia; Leukemia, Megakaryoblastic, Acute
PubMed: 34304781
DOI: 10.1016/j.cll.2021.04.002 -
Nature Mar 2024The bone marrow adjusts blood cell production to meet physiological demands in response to insults. The spatial organization of normal and stress responses are unknown...
The bone marrow adjusts blood cell production to meet physiological demands in response to insults. The spatial organization of normal and stress responses are unknown owing to the lack of methods to visualize most steps of blood production. Here we develop strategies to image multipotent haematopoiesis, erythropoiesis and lymphopoiesis in mice. We combine these with imaging of myelopoiesis to define the anatomy of normal and stress haematopoiesis. In the steady state, across the skeleton, single stem cells and multipotent progenitors distribute through the marrow enriched near megakaryocytes. Lineage-committed progenitors are recruited to blood vessels, where they contribute to lineage-specific microanatomical structures composed of progenitors and immature cells, which function as the production sites for each major blood lineage. This overall anatomy is resilient to insults, as it was maintained after haemorrhage, systemic bacterial infection and granulocyte colony-stimulating factor (G-CSF) treatment, and during ageing. Production sites enable haematopoietic plasticity as they differentially and selectively modulate their numbers and output in response to insults. We found that stress responses are variable across the skeleton: the tibia and the sternum respond in opposite ways to G-CSF, and the skull does not increase erythropoiesis after haemorrhage. Our studies enable in situ analyses of haematopoiesis, define the anatomy of normal and stress responses, identify discrete microanatomical production sites that confer plasticity to haematopoiesis, and uncover unprecedented heterogeneity of stress responses across the skeleton.
Topics: Animals; Female; Male; Mice; Aging; Bacterial Infections; Blood Vessels; Cell Lineage; Erythropoiesis; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Stem Cells; Hemorrhage; Lymphopoiesis; Megakaryocytes; Multipotent Stem Cells; Myelopoiesis; Skull; Sternum; Stress, Physiological; Tibia
PubMed: 38509363
DOI: 10.1038/s41586-024-07186-6 -
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 -
Clinical Immunology (Orlando, Fla.) Jun 2023Interleukin 27 has both pro-inflammatory and anti-inflammatory properties in autoimmunity. The anti-inflammatory effects of IL-27 are linked with inhibition of Th17...
Interleukin 27 has both pro-inflammatory and anti-inflammatory properties in autoimmunity. The anti-inflammatory effects of IL-27 are linked with inhibition of Th17 differentiation but the IL-27 effect on myeloid cells is less studied. Herein we demonstrate that IL-27 inhibits IL-23-induced inflammation associated not only with Th17 cells but also with myeloid cell infiltration in the joints and splenic myeloid populations of CD11b GR1 and CD3CD11bCD11cGR1 cells. The IL-27 anti-inflammatory response was associated with reduced levels of myeloid cells in the spleen and bone marrow. Overall, our data demonstrate that IL-27 has an immunosuppressive role that affects IL-23-dependent myelopoiesis in the bone marrow and its progression to inflammatory arthritis and plays a crucial role in controlling IL-23 driven joint inflammation by negatively regulating the expansion of myeloid cell subsets.
Topics: Animals; Interleukin-27; Cytokines; Arthritis, Experimental; Inflammation; Interleukin-23; Th17 Cells
PubMed: 37037268
DOI: 10.1016/j.clim.2023.109327 -
Inflammation Research : Official... Aug 2023Airway inflammation in chronic inflammatory lung diseases (e.g. bronchiectasis) is partly mediated by neutrophil-derived serine protease (NSP)/antiprotease imbalance....
BACKGROUND
Airway inflammation in chronic inflammatory lung diseases (e.g. bronchiectasis) is partly mediated by neutrophil-derived serine protease (NSP)/antiprotease imbalance. NSPs are activated during neutrophil myelopoiesis in bone marrow by cathepsin C (CatC; DPP1). CatC is therefore an attractive target to reduce NSP activity in the lungs of patients with bronchiectasis, restoring the protease/antiprotease balance. We report results from the preclinical pharmacological assessment of the novel CatC inhibitor BI 1291583.
METHODS
Binding kinetics of BI 1291583 to human CatC were determined by surface plasmon resonance. In vitro inhibition of human CatC activity was determined by CatC-specific fluorescent assay, and selectivity was assessed against related cathepsins and unrelated proteases. Inhibition of NSP neutrophil elastase (NE) production was assessed in a human neutrophil progenitor cell line. In vivo inhibition of NE and NSP proteinase 3 (PR3) in bronchoalveolar lavage fluid (BALF) neutrophils after lipopolysaccharide (LPS) challenge and distribution of BI 1291583 was determined in a mouse model.
RESULTS
BI 1291583 bound human CatC in a covalent, reversible manner, selectively and fully inhibiting CatC enzymatic activity. This inhibition translated to concentration-dependent inhibition of NE activation in U937 cells and dose-dependent, almost-complete inhibition of NE and PR3 activity in BALF neutrophils in an in vivo LPS-challenge model in mice. BI 1291583 exhibited up to 100 times the exposure in the target tissue bone marrow compared with plasma.
CONCLUSION
BI 1291583-mediated inhibition of CatC is expected to restore the protease-antiprotease balance in the lungs of patients with chronic airway inflammatory diseases such as bronchiectasis.
Topics: Animals; Humans; Mice; Bronchiectasis; Cathepsin C; Leukocyte Elastase; Lipopolysaccharides; Neutrophils; Protease Inhibitors; Serine Proteases
PubMed: 37542002
DOI: 10.1007/s00011-023-01774-4