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Circulation Jul 2020Diabetes mellitus is a prevalent public health problem that affects about one-third of the US population and leads to serious vascular complications with increased risk...
BACKGROUND
Diabetes mellitus is a prevalent public health problem that affects about one-third of the US population and leads to serious vascular complications with increased risk for coronary artery disease. How bone marrow hematopoiesis contributes to diabetes mellitus complications is incompletely understood. We investigated the role of bone marrow endothelial cells in diabetic regulation of inflammatory myeloid cell production.
METHODS
In 3 types of mouse diabetes mellitus, including streptozotocin, high-fat diet, and genetic induction using leptin-receptor-deficient db/db mice, we assayed leukocytes, hematopoietic stem and progenitor cells (HSPC). In addition, we investigated bone marrow endothelial cells with flow cytometry and expression profiling.
RESULTS
In diabetes mellitus, we observed enhanced proliferation of HSPC leading to augmented circulating myeloid cell numbers. Analysis of bone marrow niche cells revealed that endothelial cells in diabetic mice expressed less , a retention factor promoting HSPC quiescence. Transcriptome-wide analysis of bone marrow endothelial cells demonstrated enrichment of genes involved in epithelial growth factor receptor (Egfr) signaling in mice with diet-induced diabetes mellitus. To explore whether endothelial Egfr plays a functional role in myelopoiesis, we generated mice with endothelial-specific deletion of Egfr (). We found enhanced HSPC proliferation and increased myeloid cell production in mice compared with wild-type mice with diabetes mellitus. Disrupted Egfr signaling in endothelial cells decreased their expression of the HSPC retention factor angiopoietin-1. We tested the functional relevance of these findings for wound healing and atherosclerosis, both implicated in complications of diabetes mellitus. Inflammatory myeloid cells accumulated more in skin wounds of diabetic mice, significantly delaying wound closure. Atherosclerosis was accelerated in mice, leading to larger and more inflamed atherosclerotic lesions in the aorta.
CONCLUSIONS
In diabetes mellitus, bone marrow endothelial cells participate in the dysregulation of bone marrow hematopoiesis. Diabetes mellitus reduces endothelial production of Cxcl12, a quiescence-promoting niche factor that reduces stem cell proliferation. We describe a previously unknown counterregulatory pathway, in which protective endothelial Egfr signaling curbs HSPC proliferation and myeloid cell production.
Topics: Animals; Bone Marrow Cells; Diabetes Mellitus, Experimental; Disease Models, Animal; Endothelial Cells; Epidermal Growth Factor; ErbB Receptors; Gene Expression Profiling; Gene Expression Regulation; Male; Mice; Models, Biological; Myeloid Cells; Myelopoiesis; Signal Transduction; Transcriptome
PubMed: 32316750
DOI: 10.1161/CIRCULATIONAHA.120.046038 -
Current Osteoporosis Reports Apr 2018Changes in the bone marrow microenvironment, which accompany aging and obesity, including increased marrow adiposity, can compromise hematopoiesis. Here, we review... (Review)
Review
PURPOSE OF REVIEW
Changes in the bone marrow microenvironment, which accompany aging and obesity, including increased marrow adiposity, can compromise hematopoiesis. Here, we review deleterious shifts in molecular, cellular, and tissue activity and consider the potential of exercise to slow degenerative changes associated with aging and obesity.
RECENT FINDINGS
While bone marrow hematopoietic stem cells (HSC) are increased in frequency and myeloid-biased with age, the effect of obesity on HSC proliferation and differentiation remains controversial. HSC from both aged and obese environment have reduced hematopoietic reconstitution capacity following bone marrow transplant. Increased marrow adiposity affects HSC function, causing upregulation of myelopoiesis and downregulation of lymphopoiesis. Exercise, in contrast, can reduce marrow adiposity and restore hematopoiesis. The impact of marrow adiposity on hematopoiesis is determined mainly through correlations. Mechanistic studies are needed to determine a causative relationship between marrow adiposity and declines in hematopoiesis, which could aid in developing treatments for conditions that arise from disruptions in the marrow microenvironment.
Topics: Adiposity; Aging; Bone Marrow; Cell Differentiation; Cell Proliferation; Exercise; Hematopoiesis; Hematopoietic Stem Cells; Humans; Lymphopoiesis; Myelopoiesis; Obesity
PubMed: 29476393
DOI: 10.1007/s11914-018-0424-1 -
Arteriosclerosis, Thrombosis, and... Jan 2021Until recently, immunologic memory was considered an exclusive characteristic of adaptive immunity. However, recent advances suggest that the innate arm of the immune... (Review)
Review
Until recently, immunologic memory was considered an exclusive characteristic of adaptive immunity. However, recent advances suggest that the innate arm of the immune system can also mount a type of nonspecific memory responses. Innate immune cells can elicit a robust response to subsequent inflammatory challenges after initial activation by certain stimuli, such as fungal-derived agents or vaccines. This type of memory, termed trained innate immunity (also named innate immune memory), is associated with epigenetic and metabolic alterations. Hematopoietic progenitor cells, which are the cells responsible for the generation of mature myeloid cells at steady-state and during inflammation, have a critical contribution to the induction of innate immune memory. Inflammation-triggered alterations in cellular metabolism, the epigenome and transcriptome of hematopoietic progenitor cells in the bone marrow promote long-lasting functional changes, resulting in increased myelopoiesis and consequent generation of trained innate immune cells. In the present brief review, we focus on the involvement of hematopoietic progenitors in the process of trained innate immunity and its possible role in cardiometabolic disease.
Topics: Bone Marrow; Cardiovascular Diseases; Hematopoietic Stem Cells; Humans; Immunity, Innate; Immunologic Memory; Metabolic Diseases; Myelopoiesis
PubMed: 33207931
DOI: 10.1161/ATVBAHA.120.314215 -
European Journal of Immunology Nov 2010Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that share a common property of suppressing immune responses. Several... (Review)
Review
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that share a common property of suppressing immune responses. Several helminth and protozoan parasite species have developed efficient strategies to increase the rate of medullary or extramedullary myelopoiesis and to induce the expansion and accumulation of immature myeloid cells such as MDSC. In this review, we examine current knowledge on the factors mediating enhanced myelopoiesis and MDSC induction and recruitment during parasitic infections and how the MDSC phenotype and mechanism of immune modulation and suppression depends on the factors they encounter within the host. Finally, we place MDSC expansion in the context of the critical balance between parasite elimination and pathogenicity to the host and suggest attractive avenues for future research.
Topics: Animals; Helminthiasis; Hematopoiesis, Extramedullary; Host-Parasite Interactions; Humans; Myeloid Cells; Myelopoiesis; Protozoan Infections
PubMed: 21061431
DOI: 10.1002/eji.201040911 -
Cellular Immunology Mar 2021Adoptive T cell therapy (ACT) in combination with lymphodepleting chemotherapy is an effective strategy to induce the eradication of cancer, providing long-term... (Review)
Review
Adoptive T cell therapy (ACT) in combination with lymphodepleting chemotherapy is an effective strategy to induce the eradication of cancer, providing long-term regressions in patients. However, only a minority of patients that receive ACT with tumor-specific T cells exhibit durable benefit. Thus, there is an urgent need to characterize mechanisms of resistance and define strategies to alleviate immunosuppression in the context of ACT in cancer. This article reviews the importance of lymphodepleting regimens in promoting the optimal engraftment and expansion of T cells in hosts after adoptive transfer. In addition, we discuss the role of concomitant immunosuppression and the accumulation of myeloid derived suppressor cells (MDSCs) during immune recovery after lymphodepleting regimens and mobilization regimens.
Topics: Adoptive Transfer; Animals; Cell- and Tissue-Based Therapy; Humans; Immune Tolerance; Immunosuppression Therapy; Immunotherapy, Adoptive; Lymphocyte Depletion; Myeloid Cells; Myeloid-Derived Suppressor Cells; Myelopoiesis; Neoplasms; T-Lymphocytes
PubMed: 33476931
DOI: 10.1016/j.cellimm.2020.104277 -
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 -
Cellular and Molecular Life Sciences :... Apr 2018Hematopoiesis is hierarchically orchestrated by a very small population of hematopoietic stem cells (HSCs) that reside in the bone-marrow niche and are tightly regulated... (Review)
Review
Hematopoiesis is hierarchically orchestrated by a very small population of hematopoietic stem cells (HSCs) that reside in the bone-marrow niche and are tightly regulated to maintain homeostatic blood production. HSCs are predominantly quiescent, but they enter the cell cycle in response to inflammatory signals evoked by severe systemic infection or injury. Thus, hematopoietic stem and progenitor cells (HSPCs) can be activated by pathogen recognition receptors and proinflammatory cytokines to induce emergency myelopoiesis during infection. This emergency myelopoiesis counterbalances the loss of cells and generates lineage-restricted hematopoietic progenitors, eventually replenishing mature myeloid cells to control the infection. Controlled generation of such signals effectively augments host defense, but dysregulated stimulation by these signals is harmful to HSPCs. Such hematopoietic failure often results in blood disorders including chronic inflammatory diseases and hematological malignancies. Recently, we found that interleukin (IL)-27, one of the IL-6/IL-12 family cytokines, has a unique ability to directly act on HSCs and promote their expansion and differentiation into myeloid progenitors. This process resulted in enhanced production of neutrophils by emergency myelopoiesis during the blood-stage mouse malaria infection. In this review, we summarize recent advances in the regulation of myelopoiesis by proinflammatory cytokines including type I and II interferons, IL-6, IL-27, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, and IL-1 in infectious diseases.
Topics: Animals; Cell Cycle; Cell Differentiation; Cell Proliferation; Gene Expression Regulation; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Humans; Interferons; Interleukin-1; Interleukin-6; Interleukins; Macrophage Colony-Stimulating Factor; Malaria; Mice; Myeloid Progenitor Cells; Myelopoiesis; Neutrophils; Plasmodium berghei
PubMed: 29218601
DOI: 10.1007/s00018-017-2724-5 -
Hematology. American Society of... Dec 2017Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in over a decade ago... (Review)
Review
Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in over a decade ago heralded a new age for patient care as a consequence of improved diagnosis and the development of therapeutic JAK inhibitors. The more recent identification of mutations in calreticulin brought with it a sense of completeness, with most patients with myeloproliferative neoplasm now having a biological basis for their excessive myeloproliferation. We are also beginning to understand the processes that lead to acquisition of somatic mutations and the factors that influence subsequent clonal expansion and emergence of disease. Extended genomic profiling has established a multitude of additional acquired mutations, particularly prevalent in myelofibrosis, where their presence carries prognostic implications. A major goal is to integrate genetic, clinical, and laboratory features to identify patients who share disease biology and clinical outcome, such that therapies, both existing and novel, can be better targeted.
Topics: Animals; DNA Mutational Analysis; Hematologic Neoplasms; Humans; Janus Kinase 2; Mutation; Myelopoiesis; Myeloproliferative Disorders; Protein Kinase Inhibitors
PubMed: 29222295
DOI: 10.1182/asheducation-2017.1.470 -
Cell Reports Oct 2021In emergency myelopoiesis (EM), expansion of the myeloid progenitor compartment and increased myeloid cell production are observed and often mediated by the...
In emergency myelopoiesis (EM), expansion of the myeloid progenitor compartment and increased myeloid cell production are observed and often mediated by the pro-inflammatory cytokine interferon gamma (IFN-γ). Interleukin-10 (IL-10) inhibits IFN-γ secretion, but paradoxically, its therapeutic administration to humans causes hematologic changes similar to those observed in EM. In this work, we use different in vivo systems, including a humanized immune system mouse model, to show that IL-10 triggers EM, with a significant expansion of the myeloid progenitor compartment and production of myeloid cells. Hematopoietic progenitors display a prominent IFN-γ transcriptional signature, and we show that IFN-γ mediates IL-10-driven EM. We also find that IL-10, unexpectedly, reprograms CD4 and CD8 T cells toward an activation state that includes IFN-γ production by these T cell subsets in vivo. Therefore, in addition to its established anti-inflammatory properties, IL-10 can induce IFN-γ production and EM, opening additional perspectives for the design of IL-10-based immunotherapies.
Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Interferon-gamma; Interleukin-10; Mice; Mice, Knockout; Myeloid Progenitor Cells; Myelopoiesis
PubMed: 34706233
DOI: 10.1016/j.celrep.2021.109887 -
Journal of Cellular and Molecular... May 2012In the relatively short period of time since their discovery, microRNAs have been shown to control many important cellular functions such as cell differentiation,... (Review)
Review
In the relatively short period of time since their discovery, microRNAs have been shown to control many important cellular functions such as cell differentiation, growth, proliferation and apoptosis. In addition, microRNAs have been demonstrated as key drivers of many malignancies and can function as either tumour suppressors or oncogenes. The haematopoietic system is not outside the realm of microRNA control with microRNAs controlling aspects of stem cell and progenitor self-renewal and differentiation, with many, if not all, haematological disorders associated with aberrant microRNA expression and function. In this review, we focus on the current understanding of microRNA control of haematopoiesis and detail the evidence for the contribution and clinical relevance of aberrant microRNA function to the characteristic block of differentiation in acute myeloid leukaemia.
Topics: Animals; Apoptosis; Cell Differentiation; Gene Expression Regulation, Neoplastic; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Macrophages; Mice; MicroRNAs; Myelopoiesis
PubMed: 22225649
DOI: 10.1111/j.1582-4934.2011.01514.x