The ETS transcription factor Etv2 is necessary and sufficient for the generation of hematopoietic and endothelial cells. However, upstream regulators of Etv2 in hemangiogenesis, generation of ...hematopoietic and endothelial cells, have not been clearly addressed. Here we track the developmental route of hemangiogenic progenitors from mouse embryonic stem cells, perform genome-wide CRISPR screening, and transcriptome analysis of en route cell populations by utilizing Brachyury, Etv2, or Scl reporter embryonic stem cell lines to further understand the mechanisms that control hemangiogenesis. We identify the forkhead transcription factor Foxh1, in part through Eomes, to be critical for the formation of FLK1
mesoderm, from which the hemangiogenic fate is specified. Importantly, hemangiogenic fate is specified not simply by the onset of Etv2 expression, but by a threshold-dependent mechanism, in which VEGF-FLK1 signaling plays an instructive role by promoting Etv2 threshold expression. These studies reveal comprehensive cellular and molecular pathways governing the hemangiogenic cell lineage development.How haematopoietic and endothelial cell lineages are specified is unclear. Here, the authors identify the forkhead transcription factor Foxh1 as regulating FLK1+ mesoderm formation in mouse embryonic stem cells, which in turn specifies hemangiogenic fate via Etv2.
Silver nanoparticles (AgNPs) are widely applied in many household products and medical uses. However, studies on the effects of AgNPs on human health and environmental implications are in the ...beginning stage. Furthermore, most data on the toxicity of AgNPs have been generated using nanoparticles modified with detergents to prevent agglomeration, which may alter their toxicities. In this study, we studied toxicity using AgNPs prepared by dispersing them in fetal bovine serum (FBS), biocompatible materials. AgNPs (average size; 68.9
nm, concentrations; 0.2, 0.4, 0.8, and 1.6
ppm, exposure time; 24, 48, 72, and 96
h) showed cytotoxicity to cultured RAW264.7 cells by increasing sub G1 fraction, which indicates cellular apoptosis. AgNPs decreased intracellular glutathione level, increased NO secretion, increased TNF-α in protein and gene levels, and increased gene expression of matrix metalloproteinases (MMP-3, MMP-11, and MMP-19). When cells were treated with AgNPs, they were observed in the cytosol of the activated cells, but were not observed in the dead cells. It seemed that AgNPs were ionized in the cells to cause cytotoxicity by a Trojan-horse type mechanism suggested by previously reported studies.
Extramedullary hematopoiesis in cancer Barisas, Derek A G; Choi, Kyunghee
Experimental & molecular medicine,
03/2024, Letnik:
56, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Hematopoiesis can occur outside of the bone marrow during inflammatory stress to increase the production of primarily myeloid cells at extramedullary sites; this process is known as extramedullary ...hematopoiesis (EMH). As observed in a broad range of hematologic and nonhematologic diseases, EMH is now recognized for its important contributions to solid tumor pathology and prognosis. To initiate EMH, hematopoietic stem cells (HSCs) are mobilized from the bone marrow into the circulation and to extramedullary sites such as the spleen and liver. At these sites, HSCs primarily produce a pathological subset of myeloid cells that contributes to tumor pathology. The EMH HSC niche, which is distinct from the bone marrow HSC niche, is beginning to be characterized. The important cytokines that likely contribute to initiating and maintaining the EMH niche are KIT ligands, CXCL12, G-CSF, IL-1 family members, LIF, TNFα, and CXCR2. Further study of the role of EMH may offer valuable insights into emergency hematopoiesis and therapeutic approaches against cancer. Exciting future directions for the study of EMH include identifying common and distinct EMH mechanisms in cancer, infectious diseases, and chronic autoimmune diseases to control these conditions.
Despite frequent detection of ibuprofen in aquatic environments, the hazards associated with long-term exposure to ibuprofen have seldom been investigated. Ibuprofen is suspected of influencing sex ...steroid hormones through steroidogenic pathways in both vertebrates and invertebrates. In this study, the effect of ibuprofen on sex hormone balance and the associated mechanisms was investigated in vitro by use of H295R cells. We also conducted chronic toxicity tests using freshwater fish, Oryzias latipes, and two freshwater cladocerans, Daphnia magna and Moina macrocopa, for up to 144 and 21d of exposure, respectively. Ibuprofen exposure increased 17β-estradiol (E2) production and aromatase activity in H295R cells. Testosterone (T) production decreased in a dose-dependent manner. For D. magna, the 48h immobilization EC50 was 51.4mg/L and the 21d reproduction NOEC was <1.23mg/L; for M. macrocopa, the 48h immobilization EC50 was 72.6mg/L and the 7d reproduction NOEC was 25mg/L. For O. latipes, 120d survival NOEC was 0.0001mg/L. In addition, ibuprofen affected several endpoints related to reproduction of the fish, including induction of vitellogenin in male fish, fewer broods per pair, and more eggs per brood. Parental exposure to as low as 0.0001mg/L ibuprofen delayed hatching of eggs even when they were transferred to and cultured in clean water. Delayed hatching is environmentally relevant because this may increase the risk of being predated. For O. latipes, the acute-to-chronic ratio of ibuprofen was estimated to be greater than 1000. Overall, relatively high acute-to-chronic ratio and observation of reproduction damage in medaka fish at environmentally relevant ranges of ibuprofen warrant the need for further studies to elucidate potential ecological consequences of ibuprofen contamination in the aquatic environment.
National biomonitoring program can offer solid scientific evidence on exposure profiles of environmental chemicals at a national level, and provide a snapshot of changing exposure level over time. ...Therefore, several countries have maintained such programs for developing environmental health policies. The Korean National Environmental Health Survey (KoNEHS) was designed to understand the level of human exposure to environmental chemicals by time and location, and to identify possible sources of such exposure. The 2nd stage of KoNEHS, which was conducted between 2012 and 2014, examined a total of 6478 adult subjects over 19 years of age, and measured 21 environmental chemicals of major policy concern. Compared to the findings from the first stage monitoring (2009–2011), slightly higher levels of blood lead were observed, while those of mercury remained similar. Blood metal concentrations, however, were higher than those reported from national biomonitoring programs of United States, Germany and Canada. The urinary concentrations of phthalates metabolites were lower, but those of t,t-muconic acid and BPA were higher than those reported in the first stage survey. The urinary cotinine level decreased perhaps reflecting general declining patterns of first- and second-hand smoking. The results of the second stage survey were made available for public use since April 2016.
Some policy efforts appear to be at least in part effective on mitigating chemical exposure among people, e.g., urinary phthalate metabolites and cotinine, while further confirmations are warranted. In-depth assessments will be conducted to identify vulnerable groups and important exposure pathways.
Nuclear envelope membrane proteins (NEMPs) are a conserved family of nuclear envelope (NE) proteins that reside within the inner nuclear membrane (INM). Even though Nemp1 knockout (KO) mice are ...overtly normal, they display a pronounced splenomegaly. This phenotype and recent reports describing a requirement for NE openings during erythroblasts terminal maturation led us to examine a potential role for Nemp1 in erythropoiesis. Here, we report that Nemp1 KO mice show peripheral blood defects, anemia in neonates, ineffective erythropoiesis, splenomegaly, and stress erythropoiesis. The erythroid lineage of Nemp1 KO mice is overrepresented until the pronounced apoptosis of polychromatophilic erythroblasts. We show that NEMP1 localizes to the NE of erythroblasts and their progenitors. Mechanistically, we discovered that NEMP1 accumulates into aggregates that localize near or at the edge of NE openings and Nemp1 deficiency leads to a marked decrease of both NE openings and ensuing enucleation. Together, our results for the first time demonstrate that NEMP1 is essential for NE openings and erythropoietic maturation in vivo and provide the first mouse model of defective erythropoiesis directly linked to the loss of an INM protein.
Bone morphogenetic proteins (BMPs) regulate multiple aspects of skeletal development in vertebrates. Although exogenously applied BMPs can induce chondrogenesis de novo, the role and mechanism of ...physiologic BMP signaling during precartilaginous mesenchymal condensation is not well understood. By deleting the type I BMP receptors or the transcription factor Smad4 in the limb bud mesenchyme, we find that loss of BMP–Smad signaling abolishes skeletal development due to a failure in mesenchymal condensation. In the absence of Smad4, expression of Sox9, an essential transcription factor for chondrogenesis, initiates normally in the proximal mesenchyme of the limb bud, but fails to maintain its level or expand to the more distal territory at the later stages. However, forced-expression of Sox9 does not restore cartilage formation in the Smad4-deficeint embryo. In vitro micromass cultures show that the Smad4-deficient cells fail to condense in a cell-autonomous manner, even though they express several cell adhesion molecules either normally or even at a higher level. Thus, BMP–Smad signaling critically controls mesenchymal condensation to initiate skeletal development likely through a Sox9-independent mechanism.
•Deletion of Smad4 or type I Bmp receptors in limb bud mesenchyme abolishes appendicular skeleton.•Loss of Smad4 prevents precartilaginous mesenchymal condensation in a cell-autonomous manner.•Smad4 deletion does not impair expression of Ncad, Ncam1 and Ncam2 in limb mesenchymal cells.•Forced-expression of Sox9 does not restore limb skeleton in the absence of Smad4.
Background: Despite a growing number of investigations exploring the health problems in precarious workers, there is still a paucity of studies investigating workplace violence in workers with ...multi-party employment arrangements (WMPEAs). This study was aimed at comparing the prevalence of workplace violence between non-WMPEA and WMPEA. Methods: The 5th Korean Working Conditions Survey data were used. The study subjects were employees aged 20-74, with 26,239 non-WMPEA and 1,556 WMPEA. WMPEA included temporary agency workers and workers providing outsourced services. Workplace violence including verbal abuse, unwanted sexual attention, threats, and humiliating behaviors were used as outcome variables. The odds ratios of risk of workplace violence were calculated using multiple logistic regression. Results: The age-standardized prevalence of workplace violence was significantly higher among WMPEA. After adjusting for all covariates, the risk of workplace violence among WMPEA was still significant (OR 1.80, 95% CI 1.5-2.2) compared with non-WMPEA. The odds ratio of workplace violence among female WMPEA was 1.99 (95% CI 1.53-2.59), which is higher than that of male WMPEA (OR 1.52, 95% CI 1.18-1.96). Conclusion: We found that WMPEA were exposed to higher risk of workplace violence. Discrimination against WMPEA in the working environment and management policy need to be corrected. It is also necessary to identify the risk factors of workplace violence in WMPEA and to make efforts to prevent violence.
To understand potential risks of major pharmaceutical residues in waters, we evaluated ecotoxicities of five major veterinary pharmaceuticals, i.e., chlortetracycline, oxytetracycline, ...sulfamethazine, sulfathiazole, and erythromycin, which have been frequently detected in freshwater environment worldwide. We conducted acute and chronic toxicity tests using two freshwater invertebrates (
Daphnia magna
and
Moina macrocopa
) and a fish (
Oryzias latipes
). In general,
D. magna
exhibited greater sensitivity than
M. macrocopa
, and chronic reproduction was the most sensitive endpoints for both organisms. The population growth rate was adversely influenced by exposure to chlortetracycline, sulfamethazine, or sulfathiazole in water fleas, but reduction in population size was not expected. In
O. latipes
, the tested pharmaceuticals affected several reproduction related endpoints including time to hatch and growth. Based on the toxicity values from the present study and literature, algae appeared to be the most sensitive organism, followed by
Daphnia
and fish. Hazard quotients derived from measured environmental concentrations (MECs) and predicted no effect concentrations (PNECs) for erythromycin and oxytetracycline exceeded unity, suggesting that potential ecological effects at highly contaminated sites cannot be ruled out. Long-term consequences of veterinary pharmaceutical contamination in the environment deserve further investigation.
GATA factors interact with simple DNA motifs (WGATAR) to regulate critical processes, including hematopoiesis, but very few WGATAR motifs are occupied in genomes. Given the rudimentary knowledge of ...mechanisms underlying this restriction and how GATA factors establish genetic networks, we used ChIP-seq to define GATA-1 and GATA-2 occupancy genome-wide in erythroid cells. Coupled with genetic complementation analysis and transcriptional profiling, these studies revealed a rich collection of targets containing a characteristic binding motif of greater complexity than WGATAR. GATA factors occupied loci encoding multiple components of the Scl/TAL1 complex, a master regulator of hematopoiesis and leukemogenic target. Mechanistic analyses provided evidence for crossregulatory and autoregulatory interactions among components of this complex, including GATA-2 induction of the hematopoietic corepressor ETO-2 and an ETO-2-negative autoregulatory loop. These results establish fundamental principles underlying GATA factor mechanisms in chromatin and illustrate a complex network of considerable importance for the control of hematopoiesis.
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