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Signal Transduction and Targeted Therapy Jul 2023Traumatic brain injury (TBI) accelerates fracture healing, but the underlying mechanism remains largely unknown. Accumulating evidence indicates that the central nervous...
Traumatic brain injury (TBI) accelerates fracture healing, but the underlying mechanism remains largely unknown. Accumulating evidence indicates that the central nervous system (CNS) plays a pivotal role in regulating immune system and skeletal homeostasis. However, the impact of CNS injury on hematopoiesis commitment was overlooked. Here, we found that the dramatically elevated sympathetic tone accompanied with TBI-accelerated fracture healing; chemical sympathectomy blocks TBI-induced fracture healing. TBI-induced hypersensitivity of adrenergic signaling promotes the proliferation of bone marrow hematopoietic stem cells (HSCs) and swiftly skews HSCs toward anti-inflammation myeloid cells within 14 days, which favor fracture healing. Knockout of β3- or β2-adrenergic receptor (AR) eliminate TBI-mediated anti-inflammation macrophage expansion and TBI-accelerated fracture healing. RNA sequencing of bone marrow cells revealed that Adrb2 and Adrb3 maintain proliferation and commitment of immune cells. Importantly, flow cytometry confirmed that deletion of β2-AR inhibits M2 polarization of macrophages at 7th day and 14th day; and TBI-induced HSCs proliferation was impaired in β3-AR knockout mice. Moreover, β3- and β2-AR agonists synergistically promote infiltration of M2 macrophages in callus and accelerate bone healing process. Thus, we conclude that TBI accelerates bone formation during early stage of fracture healing process by shaping the anti-inflammation environment in the bone marrow. These results implicate that the adrenergic signals could serve as potential targets for fracture management.
Topics: Mice; Animals; Fracture Healing; Bone Marrow; Myelopoiesis; Mice, Knockout; Brain Injuries, Traumatic; Adrenergic Agents
PubMed: 37402714
DOI: 10.1038/s41392-023-01457-w -
Mitochondrial pyruvate metabolism and glutaminolysis toggle steady-state and emergency myelopoiesis.The Journal of Experimental Medicine Sep 2023To define the metabolic requirements of hematopoiesis, we examined blood lineages in mice conditionally deficient in genes required for long-chain fatty acid oxidation...
To define the metabolic requirements of hematopoiesis, we examined blood lineages in mice conditionally deficient in genes required for long-chain fatty acid oxidation (Cpt2), glutaminolysis (Gls), or mitochondrial pyruvate import (Mpc2). Genetic ablation of Cpt2 or Gls minimally impacted most blood lineages. In contrast, deletion of Mpc2 led to a sharp decline in mature myeloid cells and a slower reduction in T cells, whereas other hematopoietic lineages were unaffected. Yet MPC2-deficient monocytes and neutrophils rapidly recovered due to a transient and specific increase in myeloid progenitor proliferation. Competitive bone marrow chimera and stable isotope tracing experiments demonstrated that this proliferative burst was progenitor intrinsic and accompanied by a metabolic switch to glutaminolysis. Myeloid recovery after loss of MPC2 or cyclophosphamide treatment was delayed in the absence of GLS. Reciprocally, MPC2 was not required for myeloid recovery after cyclophosphamide treatment. Thus, mitochondrial pyruvate metabolism maintains myelopoiesis under steady-state conditions, while glutaminolysis in progenitors promotes emergency myelopoiesis.
Topics: Mice; Animals; Myelopoiesis; Hematopoiesis; Bone Marrow; Cyclophosphamide; Pyruvates
PubMed: 37249600
DOI: 10.1084/jem.20221373 -
Cardiovascular Research Feb 2024Cardiometabolic disorders are chief causes of morbidity and mortality, with chronic inflammation playing a crucial role in their pathogenesis. The release of... (Review)
Review
Cardiometabolic disorders are chief causes of morbidity and mortality, with chronic inflammation playing a crucial role in their pathogenesis. The release of differentiated myeloid cells with elevated pro-inflammatory potential, as a result of maladaptively trained myelopoiesis may be a crucial factor for the perpetuation of inflammation. Several cardiovascular risk factors, including sedentary lifestyle, unhealthy diet, hypercholesterolemia, and hyperglycemia, may modulate bone marrow hematopoietic progenitors, causing sustained functional changes that favour chronic metabolic and vascular inflammation. In the present review, we summarize recent studies that support the function of long-term inflammatory memory in progenitors of the bone marrow for the development and progression of cardiometabolic disease and related inflammatory comorbidities, including periodontitis and arthritis. We also discuss how maladaptive myelopoiesis associated with the presence of mutated hematopoietic clones, as present in clonal hematopoiesis, may accelerate atherosclerosis via increased inflammation.
Topics: Humans; Bone Marrow; Hematopoietic Stem Cells; Myelopoiesis; Atherosclerosis; Inflammation; Hematopoiesis
PubMed: 36655373
DOI: 10.1093/cvr/cvad003 -
ELife Jun 2023Polycomb repressive complex (PRC) 1 regulates stem cell fate by mediating mono-ubiquitination of histone H2A at lysine 119. While canonical PRC1 is critical for...
Polycomb repressive complex (PRC) 1 regulates stem cell fate by mediating mono-ubiquitination of histone H2A at lysine 119. While canonical PRC1 is critical for hematopoietic stem and progenitor cell (HSPC) maintenance, the role of non-canonical PRC1 in hematopoiesis remains elusive. PRC1.1, a non-canonical PRC1, consists of PCGF1, RING1B, KDM2B, and BCOR. We recently showed that PRC1.1 insufficiency induced by the loss of PCGF1 or BCOR causes myeloid-biased hematopoiesis and promotes transformation of hematopoietic cells in mice. Here we show that PRC1.1 serves as an epigenetic switch that coordinates homeostatic and emergency hematopoiesis. PRC1.1 maintains balanced output of steady-state hematopoiesis by restricting C/EBPα-dependent precocious myeloid differentiation of HSPCs and the HOXA9- and β-catenin-driven self-renewing network in myeloid progenitors. Upon regeneration, PRC1.1 is transiently inhibited to facilitate formation of granulocyte-macrophage progenitor (GMP) clusters, thereby promoting emergency myelopoiesis. Moreover, constitutive inactivation of PRC1.1 results in unchecked expansion of GMPs and eventual transformation. Collectively, our results define PRC1.1 as a novel critical regulator of emergency myelopoiesis, dysregulation of which leads to myeloid transformation.
Topics: Animals; Mice; Polycomb Repressive Complex 1; Myelopoiesis; Histones; Cell Differentiation; Hematopoietic Stem Cells
PubMed: 37266576
DOI: 10.7554/eLife.83004 -
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 -
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 -
Communications Biology Sep 2023Protection of telomeres 1a (POT1a) is a telomere binding protein. A decrease of POT1a is related to myeloid-skewed haematopoiesis with ageing, suggesting that protection...
Protection of telomeres 1a (POT1a) is a telomere binding protein. A decrease of POT1a is related to myeloid-skewed haematopoiesis with ageing, suggesting that protection of telomeres is essential to sustain multi-potency. Since mesenchymal stem cells (MSCs) are a constituent of the hematopoietic niche in bone marrow, their dysfunction is associated with haematopoietic failure. However, the importance of telomere protection in MSCs has yet to be elucidated. Here, we show that genetic deletion of POT1a in MSCs leads to intracellular accumulation of fatty acids and excessive ROS and DNA damage, resulting in impaired osteogenic-differentiation. Furthermore, MSC-specific POT1a deficient mice exhibited skeletal retardation due to reduction of IL-7 producing bone lining osteoblasts. Single-cell gene expression profiling of bone marrow from POT1a deficient mice revealed that B-lymphopoiesis was selectively impaired. These results demonstrate that bone marrow microenvironments composed of POT1a deficient MSCs fail to support B-lymphopoiesis, which may underpin age-related myeloid-bias in haematopoiesis.
Topics: Animals; Mice; Aging; Cell Differentiation; Lymphopoiesis; Telomere; Telomere-Binding Proteins
PubMed: 37773433
DOI: 10.1038/s42003-023-05374-0 -
Scientific Reports Jul 2023Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease of prematurity with limited treatment options. To uncover biomarkers of BPD risk, this study...
Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease of prematurity with limited treatment options. To uncover biomarkers of BPD risk, this study investigated epigenetic and transcriptomic signatures of prematurity at birth and during the neonatal period at day 14 and 28. Peripheral blood DNAs from preterm infants were applied to methylation arrays and cell-type composition was estimated by deconvolution. Covariate-adjusted robust linear regression elucidated BPD- and prolonged oxygen (≥ 14 days) exposure-associated CpGs. RNAs from cord and peripheral blood were sequenced, and differentially expressed genes (DEGs) for BPD or oxygen exposure were determined. Estimated neutrophil-lymphocyte ratios in peripheral blood at day 14 in BPD infants were significantly higher than nonBPD infants, suggesting an heightened inflammatory response in developing BPD. BPD-DEGs in cord blood indicated lymphopoiesis inhibition, altered Th1/Th2 responses, DNA damage, and organ degeneration. On day 14, BPD-associated CpGs were highly enriched in neutrophil activation, infection, and CD4 + T cell quantity, and BPD-DEGs were involved in DNA damage, cellular senescence, T cell homeostasis, and hyper-cytokinesis. On day 28, BPD-associated CpGs along with BPD-DEGs were enriched for phagocytosis, neurological disorder, and nucleotide metabolism. Oxygen supplementation markedly downregulated mitochondrial biogenesis genes and altered CpGs annotated to developmental genes. Prematurity-altered DNA methylation could cause abnormal lymphopoiesis, cellular assembly and cell cycle progression to increase BPD risk. Similar pathways between epigenome and transcriptome networks suggest coordination of the two in dysregulating leukopoiesis, adaptive immunity, and innate immunity. The results provide molecular insights into biomarkers for early detection and prevention of BPD.
Topics: Infant; Humans; Infant, Newborn; Infant, Premature; Bronchopulmonary Dysplasia; Epigenome; Prospective Studies; Gene Expression Profiling; Biomarkers; Oxygen
PubMed: 37507442
DOI: 10.1038/s41598-023-39313-0 -
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 -
Blood Advances Sep 2023Metabolic products of the microbiota can alter hematopoiesis. However, the contribution and site of action of bile acids is poorly understood. Here, we demonstrate that...
Metabolic products of the microbiota can alter hematopoiesis. However, the contribution and site of action of bile acids is poorly understood. Here, we demonstrate that the secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA), increase bone marrow myelopoiesis. Treatment of bone marrow cells with DCA and LCA preferentially expanded immunophenotypic and functional colony-forming unit-granulocyte and macrophage (CFU-GM) granulocyte-monocyte progenitors (GMPs). DCA treatment of sorted hematopoietic stem and progenitor cells (HSPCs) increased CFU-GMs, indicating that direct exposure of HSPCs to DCA sufficed to increase GMPs. The vitamin D receptor (VDR) was required for the DCA-induced increase in CFU-GMs and GMPs. Single-cell RNA sequencing revealed that DCA significantly upregulated genes associated with myeloid differentiation and proliferation in GMPs. The action of DCA on HSPCs to expand GMPs in a VDR-dependent manner suggests microbiome-host interactions could directly affect bone marrow hematopoiesis and potentially the severity of infectious and inflammatory disease.
Topics: Bile Acids and Salts; Myeloid Progenitor Cells; Myelopoiesis; Receptors, Calcitriol
PubMed: 37276450
DOI: 10.1182/bloodadvances.2022009618