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Cells Aug 2021Human erythropoietin (EPO) is an N-linked glycoprotein consisting of 166 aa that is produced in the kidney during the adult life and acts both as a peptide hormone and... (Review)
Review
Erythropoietin (EPO) as a Key Regulator of Erythropoiesis, Bone Remodeling and Endothelial Transdifferentiation of Multipotent Mesenchymal Stem Cells (MSCs): Implications in Regenerative Medicine.
Human erythropoietin (EPO) is an N-linked glycoprotein consisting of 166 aa that is produced in the kidney during the adult life and acts both as a peptide hormone and hematopoietic growth factor (HGF), stimulating bone marrow erythropoiesis. EPO production is activated by hypoxia and is regulated via an oxygen-sensitive feedback loop. EPO acts via its homodimeric erythropoietin receptor (EPO-R) that increases cell survival and drives the terminal erythroid maturation of progenitors BFU-Es and CFU-Es to billions of mature RBCs. This pathway involves the activation of multiple erythroid transcription factors, such as GATA1, FOG1, TAL-1, EKLF and BCL11A, and leads to the overexpression of genes encoding enzymes involved in heme biosynthesis and the production of hemoglobin. The detection of a heterodimeric complex of EPO-R (consisting of one EPO-R chain and the CSF2RB β-chain, CD131) in several tissues (brain, heart, skeletal muscle) explains the EPO pleotropic action as a protection factor for several cells, including the multipotent MSCs as well as cells modulating the innate and adaptive immunity arms. EPO induces the osteogenic and endothelial transdifferentiation of the multipotent MSCs via the activation of EPO-R signaling pathways, leading to bone remodeling, induction of angiogenesis and secretion of a large number of trophic factors (secretome). These diversely unique properties of EPO, taken together with its clinical use to treat anemias associated with chronic renal failure and other blood disorders, make it a valuable biologic agent in regenerative medicine for the treatment/cure of tissue de-regeneration disorders.
Topics: Bone Remodeling; Cell Transdifferentiation; Endothelial Cells; Erythropoiesis; Erythropoietin; Humans; Mesenchymal Stem Cells; Multipotent Stem Cells; Receptors, Erythropoietin; Regenerative Medicine
PubMed: 34440909
DOI: 10.3390/cells10082140 -
Vitamins and Hormones 2017Erythropoiesis is tightly regulated by the growth factor erythropoietin (Epo). Signal activation begins when Epo engages its cognate receptor, Epo-R, triggering receptor... (Review)
Review
Erythropoiesis is tightly regulated by the growth factor erythropoietin (Epo). Signal activation begins when Epo engages its cognate receptor, Epo-R, triggering receptor homodimerization, and recruitment of signaling intermediates including Jak2 that phosphorylates both the receptor cytoplasmic tail and downstream effectors including the transcription factor, STAT5. Transcription factors subsequently activate transcription of prosurvival and prodifferentiation genes responsible for red blood cell production. The fidelity of Epo-R signaling is dependent upon residence within detergent insoluble membrane lipid raft fractions. Lipid rafts are membrane microdomains that serve as signaling scaffolds composed of densely packed sphingolipids and cholesterol where receptors and intermediate signaling proteins are recruited and interact to execute stimuli. Disruption of lipid rafts is detrimental to Epo signaling, a phenomenon that may be utilized to design novel therapeutics for conditions in which Epo signaling is deficient. Here, we review the Epo signaling cascade, particularly, as it relates to localization and dependence on lipid rafts, and discuss considerations for novel therapeutic design.
Topics: Animals; Erythropoietin; Gene Expression Regulation; Humans; Membrane Microdomains; Receptors, Erythropoietin; Signal Transduction
PubMed: 28629526
DOI: 10.1016/bs.vh.2017.02.002 -
Vision Research Oct 2017Over the past years, knowledge has expanded with regards to the multiple roles played by erythropoietin (EPO) in the body. Once believed to be a hormone synthesised in... (Review)
Review
Over the past years, knowledge has expanded with regards to the multiple roles played by erythropoietin (EPO) in the body. Once believed to be a hormone synthesised in the kidney and involved only in the modulation of erythrocyte production, it is recognised now that EPO can be produced in many tissues, including the retina, and by many cells. In these tissues EPO is released in response to "tissue injury" and appears to have protective functions. Despite the extensive research conducted to date, the cues leading to release of EPO and its effects in the normal and diseased retina have not been fully elucidated. In vitro and in vivo experimental studies as well as small interventional clinical studies suggest a potential beneficial effect of externally administered EPO in early diabetic retinopathy and diabetic macular oedema. In contrast, controversy exists with regards to the possible use of EPO in proliferative diabetic retinopathy. Non-erythropoietic EPO-derived peptides, produced with the aim of increasing effectiveness and reducing side effects of EPO, are currently under investigation in early phase clinical trials.
Topics: Diabetic Retinopathy; Erythropoietin; Humans; Receptors, Erythropoietin; Retina
PubMed: 28652140
DOI: 10.1016/j.visres.2017.05.010 -
Asian Journal of Andrology 2020Hypoxia-induced erythropoietin signaling plays an important role in tumor growth and invasion. In the present study, we investigated the contribution of erythropoietin...
Hypoxia-induced erythropoietin signaling plays an important role in tumor growth and invasion. In the present study, we investigated the contribution of erythropoietin signaling pathway to castration-resistant prostate cancer and the development of a neuroendocrine phenotype. Immunohistochemical staining showed that the erythropoietin and erythropoietin receptor scores in castration-resistant prostate cancer and androgen-dependent prostate cancer were 7.55 versus 4.5 and 7.45 versus 5.9,respectively (P < 0.001). Furthermore, a cell proliferation assay was conducted, and the differential expression of erythropoietin and erythropoietin receptor in LNCaP cells and hypoxia-induced LNCaP cells was evaluated using western blot and quantitative real-time PCR. The proliferation capacity of hypoxia-induced LNCaP cells was similar in cultures of both fetal bovine serum and charcoal-stripped fetal bovine serum, suggesting that LNCaP cells acquired hypoxia-induced androgen-independent growth. After 2 weeks of hypoxic culture, LNCaP cells showed a neuroendocrine cell change and increased expression of neuron-specific enolase, erythropoietin, and erythropoietin receptor; knockdown of erythropoietin receptor reversed the hypoxia-induced upregulation of neuron-specific enolase in the LNCaP cells. In conclusion, the concurrent upregulation of erythropoietin and erythropoietin receptor in castration-resistant prostate cancer suggests that the erythropoietin/erythropoietin receptor autocrine loop plays an important role in the progression of castration resistance and is responsible for the development of a neuroendocrine phenotype.
Topics: Aged; Blotting, Western; Carcinoma; Cell Line, Tumor; Cell Proliferation; Erythropoietin; Humans; Immunohistochemistry; Male; Middle Aged; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Tumor Hypoxia; Up-Regulation
PubMed: 31417010
DOI: 10.4103/aja.aja_80_19 -
Medicine Jan 2021To investigate whether laryngeal cancer cells express erythropoietin (Epo) and erythropoietin receptor (EpoR) and what is their possible relationship with clinical and...
To investigate whether laryngeal cancer cells express erythropoietin (Epo) and erythropoietin receptor (EpoR) and what is their possible relationship with clinical and pathological features of the tumor.We performed immunohistochemical analysis of Epo and EpoR expression on 78 tissue samples of invasive and in situ squamous cell laryngeal carcinoma.The statistical analysis showed a weak positive and statistically significant correlation of EpoHS and EpoR HS expression levels. Epo HS and EpoR HS levels did not correlate with patient sex or age, type of diagnosis, cancer stage, histological tumor grade, presence or absence of disease recurrence, type of oncologic cancer therapy provided, or results of selected laboratory blood work. The results show a statistically significant difference in Epo expression with respect to survival.We confirmed the presence of Epo an EpoR in malignant laryngeal tumors and demonstrated the correlation between Epo expression and survival. Further studies are needed to more precisely define the role of Epo and EpoR in treatment of patients with laryngeal cancer.
Topics: Aged; Aged, 80 and over; Erythropoietin; Female; Humans; Laryngeal Neoplasms; Male; Middle Aged; ROC Curve; Receptors, Erythropoietin; Statistics, Nonparametric
PubMed: 33545970
DOI: 10.1097/MD.0000000000023943 -
Expert Opinion on Therapeutic Targets 2016Recombinant human erythropoietin (rhEPO) is a first-line therapeutic for the anemia of chronic kidney disease, cancer chemotherapy, AIDS (Zidovudine therapy), and... (Review)
Review
INTRODUCTION
Recombinant human erythropoietin (rhEPO) is a first-line therapeutic for the anemia of chronic kidney disease, cancer chemotherapy, AIDS (Zidovudine therapy), and lower-risk myelodysplastic syndrome. However, rhEPO frequently elevates hypertension, is costly, and may affect cancer progression. Potentially high merit therefore exists for defining new targets for anti-anemia agents within erythropoietin (EPO) and EPO receptor (EPOR) regulatory circuits.
AREAS COVERED
EPO production by renal interstitial fibroblasts is subject to modulation by several regulators of hypoxia-inducible factor 2a (HIF2a) including Iron Response Protein-1, prolyl hydroxylases, and HIF2a acetylases, each of which holds potential as anti-anemia drug targets. The cell surface receptor for EPO (EPOR) preassembles as a homodimer, together with Janus Kinase 2 (JAK2), and therefore it remains attractive to develop novel agents that trigger EPOR complex activation (activating antibodies, mimetics, small-molecule agonists). Additionally, certain downstream transducers of EPOR/JAK2 signaling may be druggable, including Erythroferrone (a hepcidin regulator), a cytoprotective Spi2a serpin, and select EPOR-associated protein tyrosine phosphatases.
EXPERT OPINION
While rhEPO (and biosimilars) are presently important mainstay erythropoiesis-stimulating agents (ESAs), impetus exists for studies of novel ESAs that fortify HIF2a's effects, act as EPOR agonists, and/or bolster select downstream EPOR pathways to erythroid cell formation. Such agents could lessen rhEPO dosing, side effects, and/or costs.
Topics: Anemia; Animals; Drug Design; Erythropoiesis; Erythropoietin; Hematinics; Humans; Molecular Targeted Therapy; Receptors, Erythropoietin; Recombinant Proteins
PubMed: 26419263
DOI: 10.1517/14728222.2016.1090975 -
International Journal of Laboratory... Apr 2019Erythrocytosis is characterized by the expansion of erythrocyte compartment including elevated red blood cell number, hematocrit, and hemoglobin content. Familial... (Review)
Review
OBJECTIVES
Erythrocytosis is characterized by the expansion of erythrocyte compartment including elevated red blood cell number, hematocrit, and hemoglobin content. Familial erythrocytosis (FE) is a congenital disorder with different genetic background. Type 1 FE is primary FE caused by mutation in erythropoietin receptor gene (EPOR). Type 2-5 FE are secondary FEs caused by mutations of genes involved in oxygen sensing pathway important for erythropoietin (EPO) regulation. In the present study, we summarized associations between EPOR and EPO gene variations with development of FE and searched for genetic variants located within regulatory regions.
METHODS
Publications reporting EPOR and EPO sequence variants associated with FE or clinical features of erythrocytosis were retrieved from PubMed and WoS. In silico, sequence reanalysis was performed using Ensembl genomic browser, release 89 to screen for variants located within regulatory regions.
RESULTS
To date, 28 variants of the EPOR and seven variants of the EPO gene have been associated with erythrocytosis or upper hematocrit. Sequence variants were also found to be present within regulatory regions.
CONCLUSIONS
Role of variants in regulatory regions of the EPO gene should be further investigated.
Topics: Erythropoietin; Female; Genetic Variation; Humans; Male; Polycythemia; Receptors, Erythropoietin
PubMed: 30507031
DOI: 10.1111/ijlh.12949 -
Kidney International. Supplement Nov 2007The erythropoietin-erythropoietin-receptor (EPO-EPO-R) system has recently been identified as an important cellular survival pathway. Its presence has also been... (Review)
Review
The erythropoietin-erythropoietin-receptor (EPO-EPO-R) system has recently been identified as an important cellular survival pathway. Its presence has also been demonstrated in the kidney and identified as a therapeutic target to prevent loss of renal function. Part of the protective effects may be related to the action of erythropoietin on endothelial function and expansion of endothelial progenitor cells. This paper reviews current evidence for involvement of these mechanisms in EPO-mediated renoprotection.
Topics: Animals; Cell Survival; Endothelial Cells; Erythropoietin; Humans; Kidney; Receptors, Erythropoietin; Regeneration; Stem Cells
PubMed: 17943139
DOI: 10.1038/sj.ki.5002483 -
International Journal of Molecular... Jul 2021Erythropoietin (EPO) acts on multiple tissues through its receptor EPOR, a member of a cytokine class I receptor superfamily with pleiotropic effects. The interaction of... (Review)
Review
Erythropoietin (EPO) acts on multiple tissues through its receptor EPOR, a member of a cytokine class I receptor superfamily with pleiotropic effects. The interaction of EPO and EPOR triggers the activation of several signaling pathways that induce erythropoiesis, including JAK2/STAT5, PI3K/AKT, and MAPK. The canonical EPOR/JAK2/STAT5 pathway is a known regulator of differentiation, proliferation, and cell survival of erythroid progenitors. In addition, its role in the protection of other cells, including cancer cells, is under intense investigation. The involvement of EPOR/JAK2/STAT5 in other processes such as mRNA splicing, cytoskeleton reorganization, and cell metabolism has been recently described. The transcriptomics, proteomics, and epigenetic studies reviewed in this article provide a detailed understanding of EPO signalization. Advances in this area of research may be useful for improving the efficacy of EPO therapy in hematologic disorders, as well as in cancer treatment.
Topics: Animals; Cell Differentiation; Epigenomics; Erythropoiesis; Erythropoietin; Humans; Janus Kinase 2; Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Phosphorylation; Proteomics; Proto-Oncogene Proteins c-akt; Receptors, Erythropoietin; STAT5 Transcription Factor; Signal Transduction; Trans-Activators; Transcriptome
PubMed: 34281163
DOI: 10.3390/ijms22137109 -
Current Opinion in Hematology May 2010In 1985-1989, erythropoietin (EPO), its receptor (EPOR), and janus kinase 2 were cloned; established to be essential for definitive erythropoiesis; and initially... (Review)
Review
PURPOSE OF REVIEW
In 1985-1989, erythropoietin (EPO), its receptor (EPOR), and janus kinase 2 were cloned; established to be essential for definitive erythropoiesis; and initially intensely studied. Recently, new impetus, tools, and model systems have emerged to re-examine EPO/EPOR actions, and are addressed in this review. Impetus includes indications that EPO affects significantly more than standard erythroblast survival pathways, the development of novel erythropoiesis-stimulating agents, increasing evidence for EPO/EPOR cytoprotection of ischemically injured tissues, and potential EPO-mediated worsening of tumorigenesis.
RECENT FINDINGS
New findings are reviewed in four functional contexts: (pro)erythroblast survival mechanisms, new candidate EPO/EPOR effects on erythroid cell development and new EPOR responses, EPOR downmodulation and trafficking, and novel erythropoiesis-stimulating agents.
SUMMARY
As Current Opinion, this monograph seeks to summarize, and provoke, new EPO/EPOR action concepts. Specific problems addressed include: beyond (and before) BCL-XL, what key survival factors are deployed in early-stage proerythroblasts? Are distinct EPO/EPOR signals transduced in stage-selective fashions? Is erythroblast proliferation also modulated by EPO/EPOR signals? What functions are subserved by new noncanonical EPO/EPOR response factors (e.g. podocalyxin like-1, tribbles 3, reactive oxygen species, and nuclear factor kappa B)? What key regulators mediate EPOR inhibition and trafficking? And for emerging erythropoiesis-stimulating agents, to what extent do activities parallel EPOs (or differ in advantageous, potentially complicating ways, or both)?
Topics: Animals; Erythroblasts; Erythropoietin; Humans; Receptors, Erythropoietin; Signal Transduction
PubMed: 20173635
DOI: 10.1097/MOH.0b013e328338008b