scholarly journals Hypoxia Pathway Proteins in Normal and Malignant Hematopoiesis

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 155 ◽  
Author(s):  
Ben Wielockx ◽  
Tatyana Grinenko ◽  
Peter Mirtschink ◽  
Triantafyllos Chavakis
Keyword(s):  
Cell Fate ◽  
Current Knowledge ◽  
Hypoxia Inducible Factor ◽  
Adult Life ◽  
Low Oxygen ◽  
Hematopoietic Stem ◽  
Metabolism Regulation ◽  
Hsc Niche ◽  
Hif Pathway ◽  
The Impact

The regulation of oxygen (O2) levels is crucial in embryogenesis and adult life, as O2 controls a multitude of key cellular functions. Low oxygen levels (hypoxia) are relevant for tissue physiology as they are integral to adequate metabolism regulation and cell fate. Hence, the hypoxia response is of utmost importance for cell, organ and organism function and is dependent on the hypoxia-inducible factor (HIF) pathway. HIF pathway activity is strictly regulated by the family of oxygen-sensitive HIF prolyl hydroxylase domain (PHD) proteins. Physiologic hypoxia is a hallmark of the hematopoietic stem cell (HSC) niche in the bone marrow. This niche facilitates HSC quiescence and survival. The present review focuses on current knowledge and the many open questions regarding the impact of PHDs/HIFs and other proteins of the hypoxia pathway on the HSC niche and on normal and malignant hematopoiesis.

scholarly journals Hypoxia and Hypoxia-Inducible Factor Signaling in Muscular Dystrophies: Cause and Consequences

2021 ◽  
Vol 22 (13) ◽  
pp. 7220
Author(s):  
Thuy-Hang Nguyen ◽  
Stephanie Conotte ◽  
Alexandra Belayew ◽  
Anne-Emilie Declèves ◽  
Alexandre Legrand ◽  
...  
Keyword(s):  
Cell Function ◽  
Current Knowledge ◽  
Genetic Defect ◽  
Hypoxia Inducible Factor ◽  
Muscular Dystrophies ◽  
Compensatory Mechanisms ◽  
Hypoxia Response ◽  
Muscle Disorders ◽  
Almost All ◽  
The Impact

Muscular dystrophies (MDs) are a group of inherited degenerative muscle disorders characterized by a progressive skeletal muscle wasting. Respiratory impairments and subsequent hypoxemia are encountered in a significant subgroup of patients in almost all MD forms. In response to hypoxic stress, compensatory mechanisms are activated especially through Hypoxia-Inducible Factor 1 α (HIF-1α). In healthy muscle, hypoxia and HIF-1α activation are known to affect oxidative stress balance and metabolism. Recent evidence has also highlighted HIF-1α as a regulator of myogenesis and satellite cell function. However, the impact of HIF-1α pathway modifications in MDs remains to be investigated. Multifactorial pathological mechanisms could lead to HIF-1α activation in patient skeletal muscles. In addition to the genetic defect per se, respiratory failure or blood vessel alterations could modify hypoxia response pathways. Here, we will discuss the current knowledge about the hypoxia response pathway alterations in MDs and address whether such changes could influence MD pathophysiology.

The evolutionary and physiological significance of the Hif pathway in teleost fishes

2021 ◽  
Vol 224 (18) ◽  
Author(s):  
Milica Mandic ◽  
William Joyce ◽  
Steve F. Perry
Keyword(s):  
Hypoxia Inducible Factor ◽  
Duplication Event ◽  
Hypoxia Tolerance ◽  
Evolutionary Significance ◽  
Hypoxic Exposure ◽  
Cardiorespiratory System ◽  
Genome Duplication Event ◽  
Hypoxic Response ◽  
Hif Pathway ◽  
The Impact

ABSTRACT The hypoxia-inducible factor (HIF) pathway is a key regulator of cellular O2 homeostasis and an important orchestrator of the physiological responses to hypoxia (low O2) in vertebrates. Fish can be exposed to significant and frequent changes in environmental O2, and increases in Hif-α (the hypoxia-sensitive subunit of the transcription factor Hif) have been documented in a number of species as a result of a decrease in O2. Here, we discuss the impact of the Hif pathway on the hypoxic response and the contribution to hypoxia tolerance, particularly in fishes of the cyprinid lineage, which includes the zebrafish (Danio rerio). The cyprinids are of specific interest because, unlike in most other fishes, duplicated paralogs of the Hif-α isoforms arising from a teleost-specific genome duplication event have been retained. Positive selection has acted on the duplicated paralogs of the Hif-α isoforms in some cyprinid sub-families, pointing to adaptive evolutionary change in the paralogs. Thus, cyprinids are valuable models for exploring the evolutionary significance and physiological impact of the Hif pathway on the hypoxic response. Knockout in zebrafish of either paralog of Hif-1α greatly reduces hypoxia tolerance, indicating the importance of both paralogs to the hypoxic response. Here, with an emphasis on the cardiorespiratory system, we focus on the role of Hif-1α in the hypoxic ventilatory response and the regulation of cardiac function. We explore the effects of the duration of the hypoxic exposure (acute, sustained or intermittent) on the impact of Hif-1α on cardiorespiratory function and compare relevant data with those from mammalian systems.

scholarly journals The Hypoxia-Inducible Factor Pathway, Prolyl Hydroxylase Domain Protein Inhibitors, and Their Roles in Bone Repair and Regeneration

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Lihong Fan ◽  
Jia Li ◽  
Zefeng Yu ◽  
Xiaoqian Dang ◽  
Kunzheng Wang
Keyword(s):  
Cell Fate ◽  
Bone Repair ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Bone Tumours ◽  
Cell Fate Decisions ◽  
Tightly Coupled ◽  
Hif Pathway ◽  
Prolyl Hydroxylase Domain

Hypoxia-inducible factors (HIFs) are oxygen-dependent transcriptional activators that play crucial roles in angiogenesis, erythropoiesis, energy metabolism, and cell fate decisions. The group of enzymes that can catalyse the hydroxylation reaction of HIF-1 is prolyl hydroxylase domain proteins (PHDs). PHD inhibitors (PHIs) activate the HIF pathway by preventing degradation of HIF-αvia inhibiting PHDs. Osteogenesis and angiogenesis are tightly coupled during bone repair and regeneration. Numerous studies suggest that HIFs and their target gene, vascular endothelial growth factor (VEGF), are critical regulators of angiogenic-osteogenic coupling. In this brief perspective, we review current studies about the HIF pathway and its role in bone repair and regeneration, as well as the cellular and molecular mechanisms involved. Additionally, we briefly discuss the therapeutic manipulation of HIFs and VEGF in bone repair and bone tumours. This review will expand our knowledge of biology of HIFs, PHDs, PHD inhibitors, and bone regeneration, and it may also aid the design of novel therapies for accelerating bone repair and regeneration or inhibiting bone tumours.

scholarly journals How I treat posttransplant lymphoproliferative disorders

Blood ◽  
2015 ◽  
Vol 126 (20) ◽  
pp. 2274-2283 ◽  
Author(s):  
Daan Dierickx ◽  
Thomas Tousseyn ◽  
Olivier Gheysens
Keyword(s):  
Current Knowledge ◽  
Case Reports ◽  
Immune Surveillance ◽  
Organ Transplant ◽  
Solid Organ ◽  
Cell Transplant ◽  
Treatment Optimization ◽  
Hematopoietic Stem ◽  
Barr Virus ◽  
The Impact

AbstractPosttransplant lymphoproliferative disorder (PTLD) is a potentially fatal disorder arising after solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT). Iatrogenically impaired immune surveillance and Epstein-Barr virus (EBV) primary infection/reactivation are key factors in the pathogenesis. However, current knowledge on all aspects of PTLD is limited due to its rarity, morphologic heterogeneity, and the lack of prospective trials. Furthermore, the broad spectrum of underlying immune disorders and the type of graft represent important confounding factors. Despite these limitations, several reviews have been written aimed at offering a guide for pathologists and clinicians in diagnosing and treating PTLD. Rather than providing another classical review on PTLD, this “How I Treat” article, based on 2 case reports, focuses on specific challenges, different perspectives, and novel insights regarding the pathogenesis, diagnosis, and treatment of PTLD. These challenges include the wide variety of PTLD presentation (making treatment optimization difficult), the impact of EBV on pathogenesis and clinical behavior, and the controversial treatment of Burkitt lymphoma (BL)-PTLD.

scholarly journals The science behind the hypoxic niche of hematopoietic stem and progenitors

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 542-547 ◽  
Author(s):  
César Nombela-Arrieta ◽  
Leslie E. Silberstein
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Close Association ◽  
Adult Life ◽  
Vascular Networks ◽  
Tissue Oxygen ◽  
Cellular Functions ◽  
Hematopoietic Stem ◽  
Oxygen Levels ◽  
Oxygen Carrying Capacity

Abstract In blood, oxygen is transported principally by hemoglobin tetrameric molecules in erythocytes, which allow for the delivery to tissue cells. When anemia occurs, such as perisurgically or after trauma, blood transfusion is administered to replace the deficit in oxygen-carrying capacity. During embryogenesis and later in adult life, tissue oxygen levels control multiple key cellular functions. Low tissue oxygen levels in particular are physiologically relevant to stem cells by controlling their metabolism and cell fate. In adult life, hematopoietic stem cells reside in specified BM microenvironments/niches, where their quiescence and differentiation are presumably also influenced by cell-intrinsic and cell-extrinsic (niche) factors. Novel imaging technologies have allowed determination of the spatial localization of hematopoietic stem/progenitor cells (HSPCs), as well as the topography of oxygen distribution in BM cavities. Together, these recent advances have contributed to the emergence of a novel model that challenges the previous concept of a hypoxic hematopoietic stem cell niche characterized by poorly perfused endosteal zones with the deepest hypoxia. HSPCs display a hypoxic phenotype despite residing in close association with arterial or sinusoidal vascular networks. The entire BM cavity is hypoxic and unexpectedly exhibits an opposite oxygen gradient to the one initially proposed because arteriole-rich endosteal zones are relatively less hypoxic than deeper regions of the BM perfused by dense sinusoidal networks. Therefore, further studies are warranted to elucidate to what extent differences in oxygen tensions in these diverse microenvironments influence HSPC homeostasis.

scholarly journals Relevance of Polymorphic KIR and HLA Class I Genes in NK-Cell-Based Immunotherapies for Adult Leukemic Patients

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3767
Author(s):  
Léa Dubreuil ◽  
Patrice Chevallier ◽  
Christelle Retière ◽  
Katia Gagne
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Current Knowledge ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Cell Repertoire ◽  
Hematopoietic Stem ◽  
Structural Formation ◽  
The Impact

Since the mid-1990s, the biology and functions of natural killer (NK) cells have been deeply investigated in healthy individuals and in people with diseases. These effector cells play a particularly crucial role after allogeneic hematopoietic stem-cell transplantation (HSCT) through their graft-versus-leukemia (GvL) effect, which is mainly mediated through polymorphic killer-cell immunoglobulin-like receptors (KIRs) and their cognates, HLA class I ligands. In this review, we present how KIRs and HLA class I ligands modulate the structural formation and the functional education of NK cells. In particular, we decipher the current knowledge about the extent of KIR and HLA class I gene polymorphisms, as well as their expression, interaction, and functional impact on the KIR+ NK cell repertoire in a physiological context and in a leukemic context. In addition, we present the impact of NK cell alloreactivity on the outcomes of HSCT in adult patients with acute leukemia, as well as a description of genetic models of KIRs and NK cell reconstitution, with a focus on emergent T-cell-repleted haplo-identical HSCT using cyclosphosphamide post-grafting (haplo-PTCy). Then, we document how the immunogenetics of KIR/HLA and the immunobiology of NK cells could improve the relapse incidence after haplo-PTCy. Ultimately, we review the emerging NK-cell-based immunotherapies for leukemic patients in addition to HSCT.

scholarly journals Hematopoietic stem cells: to be or Notch to be

Blood ◽  
2012 ◽  
Vol 119 (14) ◽  
pp. 3226-3235 ◽  
Author(s):  
Anna Bigas ◽  
Lluis Espinosa
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Development ◽  
Cell Fate ◽  
Cell Biology ◽  
Adult Life ◽  
Notch Pathway ◽  
Hematopoietic Stem ◽  
Experimental Systems ◽  
Cell Diversity

Abstract Notch is a well-conserved signaling pathway and its function in cell fate determination is crucial in embryonic development and in the maintenance of tissue homeostasis during adult life. Notch activation depends on cell-cell interactions that are essential for the generation of cell diversity from initially equivalent cell populations. In the adult hematopoiesis, Notch is undoubtedly a very efficient promoter of T-cell differentiation, and this has masked for a long time the effects of Notch on other blood lineages, which are gradually being identified. However, the adult hematopoietic stem cell (HSC) remains mostly refractory to Notch intervention in experimental systems. In contrast, Notch is essential for the generation of the HSCs, which takes place during embryonic development. This review summarizes the knowledge accumulated in recent years regarding the role of the Notch pathway in the different stages of HSC ontology from embryonic life to fetal and adult bone marrow stem cells. In addition, we briefly examine other systems where Notch regulates specific stem cell capacities, in an attempt to understand how Notch functions in stem cell biology.

scholarly journals Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance

2015 ◽  
Vol 212 (13) ◽  
pp. 2223-2234 ◽  
Author(s):  
Milica Vukovic ◽  
Amelie V. Guitart ◽  
Catarina Sepulveda ◽  
Arnaud Villacreces ◽  
Eoghan O'Duibhir ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Hypoxia Inducible Factor ◽  
Leukemic Cells ◽  
Wild Type ◽  
Hypoxic Conditions ◽  
Downstream Effectors ◽  
Human Acute Myeloid Leukemia ◽  
Genetic Deletion ◽  
Hif Pathway ◽  
The Impact

Leukemogenesis occurs under hypoxic conditions within the bone marrow (BM). Knockdown of key mediators of cellular responses to hypoxia with shRNA, namely hypoxia-inducible factor-1α (HIF-1α) or HIF-2α, in human acute myeloid leukemia (AML) samples results in their apoptosis and inability to engraft, implicating HIF-1α or HIF-2α as therapeutic targets. However, genetic deletion of Hif-1α has no effect on mouse AML maintenance and may accelerate disease development. Here, we report the impact of conditional genetic deletion of Hif-2α or both Hif-1α and Hif-2α at different stages of leukemogenesis in mice. Deletion of Hif-2α accelerates development of leukemic stem cells (LSCs) and shortens AML latency initiated by Mll-AF9 and its downstream effectors Meis1 and Hoxa9. Notably, the accelerated initiation of AML caused by Hif-2α deletion is further potentiated by Hif-1α codeletion. However, established LSCs lacking Hif-2α or both Hif-1α and Hif-2α propagate AML with the same latency as wild-type LSCs. Furthermore, pharmacological inhibition of the HIF pathway or HIF-2α knockout using the lentiviral CRISPR-Cas9 system in human established leukemic cells with MLL-AF9 translocation have no impact on their functions. We therefore conclude that although Hif-1α and Hif-2α synergize to suppress the development of AML, they are not required for LSC maintenance.

scholarly journals Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity

2015 ◽  
Vol 112 (52) ◽  
pp. 15988-15993 ◽  
Author(s):  
Jie Yin ◽  
Jianmei W. Leavenworth ◽  
Yang Li ◽  
Qi Luo ◽  
Huafeng Xie ◽  
...  
Keyword(s):  
Natural Killer ◽  
Cell Fate ◽  
Nk Cell ◽  
Cell Lineage ◽  
Hematopoietic Stem ◽  
Lectin Receptor ◽  
Positive Effects ◽  
Cell Commitment ◽  
And Function ◽  
The Impact

Changes of histone modification status at critical lineage-specifying gene loci in multipotent precursors can influence cell fate commitment. The contribution of these epigenetic mechanisms to natural killer (NK) cell lineage determination from common lymphoid precursors is not understood. Here we investigate the impact of histone methylation repressive marks (H3 Lys27 trimethylation; H3K27me3) on early NK cell differentiation. We demonstrate that selective loss of the histone-lysine N-methyltransferase Ezh2 (enhancer of zeste homolog 2) or inhibition of its enzymatic activity with small molecules unexpectedly increased generation of the IL-15 receptor (IL-15R) CD122+ NK precursors and mature NK progeny from both mouse and human hematopoietic stem and progenitor cells. Mechanistic studies revealed that enhanced NK cell expansion and cytotoxicity against tumor cells were associated with up-regulation of CD122 and the C-type lectin receptor NKG2D. Moreover, NKG2D deficiency diminished the positive effects of Ezh2 inhibitors on NK cell commitment. Identification of the contribution of Ezh2 to NK lineage specification and function reveals an epigenetic-based mechanism that regulates NK cell development and provides insight into the clinical application of Ezh2 inhibitors in NK-based cancer immunotherapies.

scholarly journals Cell-Free Hemoglobin Does Not Attenuate the Effects of SARS-CoV-2 Spike Protein S1 Subunit in Pulmonary Endothelial Cells

2021 ◽  
Vol 22 (16) ◽  
pp. 9041
Author(s):  
Sirsendu Jana ◽  
Michael R. Heaven ◽  
Abdu I. Alayash
Keyword(s):  
Endothelial Cells ◽  
Hypoxia Inducible Factor ◽  
Spike Protein ◽  
Receptor Interaction ◽  
Low Oxygen ◽  
Viral Receptor ◽  
Hypoxic Conditions ◽  
Viral Components ◽  
Induced Changes ◽  
The Impact

SARS-CoV-2 primarily infects epithelial airway cells that express the host entry receptor angiotensin-converting enzyme 2 (ACE2), which binds to the S1 spike protein on the surface of the virus. To delineate the impact of S1 spike protein interaction with the ACE2 receptor, we incubated the S1 spike protein with human pulmonary arterial endothelial cells (HPAEC). HPAEC treatment with the S1 spike protein caused disruption of endothelial barrier function, increased levels of numerous inflammatory molecules (VCAM-1, ICAM-1, IL-1β, CCL5, CXCL10), elevated mitochondrial reactive oxygen species (ROS), and a mild rise in glycolytic reserve capacity. Because low oxygen tension (hypoxia) is associated with severe cases of COVID-19, we also evaluated treatment with hemoglobin (HbA) as a potential countermeasure in hypoxic and normal oxygen environments in analyses with the S1 spike protein. We found hypoxia downregulated the expression of the ACE2 receptor and increased the critical oxygen homeostatic signaling protein, hypoxia-inducible factor (HIF-1α); however, treatment of the cells with HbA yielded no apparent change in the levels of ACE2 or HIF-1α. Use of quantitative proteomics revealed that S1 spike protein-treated cells have few differentially regulated proteins in hypoxic conditions, consistent with the finding that ACE2 serves as the host viral receptor and is reduced in hypoxia. However, in normoxic conditions, we found perturbed abundance of proteins in signaling pathways related to lysosomes, extracellular matrix receptor interaction, focal adhesion, and pyrimidine metabolism. We conclude that the spike protein alone without the rest of the viral components is sufficient to elicit cell signaling in HPAEC, and that treatment with HbA failed to reverse the vast majority of these spike protein-induced changes.

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