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Striking parallels between carotid body glomus cell and adrenal chromaffin cell development.
Hockman D, Adameyko I, Kaucka M, Barraud P, Otani T, Hunt A, Hartwig AC, Sock E, Waithe D, Franck MCM, Ernfors P, Ehinger S, Howard MJ, Brown N, Reese J, Baker CVH
(2018) Dev Biol 444 Suppl 1: S308-S324
MeSH Terms: Adrenal Glands, Animals, Basic Helix-Loop-Helix Transcription Factors, Body Patterning, Carotid Body, Cell Differentiation, Cell Hypoxia, Chick Embryo, Chickens, Chromaffin Cells, Mice, Mice, Knockout, Myelin Proteolipid Protein, Neural Crest, Neurons, Pericytes, Transcription Factors
Show Abstract · Added May 30, 2018
Carotid body glomus cells mediate essential reflex responses to arterial blood hypoxia. They are dopaminergic and secrete growth factors that support dopaminergic neurons, making the carotid body a potential source of patient-specific cells for Parkinson's disease therapy. Like adrenal chromaffin cells, which are also hypoxia-sensitive, glomus cells are neural crest-derived and require the transcription factors Ascl1 and Phox2b; otherwise, their development is little understood at the molecular level. Here, analysis in chicken and mouse reveals further striking molecular parallels, though also some differences, between glomus and adrenal chromaffin cell development. Moreover, histology has long suggested that glomus cell precursors are 'émigrés' from neighbouring ganglia/nerves, while multipotent nerve-associated glial cells are now known to make a significant contribution to the adrenal chromaffin cell population in the mouse. We present conditional genetic lineage-tracing data from mice supporting the hypothesis that progenitors expressing the glial marker proteolipid protein 1, presumably located in adjacent ganglia/nerves, also contribute to glomus cells. Finally, we resolve a paradox for the 'émigré' hypothesis in the chicken - where the nearest ganglion to the carotid body is the nodose, in which the satellite glia are neural crest-derived, but the neurons are almost entirely placode-derived - by fate-mapping putative nodose neuronal 'émigrés' to the neural crest.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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17 MeSH Terms
Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development.
Kobayashi H, Liu J, Urrutia AA, Burmakin M, Ishii K, Rajan M, Davidoff O, Saifudeen Z, Haase VH
(2017) Kidney Int 92: 1370-1383
MeSH Terms: Anemia, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Hypoxia, Clinical Trials, Phase III as Topic, Disease Models, Animal, Enzyme Inhibitors, Forkhead Transcription Factors, Humans, Hydroxylation, Hypoxia-Inducible Factor-Proline Dioxygenases, Kidney, Kidney Diseases, Mice, Molecular Targeted Therapy, Mutation, Organ Size, Procollagen-Proline Dioxygenase, Renal Insufficiency, Stromal Cells
Show Abstract · Added November 21, 2017
Hypoxia in the embryo is a frequent cause of intra-uterine growth retardation, low birth weight, and multiple organ defects. In the kidney, this can lead to low nephron endowment, predisposing to chronic kidney disease and arterial hypertension. A key component in cellular adaptation to hypoxia is the hypoxia-inducible factor pathway, which is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3. In the adult kidney, PHD oxygen sensors are differentially expressed in a cell type-dependent manner and control the production of erythropoietin in interstitial cells. However, the role of interstitial cell PHDs in renal development has not been examined. Here we used a genetic approach in mice to interrogate PHD function in FOXD1-expressing stroma during nephrogenesis. We demonstrate that PHD2 and PHD3 are essential for normal kidney development as the combined inactivation of stromal PHD2 and PHD3 resulted in renal failure that was associated with reduced kidney size, decreased numbers of glomeruli, and abnormal postnatal nephron formation. In contrast, nephrogenesis was normal in animals with individual PHD inactivation. We furthermore demonstrate that the defect in nephron formation in PHD2/PHD3 double mutants required intact hypoxia-inducible factor-2 signaling and was dependent on the extent of stromal hypoxia-inducible factor activation. Thus, hypoxia-inducible factor prolyl-4-hydroxylation in renal interstitial cells is critical for normal nephron formation.
Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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20 MeSH Terms
Evolution of the hypoxia-sensitive cells involved in amniote respiratory reflexes.
Hockman D, Burns AJ, Schlosser G, Gates KP, Jevans B, Mongera A, Fisher S, Unlu G, Knapik EW, Kaufman CK, Mosimann C, Zon LI, Lancman JJ, Dong PDS, Lickert H, Tucker AS, Baker CV
(2017) Elife 6:
MeSH Terms: Animals, Anura, Biological Evolution, Cell Hypoxia, Cell Lineage, Lampreys, Neuroendocrine Cells, Neuroepithelial Cells, Zebrafish
Show Abstract · Added April 26, 2017
The evolutionary origins of the hypoxia-sensitive cells that trigger amniote respiratory reflexes - carotid body glomus cells, and 'pulmonary neuroendocrine cells' (PNECs) - are obscure. Homology has been proposed between glomus cells, which are neural crest-derived, and the hypoxia-sensitive 'neuroepithelial cells' (NECs) of fish gills, whose embryonic origin is unknown. NECs have also been likened to PNECs, which differentiate in situ within lung airway epithelia. Using genetic lineage-tracing and neural crest-deficient mutants in zebrafish, and physical fate-mapping in frog and lamprey, we find that NECs are not neural crest-derived, but endoderm-derived, like PNECs, whose endodermal origin we confirm. We discover neural crest-derived catecholaminergic cells associated with zebrafish pharyngeal arch blood vessels, and propose a new model for amniote hypoxia-sensitive cell evolution: endoderm-derived NECs were retained as PNECs, while the carotid body evolved via the aggregation of neural crest-derived catecholaminergic (chromaffin) cells already associated with blood vessels in anamniote pharyngeal arches.
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9 MeSH Terms
Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system.
Cho SH, Raybuck AL, Stengel K, Wei M, Beck TC, Volanakis E, Thomas JW, Hiebert S, Haase VH, Boothby MR
(2016) Nature 537: 234-238
MeSH Terms: Animals, Antibodies, B-Lymphocytes, Cell Hypoxia, Cell Proliferation, Cell Survival, Cytosine Deaminase, Germinal Center, Hypoxia, Immunoglobulin Class Switching, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Multiprotein Complexes, TOR Serine-Threonine Kinases
Show Abstract · Added August 9, 2016
Germinal centres (GCs) promote humoral immunity and vaccine efficacy. In GCs, antigen-activated B cells proliferate, express high-affinity antibodies, promote antibody class switching, and yield B cell memory. Whereas the cytokine milieu has long been known to regulate effector functions that include the choice of immunoglobulin class, both cell-autonomous and extrinsic metabolic programming have emerged as modulators of T-cell-mediated immunity. Here we show in mice that GC light zones are hypoxic, and that low oxygen tension () alters B cell physiology and function. In addition to reduced proliferation and increased B cell death, low impairs antibody class switching to the pro-inflammatory IgG2c antibody isotype by limiting the expression of activation-induced cytosine deaminase (AID). Hypoxia induces HIF transcription factors by restricting the activity of prolyl hydroxyl dioxygenase enzymes, which hydroxylate HIF-1α and HIF-2α to destabilize HIF by binding the von Hippel-Landau tumour suppressor protein (pVHL). B-cell-specific depletion of pVHL leads to constitutive HIF stabilization, decreases antigen-specific GC B cells and undermines the generation of high-affinity IgG, switching to IgG2c, early memory B cells, and recall antibody responses. HIF induction can reprogram metabolic and growth factor gene expression. Sustained hypoxia or HIF induction by pVHL deficiency inhibits mTOR complex 1 (mTORC1) activity in B lymphoblasts, and mTORC1-haploinsufficient B cells have reduced clonal expansion, AID expression, and capacities to yield IgG2c and high-affinity antibodies. Thus, the normal physiology of GCs involves regional variegation of hypoxia, and HIF-dependent oxygen sensing regulates vital functions of B cells. We propose that the restriction of oxygen in lymphoid organs, which can be altered in pathophysiological states, modulates humoral immunity.
1 Communities
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15 MeSH Terms
Hypoxia and Reactive Oxygen Species Homeostasis in Mesenchymal Progenitor Cells Define a Molecular Mechanism for Fracture Nonunion.
Muinos-López E, Ripalda-Cemboráin P, López-Martínez T, González-Gil AB, Lamo-Espinosa JM, Valentí A, Mortlock DP, Valentí JR, Prósper F, Granero-Moltó F
(2016) Stem Cells 34: 2342-53
MeSH Terms: Animals, Bone Morphogenetic Protein 2, Cell Hypoxia, Cell Separation, Disulfides, Fracture Healing, Fractures, Ununited, Homeostasis, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Imidazoles, Male, Mesenchymal Stem Cells, Mice, Inbred C57BL, Osteogenesis, Oxidative Stress, Periosteum, Reactive Oxygen Species
Show Abstract · Added February 3, 2017
Fracture nonunion is a major complication of bone fracture regeneration and repair. The molecular mechanisms that result in fracture nonunion appearance are not fully determined. We hypothesized that fracture nonunion results from the failure of hypoxia and hematoma, the primary signals in response to bone injury, to trigger Bmp2 expression by mesenchymal progenitor cells (MSCs). Using a model of nonstabilized fracture healing in transgenic 5'Bmp2BAC mice we determined that Bmp2 expression appears in close association with hypoxic tissue and hematoma during the early phases of fracture healing. In addition, BMP2 expression is induced when human periosteum explants are exposed to hypoxia ex vivo. Transient interference of hypoxia signaling in vivo with PX-12, a thioredoxin inhibitor, results in reduced Bmp2 expression, impaired fracture callus formation and atrophic-like nonunion by a HIF-1α independent mechanism. In isolated human periosteum-derived MSCs, BMP2 expression could be induced with the addition of platelets concentrate lysate but not with hypoxia treatment, confirming HIF-1α-independent BMP2 expression. Interestingly, in isolated human periosteum-derived mesenchymal progenitor cells, inhibition of BMP2 expression by PX-12 is accomplished only under hypoxic conditions seemingly through dis-regulation of reactive oxygen species (ROS) levels. In conclusion, we provide evidence of a molecular mechanism of hypoxia-dependent BMP2 expression in MSCs where interference with ROS homeostasis specifies fracture nonunion-like appearance in vivo through inhibition of Bmp2 expression. Stem Cells 2016;34:2342-2353.
© 2016 AlphaMed Press.
1 Communities
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18 MeSH Terms
The Endothelial Prolyl-4-Hydroxylase Domain 2/Hypoxia-Inducible Factor 2 Axis Regulates Pulmonary Artery Pressure in Mice.
Kapitsinou PP, Rajendran G, Astleford L, Michael M, Schonfeld MP, Fields T, Shay S, French JL, West J, Haase VH
(2016) Mol Cell Biol 36: 1584-94
MeSH Terms: Animals, Arterial Pressure, Cell Hypoxia, Disease Models, Animal, Hypertension, Pulmonary, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases, Mice, Mutation, Pulmonary Artery, Signal Transduction, Transcription Factors
Show Abstract · Added March 16, 2016
Hypoxia-inducible factors 1 and 2 (HIF-1 and -2) control oxygen supply to tissues by regulating erythropoiesis, angiogenesis and vascular homeostasis. HIFs are regulated in response to oxygen availability by prolyl-4-hydroxylase domain (PHD) proteins, with PHD2 being the main oxygen sensor that controls HIF activity under normoxia. In this study, we used a genetic approach to investigate the endothelial PHD2/HIF axis in the regulation of vascular function. We found that inactivation of Phd2 in endothelial cells specifically resulted in severe pulmonary hypertension (∼118% increase in right ventricular systolic pressure) but not polycythemia and was associated with abnormal muscularization of peripheral pulmonary arteries and right ventricular hypertrophy. Concurrent inactivation of either Hif1a or Hif2a in endothelial cell-specific Phd2 mutants demonstrated that the development of pulmonary hypertension was dependent on HIF-2α but not HIF-1α. Furthermore, endothelial HIF-2α was required for the development of increased pulmonary artery pressures in a model of pulmonary hypertension induced by chronic hypoxia. We propose that these HIF-2-dependent effects are partially due to increased expression of vasoconstrictor molecule endothelin 1 and a concomitant decrease in vasodilatory apelin receptor signaling. Taken together, our data identify endothelial HIF-2 as a key transcription factor in the pathogenesis of pulmonary hypertension.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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2 Members
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12 MeSH Terms
Bacterial Hypoxic Responses Revealed as Critical Determinants of the Host-Pathogen Outcome by TnSeq Analysis of Staphylococcus aureus Invasive Infection.
Wilde AD, Snyder DJ, Putnam NE, Valentino MD, Hammer ND, Lonergan ZR, Hinger SA, Aysanoa EE, Blanchard C, Dunman PM, Wasserman GA, Chen J, Shopsin B, Gilmore MS, Skaar EP, Cassat JE
(2015) PLoS Pathog 11: e1005341
MeSH Terms: Animals, Cell Hypoxia, Cell Line, DNA Transposable Elements, Disease Models, Animal, Female, Gene Expression Regulation, Bacterial, Genes, Viral, Host-Pathogen Interactions, Humans, Mice, Mice, Inbred C57BL, Oligonucleotide Array Sequence Analysis, Osteomyelitis, Quorum Sensing, Reverse Transcriptase Polymerase Chain Reaction, Staphylococcal Infections, Staphylococcus aureus, Virulence, Virulence Factors
Show Abstract · Added February 8, 2016
Staphylococcus aureus is capable of infecting nearly every organ in the human body. In order to infiltrate and thrive in such diverse host tissues, staphylococci must possess remarkable flexibility in both metabolic and virulence programs. To investigate the genetic requirements for bacterial survival during invasive infection, we performed a transposon sequencing (TnSeq) analysis of S. aureus during experimental osteomyelitis. TnSeq identified 65 genes essential for staphylococcal survival in infected bone and an additional 148 mutants with compromised fitness in vivo. Among the loci essential for in vivo survival was SrrAB, a staphylococcal two-component system previously reported to coordinate hypoxic and nitrosative stress responses in vitro. Healthy bone is intrinsically hypoxic, and intravital oxygen monitoring revealed further decreases in skeletal oxygen concentrations upon S. aureus infection. The fitness of an srrAB mutant during osteomyelitis was significantly increased by depletion of neutrophils, suggesting that neutrophils impose hypoxic and/or nitrosative stresses on invading bacteria. To more globally evaluate staphylococcal responses to changing oxygenation, we examined quorum sensing and virulence factor production in staphylococci grown under aerobic or hypoxic conditions. Hypoxic growth resulted in a profound increase in quorum sensing-dependent toxin production, and a concomitant increase in cytotoxicity toward mammalian cells. Moreover, aerobic growth limited quorum sensing and cytotoxicity in an SrrAB-dependent manner, suggesting a mechanism by which S. aureus modulates quorum sensing and toxin production in response to environmental oxygenation. Collectively, our results demonstrate that bacterial hypoxic responses are key determinants of the staphylococcal-host interaction.
0 Communities
2 Members
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20 MeSH Terms
Anaemia in kidney disease: harnessing hypoxia responses for therapy.
Koury MJ, Haase VH
(2015) Nat Rev Nephrol 11: 394-410
MeSH Terms: Anemia, Basic Helix-Loop-Helix Transcription Factors, Cell Hypoxia, Erythropoiesis, Humans, Hypoxia-Inducible Factor 1, Renal Insufficiency, Chronic, Signal Transduction
Show Abstract · Added June 10, 2015
Improved understanding of the oxygen-dependent regulation of erythropoiesis has provided new insights into the pathogenesis of anaemia associated with renal failure and has led to the development of novel therapeutic agents for its treatment. Hypoxia-inducible factor (HIF)-2 is a key regulator of erythropoiesis and iron metabolism. HIF-2 is activated by hypoxic conditions and controls the production of erythropoietin by renal peritubular interstitial fibroblast-like cells and hepatocytes. In anaemia associated with renal disease, erythropoiesis is suppressed due to inadequate erythropoietin production in the kidney, inflammation and iron deficiency; however, pharmacologic agents that activate the HIF axis could provide a physiologic approach to the treatment of renal anaemia by mimicking hypoxia responses that coordinate erythropoiesis with iron metabolism. This Review discusses the functional inter-relationships between erythropoietin, iron and inflammatory mediators under physiologic conditions and in relation to the pathogenesis of renal anaemia, as well as recent insights into the molecular and cellular basis of erythropoietin production in the kidney. It furthermore provides a detailed overview of current clinical experience with pharmacologic activators of HIF signalling as a novel comprehensive and physiologic approach to the treatment of anaemia.
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8 MeSH Terms
Phosphorescence monitoring of hypoxic microenvironment in solid-tumors to evaluate chemotherapeutic effects using the hypoxia-sensitive iridium (III) coordination compound.
Zeng Y, Liu Y, Shang J, Ma J, Wang R, Deng L, Guo Y, Zhong F, Bai M, Zhang S, Wu D
(2015) PLoS One 10: e0121293
MeSH Terms: Adenocarcinoma, Animals, Antineoplastic Agents, Biological Transport, Cell Hypoxia, Cell Line, Tumor, Cell Survival, Cisplatin, Colonic Neoplasms, Coordination Complexes, Iridium, Luminescent Agents, Luminescent Measurements, Mice, Optical Imaging, Organometallic Compounds, Treatment Outcome, Tumor Microenvironment
Show Abstract · Added April 2, 2019
OBJECTIVES - To utilize phosphorescence to monitor hypoxic microenvironment in solid-tumors and investigate cancer chemotherapeutic effects in vivo.
METHODS - A hypoxia-sensitive probe named BTP was used to monitor hypoxic microenvironment in solid-tumors. The low-dose metronomic treatment with cisplatin was used in anti-angiogenetic chemotherapeutic programs. The phosphorescence properties of BTP were detected by a spectrofluorometer. BTP cytotoxicity utilized cell necrosis and apoptosis, which were evaluated by trypan blue dye exclusion and Hoechst33342 plus propidium iodide assays. Tumor-bearing mouse models of colon adenocarcinoma were used for tumor imaging in vivo. Monitoring of the hypoxic microenvironment in tumors was performed with a Maestro 2 fluorescence imaging system. Tumor tissues in each group were harvested regularly and treated with pathological hematoxylin and eosin and immunohistochemical staining to confirm imaging results.
RESULTS - BTP did not feature obvious cytotoxicity for cells, and tumor growth in low-dose metronomic cisplatin treated mice was significantly inhibited by chemotherapy. Hypoxic levels significantly increased due to cisplatin, as proven by the expression level of related proteins. Phosphorescence intensity in the tumors of mice in the cisplatin group was stronger and showed higher contrast than that in tumors of saline treated mice.
CONCLUSIONS - We develop a useful phosphorescence method to evaluate the chemotherapeutic effects of cisplatin. The proposed method shows potential as a phosphorescence imaging approach for evaluating chemotherapeutic effects in vivo, especially anti-angiogenesis.
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MeSH Terms
HIF targets in bone remodeling and metastatic disease.
Johnson RW, Schipani E, Giaccia AJ
(2015) Pharmacol Ther 150: 169-77
MeSH Terms: Antineoplastic Agents, Bone Development, Bone Neoplasms, Bone Remodeling, Cell Hypoxia, Humans, Hypoxia-Inducible Factor 1, Molecular Targeted Therapy, Prolyl Hydroxylases, Tumor Microenvironment, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added March 26, 2019
The bone marrow is a hypoxic microenvironment that is rich in growth factors and blood vessels and is readily colonized by tumor cells disseminated from numerous cancers including tumors of the breast, prostate, lung, and skin. The origin of metastatic growth promoting factors for tumor cells disseminated to the bone marrow is derived from multiple sources: the bone matrix, which is a reservoir for growth factors, and cells residing in the marrow and along bone surfaces, such as osteoblasts, osteoclasts, macrophages, and T cells, which secrete cytokines and chemokines. Low oxygen levels within the bone marrow induce hypoxia signaling pathways such as hypoxia inducible factor (HIF), which is regulated by oxygen requiring prolyl hydroxylases (PHDs) and von Hippel-Lindau (VHL) tumor suppressor. These hypoxia signaling pathways have profound effects on bone development and homeostasis. Likewise, hypoxic conditions observed in local breast and prostate tumors point to a role for hypoxia-inducible genes in metastasis to and colonization of the bone marrow. This review will explore the role of hypoxia-regulated factors in bone development and remodeling, and how these elements may contribute to solid tumor metastasis to the bone.
Copyright © 2015 Elsevier Inc. All rights reserved.
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