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Nature Cardiovascular Research Dec 2023After myocardial infarction (MI), emergency hematopoiesis produces inflammatory myeloid cells that accelerate atherosclerosis and promote heart failure. Since the...
After myocardial infarction (MI), emergency hematopoiesis produces inflammatory myeloid cells that accelerate atherosclerosis and promote heart failure. Since the balance between glycolysis and mitochondrial metabolism regulates hematopoietic stem cell homeostasis, metabolic cues may influence emergency myelopoiesis. Here, we show in humans and female mice that hematopoietic progenitor cells increase fatty acid metabolism after MI. Blockade of fatty acid oxidation by deleting carnitine palmitoyltransferase () in hematopoietic cells of mice limited hematopoietic progenitor proliferation and myeloid cell expansion after MI. We also observed reduced bone marrow adiposity in humans, pigs and mice following MI. Inhibiting lipolysis in adipocytes using mice or local depletion of bone marrow adipocytes in mice also curbed emergency hematopoiesis. Furthermore, systemic and regional sympathectomy prevented bone marrow adipocyte shrinkage after MI. These data establish a critical role for fatty acid metabolism in post-MI emergency hematopoiesis.
PubMed: 38344689
DOI: 10.1038/s44161-023-00388-7 -
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 -
Frontiers in Cellular and Infection... 2023Jun B proto-oncogene (JunB) is a crucial member of dimeric activator protein-1 (AP-1) complex, which plays a significant role in various physiological processes, such as... (Review)
Review
Jun B proto-oncogene (JunB) is a crucial member of dimeric activator protein-1 (AP-1) complex, which plays a significant role in various physiological processes, such as placental formation, cardiovascular development, myelopoiesis, angiogenesis, endochondral ossification and epidermis tissue homeostasis. Additionally, it has been reported that JunB has great regulatory functions in innate and adaptive immune responses by regulating the differentiation and cytokine secretion of immune cells including T cells, dendritic cells and macrophages, while also facilitating the effector of neutrophils and natural killer cells. Furthermore, a growing body of studies have shown that JunB is involved in tumorigenesis through regulating cell proliferation, differentiation, senescence and metastasis, particularly affecting the tumor microenvironment through transcriptional promotion or suppression of oncogenes in tumor cells or immune cells. This review summarizes the physiological function of JunB, its immune regulatory function, and its contribution to tumorigenesis, especially focusing on its regulatory mechanisms within tumor-associated immune processes.
Topics: Female; Pregnancy; Humans; Placenta; Neoplasms; Carcinogenesis; Cell Transformation, Neoplastic; Immunity; Tumor Microenvironment; Transcription Factors
PubMed: 37731821
DOI: 10.3389/fcimb.2023.1222265 -
Haematologica Oct 2023Shwachman-Diamond syndrome is a rare inherited bone marrow failure syndrome characterized by neutropenia, exocrine pancreatic insufficiency, and skeletal abnormalities....
Shwachman-Diamond syndrome is a rare inherited bone marrow failure syndrome characterized by neutropenia, exocrine pancreatic insufficiency, and skeletal abnormalities. In 10-30% of cases, transformation to a myeloid neoplasm occurs. Approximately 90% of patients have biallelic pathogenic variants in the SBDS gene located on human chromosome 7q11. Over the past several years, pathogenic variants in three other genes have been identified to cause similar phenotypes; these are DNAJC21, EFL1, and SRP54. Clinical manifestations involve multiple organ systems and those classically associated with the Shwachman-Diamond syndrome (bone, blood, and pancreas). Neurocognitive, dermatologic, and retinal changes may also be found. There are specific gene-phenotype differences. To date, SBDS, DNAJC21, and SRP54 variants have been associated with myeloid neoplasia. Common to SBDS, EFL1, DNAJC21, and SRP54 is their involvement in ribosome biogenesis or early protein synthesis. These four genes constitute a common biochemical pathway conserved from yeast to humans that involve early stages of protein synthesis and demonstrate the importance of this synthetic pathway in myelopoiesis.
Topics: Humans; Shwachman-Diamond Syndrome; Lipomatosis; Bone Marrow Diseases; Mutation; Exocrine Pancreatic Insufficiency; Signal Recognition Particle
PubMed: 37226705
DOI: 10.3324/haematol.2023.282949 -
The Journal of Clinical Investigation Dec 2023We previously demonstrated that a subset of acute myeloid leukemia (AML) patients with concurrent RAS pathway and TP53 mutations have an extremely poor prognosis and...
We previously demonstrated that a subset of acute myeloid leukemia (AML) patients with concurrent RAS pathway and TP53 mutations have an extremely poor prognosis and that most of these TP53 mutations are missense mutations. Here, we report that, in contrast to the mixed AML and T cell malignancy that developed in NrasG12D/+ p53-/- (NP-/-) mice, NrasG12D/+ p53R172H/+ (NPmut) mice rapidly developed inflammation-associated AML. Under the inflammatory conditions, NPmut hematopoietic stem and progenitor cells (HSPCs) displayed imbalanced myelopoiesis and lymphopoiesis and mostly normal cell proliferation despite MEK/ERK hyperactivation. RNA-Seq analysis revealed that oncogenic NRAS signaling and mutant p53 synergized to establish an NPmut-AML transcriptome distinct from that of NP-/- cells. The NPmut-AML transcriptome showed GATA2 downregulation and elevated the expression of inflammatory genes, including those linked to NF-κB signaling. NF-κB was also upregulated in human NRAS TP53 AML. Exogenous expression of GATA2 in human NPmut KY821 AML cells downregulated inflammatory gene expression. Mouse and human NPmut AML cells were sensitive to MEK and NF-κB inhibition in vitro. The proteasome inhibitor bortezomib stabilized the NF-κB-inhibitory protein IκBα, reduced inflammatory gene expression, and potentiated the survival benefit of a MEK inhibitor in NPmut mice. Our study demonstrates that a p53 structural mutant synergized with oncogenic NRAS to promote AML through mechanisms distinct from p53 loss.
Topics: Animals; Humans; Mice; Gain of Function Mutation; GTP Phosphohydrolases; Leukemia, Myeloid, Acute; Membrane Proteins; Mitogen-Activated Protein Kinase Kinases; Mutation; NF-kappa B; Tumor Suppressor Protein p53
PubMed: 37847561
DOI: 10.1172/JCI173116 -
Frontiers in Oncology 2024Hematopoiesis is a tightly regulated process that produces all adult blood cells and immune cells from multipotent hematopoietic stem cells (HSCs). HSCs usually remain... (Review)
Review
Hematopoiesis is a tightly regulated process that produces all adult blood cells and immune cells from multipotent hematopoietic stem cells (HSCs). HSCs usually remain quiescent, and in the presence of external stimuli like infection or inflammation, they undergo division and differentiation as a compensatory mechanism. Normal hematopoiesis is impacted by systemic inflammation, which causes HSCs to transition from quiescence to emergency myelopoiesis. At the molecular level, inflammatory cytokine signaling molecules such as tumor necrosis factor (TNF), interferons, interleukins, and toll-like receptors can all cause HSCs to multiply directly. These cytokines actively encourage HSC activation, proliferation, and differentiation during inflammation, which results in the generation and activation of immune cells required to combat acute injury. The bone marrow niche provides numerous soluble and stromal cell signals, which are essential for maintaining normal homeostasis and output of the bone marrow cells. Inflammatory signals also impact this bone marrow microenvironment called the HSC niche to regulate the inflammatory-induced hematopoiesis. Continuous pro-inflammatory cytokine and chemokine activation can have detrimental effects on the hematopoietic system, which can lead to cancer development, HSC depletion, and bone marrow failure. Reactive oxygen species (ROS), which damage DNA and ultimately lead to the transformation of HSCs into cancerous cells, are produced due to chronic inflammation. The biological elements of the HSC niche produce pro-inflammatory cytokines that cause clonal growth and the development of leukemic stem cells (LSCs) in hematological malignancies. The processes underlying how inflammation affects hematological malignancies are still not fully understood. In this review, we emphasize the effects of inflammation on normal hematopoiesis, the part it plays in the development and progression of hematological malignancies, and potential therapeutic applications for targeting these pathways for therapy in hematological malignancies.
PubMed: 38571491
DOI: 10.3389/fonc.2024.1347402 -
The Journal of Experimental Medicine Dec 2023Infection is able to promote innate immunity by enhancing a long-term myeloid output even after the inciting infectious agent has been cleared. However, the mechanisms...
Infection is able to promote innate immunity by enhancing a long-term myeloid output even after the inciting infectious agent has been cleared. However, the mechanisms underlying such a regulation are not fully understood. Using a mouse polymicrobial peritonitis (sepsis) model, we show that severe infection leads to increased, sustained myelopoiesis after the infection is resolved. In post-infection mice, the tissue inhibitor of metalloproteinases 1 (TIMP1) is constitutively upregulated. TIMP1 antagonizes the function of ADAM10, an essential cleavage enzyme for the activation of the Notch signaling pathway, which suppresses myelopoiesis. While TIMP1 is dispensable for myelopoiesis under the steady state, increased TIMP1 enhances myelopoiesis after infection. Thus, our data establish TIMP1 as a molecular reporter of past infection in the host, sustaining hyper myelopoiesis and serving as a potential therapeutic target for modulating HSPC cell fate.
Topics: Animals; Mice; Cell Differentiation; Hematopoiesis; Immunity, Innate; Myelopoiesis; Sepsis; Tissue Inhibitor of Metalloproteinase-1
PubMed: 37851372
DOI: 10.1084/jem.20230018 -
British Journal of Haematology Jan 2024Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency and skeletal abnormalities. SDS bone marrow haematopoietic...
Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency and skeletal abnormalities. SDS bone marrow haematopoietic progenitors show increased apoptosis and impairment in granulocytic differentiation. Loss of Shwachman-Bodian-Diamond syndrome (SBDS) expression results in reduced eukaryotic 80S ribosome maturation. Biallelic mutations in the SBDS gene are found in ~90% of SDS patients, ~55% of whom carry the c.183-184TA>CT nonsense mutation. Several translational readthrough-inducing drugs aimed at suppressing nonsense mutations have been developed. One of these, ataluren, has received approval in Europe for the treatment of Duchenne muscular dystrophy. We previously showed that ataluren can restore full-length SBDS protein synthesis in SDS-derived bone marrow cells. Here, we extend our preclinical study to assess the functional restoration of SBDS capabilities in vitro and ex vivo. Ataluren improved 80S ribosome assembly and total protein synthesis in SDS-derived cells, restored myelopoiesis in myeloid progenitors, improved neutrophil chemotaxis in vitro and reduced neutrophil dysplastic markers ex vivo. Ataluren also restored full-length SBDS synthesis in primary osteoblasts, suggesting that its beneficial role may go beyond the myeloid compartment. Altogether, our results strengthened the rationale for a Phase I/II clinical trial of ataluren in SDS patients who harbour the nonsense mutation.
Topics: Humans; Shwachman-Diamond Syndrome; Tumor Suppressor Protein p53; Lipomatosis; Codon, Nonsense; Myelopoiesis; Neutrophils; Chemotaxis; Bone Marrow Diseases; Exocrine Pancreatic Insufficiency; Ribosomes
PubMed: 37876306
DOI: 10.1111/bjh.19134 -
ELife Aug 2023Monocytes are heterogeneous innate effector leukocytes generated in the bone marrow and released into circulation in a CCR2-dependent manner. During infection or...
Monocytes are heterogeneous innate effector leukocytes generated in the bone marrow and released into circulation in a CCR2-dependent manner. During infection or inflammation, myelopoiesis is modulated to rapidly meet the demand for more effector cells. Danger signals from peripheral tissues can influence this process. Herein we demonstrate that repetitive TLR7 stimulation via the epithelial barriers drove a potent emergency bone marrow monocyte response in mice. This process was unique to TLR7 activation and occurred independently of the canonical CCR2 and CX3CR1 axes or prototypical cytokines. The monocytes egressing the bone marrow had an immature Ly6C-high profile and differentiated into vascular Ly6C-low monocytes and tissue macrophages in multiple organs. They displayed a blunted cytokine response to further TLR7 stimulation and reduced lung viral load after RSV and influenza virus infection. These data provide insights into the emergency myelopoiesis likely to occur in response to the encounter of single-stranded RNA viruses at barrier sites.
Topics: Animals; Mice; Cytokines; Lung; Mice, Inbred C57BL; Monocytes; Myelopoiesis; Toll-Like Receptor 7; Virus Diseases
PubMed: 37566453
DOI: 10.7554/eLife.85647