scholarly journals Erythropoietin (EPO) as a Key Regulator of Erythropoiesis, Bone Remodeling and Endothelial Transdifferentiation of Multipotent Mesenchymal Stem Cells (MSCs): Implications in Regenerative Medicine

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2140
Author(s):  
Asterios S. Tsiftsoglou
Keyword(s):  
Regenerative Medicine ◽  
Bone Remodeling ◽  
Adult Life ◽  
Peptide Hormone ◽  
Erythropoietin Receptor ◽  
Trophic Factors ◽  
Biologic Agent ◽  
Protection Factor ◽  
Human Erythropoietin ◽  
Multipotent Mesenchymal Stem Cells

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.

Genomic organization of the human erythropoietin receptor gene

Genomics ◽  
1991 ◽  
Vol 11 (4) ◽  
pp. 974-980 ◽  
Author(s):  
Laura A. Penny ◽  
Bernard G. Forget
Keyword(s):  
Genomic Organization ◽  
Receptor Gene ◽  
Erythropoietin Receptor ◽  
Human Erythropoietin

scholarly journals Regulated Human Erythropoietin Receptor Expression in Mouse Brain

1997 ◽  
Vol 272 (51) ◽  
pp. 32395-32400 ◽  
Author(s):  
Chun Liu ◽  
Kun Shen ◽  
Ziyao Liu ◽  
Constance Tom Noguchi
Keyword(s):  
Mouse Brain ◽  
Erythropoietin Receptor ◽  
Receptor Expression ◽  
Human Erythropoietin

scholarly journals Cloning of the human erythropoietin receptor gene

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2548-2556 ◽  
Author(s):  
CT Noguchi ◽  
KS Bae ◽  
K Chin ◽  
Y Wada ◽  
AN Schechter ◽  
...  
Keyword(s):  
Binding Site ◽  
Translational Control ◽  
Transcription Initiation ◽  
Repetitive Sequences ◽  
Cdna Probe ◽  
Gc Content ◽  
Erythropoietin Receptor ◽  
Coding Region ◽  
Epo Receptor ◽  
Human Erythropoietin

We have isolated and characterized a genomic clone of the human erythropoietin (Epo) receptor from a placental genomic library using a cDNA probe for the murine Epo receptor. The coding region spans about 6.5 kb with seven intervening sequences ranging in size from 81 bp to 2.1 kb. A stretch of 123 purines is found in the 5′ region from -456 to -578 upstream from the first codon and flanking the Alu repetitive sequences located further upstream. The human Epo receptor contains a palindromic sequence 5′ of the translated region that consists of an almost perfect inverted repeat of 12 nucleotides (CAGCTGC(G/C)TCCG) centered about G at -92 from the first codon. An inverted SP1 binding site (CCGCCC) and an inverted GATA-1 binding site (TTATCT) are located at positions -151 and -179, respectively, and CACCC sequences are located at -585 and further upstream. No TATA or CAAT sequences are in this 5′ flanking region. However, this region as far as -275 has a 72% GC content compared with an overall GC content of 56%. A 1-kb BamHI fragment of the human Epo receptor containing 700 bp of sequences 5′ of the coding region was transcribed in an in vitro transcription assay; initiation of transcription appeared to be around 132 +/- 5 just downstream from the inverted SP1 site at -151. T1 analysis of human Epo receptor messenger RNA also maps the site of transcription initiation to this region. Within 180 nucleotides 5′ to the first exon are three regions with 70% or greater homology with the murine Epo receptor. The study of this gene, including its similarities with the murine Epo receptor, should help elucidate aspects of the transcriptional and possible translational control of the Epo receptor in human erythroid cells and thus its role in signal transduction and erythroid differentiation.

scholarly journals Predisposition to Myeloproliferative Neoplasms

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-33-SCI-33
Author(s):  
Radek C. Skoda
Keyword(s):  
Germline Mutation ◽  
Myeloproliferative Neoplasms ◽  
Single Gene ◽  
Adult Life ◽  
Gene Mutations ◽  
Germline Mutations ◽  
Erythropoietin Receptor ◽  
Driver Mutations ◽  
Disease Manifestation

Familial forms of myeloproliferative neoplasms (MPN) and genetic contribution to sporadic cases of MPN have long been recognized. In the majority of cases, familial MPN is inherited as an autosomal dominant trait. The penetrance varies from around 20% to up to 100% in some pedigrees. We can distinguish two types of familial MPN. Type 1 has high penetrance, polyclonal hematopoiesis and hyperproliferation of a single hematopoietic lineage, caused by mutations in a single gene and usually manifesting at birth or early childhood. Examples are mutations in the genes for the erythropoietin receptor, thrombopoietin or its receptor, MPL. The type 2 familial MPNs are characterized by clonal hematopoiesis, low penetrance and manifestation beginning in most cases later in adult life. These type 2 familial MPNs are classical examples of inherited predisposition to a clonal malignant disease, in which acquired somatic mutations in hematopoietic cells are required for disease manifestation. Affected family members typically display the same acquired driver mutations in the genes for JAK2 (JAK2-V617F or JAK2-exon12), MPL (MPL-W515), or calreticulin (CALR) as patients with sporadic MPN. The mutated genes and the mechanism of how these inherited germline mutations predispose to MPN have not yet been elucidated. The search for these germline mutations has been hampered by the low penetrance of MPN manifestation and the rare occurrence of pedigrees that are large enough for genetic studies. Furthermore, the few candidate gene mutations that have been identified to date do not map to one gene locus and the function of the candidate genes does not fall into a common category. Two models of how the germline predisposition interacts with acquired driver mutations can be considered. First, the germline mutation may increase the mutation rate for gene mutations in JAK2, MPL, and CALR. Second, the germline mutation functionally synergizes with mutations in JAK2, MPL, and CALR and promotes disease initiation. The current state of our studies and studies in other laboratories will be discussed. Disclosures Skoda: Novartis: Consultancy; Sanofi: Consultancy.

scholarly journals Therapeutic Potential of “Exosomes Derived Multiple Allogeneic Proteins Paracrine Signaling: Exosomes d-MAPPS” is Based on the Effects of Exosomes, Immunosuppressive and Trophic Factors

2019 ◽  
Vol 20 (3) ◽  
pp. 189-197 ◽  
Author(s):  
Carl Randall Harrell ◽  
Crissy Fellabaum ◽  
Bojana Simovic Markovic ◽  
Aleksandar Arsenijevic ◽  
Vladislav Volarevic
Keyword(s):  
Regenerative Medicine ◽  
Therapeutic Potential ◽  
Interleukin 1 ◽  
Growth Factor Receptor ◽  
Trophic Factors ◽  
Chronic Obstructive ◽  
Paracrine Signaling ◽  
High Concentration ◽  
Anti Inflammatory ◽  
High Concentrations

Abstract Due to their differentiation capacity and potent immunosuppressive and pro-angiogenic properties, mesenchymal stem cells (MSCs) have been considered as new therapeutic agents in regenerative medicine. Since most of MSC-mediated beneficent effects are a consequence of their paracrine action, we designed MSC-based product “Exosomes Derived Multiple Allogeneic Proteins Paracrine Signaling (Exosomes d-MAPPS), which activity is based on MSCs-derived growth factors and immunomodulatory cytokines capable to attenuate inflammation and to promote regeneration of injured tissues. Interleukin 1 receptor antagonist (IL-1Ra) and IL-27 were found in high concentrations in Exosomes d-MAPPS samples indicating strong anti-inflammatory and immunosuppressive potential of Exosomes d-MAPPS. Additionally, high concentrations of vascular endothelial growth factor receptor (VEGFR1) and chemokines (CXCL16, CCL21, CXCL14) were noticed at Exosomes d-MAPPS samples suggesting their potential to promote generation of new blood vessels and migration of CXCR6, CCR7 and CXCR4 expressing cells. Since all proteins which were found in high concentration in Exosomes d-MAPPS samples (IL-1Ra, CXCL16, CXCL14, CCL21, IL-27 and VEGFR1) are involved in modulation of lung, eye, and synovial inflammation, Exosomes d-MAPPS samples were prepared as inhalation and ophthalmic solutions in addition to injection formulations; their application in several patients suffering from chronic obstructive pulmonary disease, osteoarthritis, and dry eye syndrome resulted with significant improvement of biochemical and functional parameters. In conclusion, Exosomes d-MAPPS, due to the presence of important anti-inflammatory, immunomodulatory, and pro-angiogenic factors, represents potentially new therapeutic agent in regenerative medicine that should be further tested in large clinical studies.

scholarly journals Retroviral transfer of the recombinant human erythropoietin receptor gene into single hematopoietic stem/progenitor cells from human cord blood increases the number of erythropoietin-dependent erythroid colonies

Blood ◽  
1996 ◽  
Vol 87 (2) ◽  
pp. 525-534 ◽  
Author(s):  
L Lu ◽  
Y Ge ◽  
ZH Li ◽  
W Keeble ◽  
D Kabat ◽  
...  
Keyword(s):  
Growth Factors ◽  
Cord Blood ◽  
Progenitor Cells ◽  
Single Cells ◽  
Erythropoietin Receptor ◽  
Proliferative Potential ◽  
Human Cord Blood ◽  
Hematopoietic Stem ◽  
Colony Forming Unit ◽  
Human Erythropoietin

To test whether an enforced expression of a lineage-specific cytokine receptor would influence the proliferation/differentiation of hematopoietic stem/progenitor cells, retroviral vectors containing the human erythropoietin receptor (hEpoR) gene were used to transduce the hEpoR gene into phenotypically sorted subsets of cells. CD34 , CD34++CD33-, and CD34++CD33+ populations of human cord blood, highly enriched for hematopoietic stem/progenitor cells, were sorted and plated as single cells per well in methylcellulose culture medium containing early acting growth factors in the presence or absence of Epo. The hEpoR gene was efficiently transduced into single high proliferative potential colony-forming cells (HPP-CFC) and multipotential (colony-forming unit granulocyte, erythroid, monocyte, megakaryocyte [CFU-GEMM]), erythroid (burst-forming unit-erythroid [BFU- E]), and granulocyte-macrophage (colony-forming unit-granulocyte- macrophage [CFU-GM]) progenitor cells. As expected in cultures grown in the absence of Epo, no BFU-E or CFU-GEMM colonies grew. In the presence of Epo, the hEpoR-gene transduced cells formed significantly more CFU- GEMM and BFU-E colonies than did the controls. A significant decrease in HPP-CFC colonies was also observed under these conditions. Little or no effect of hEpoR gene transduction was apparent in the numbers of CFU- GM colonies formed in the presence or absence of Epo. All of the above results were similar whether the cell populations assessed were CD34 or their CD33- or CD33+ subsets plated in the presence of growth factors at 200 cells/mL or after limiting dilution at 2 cells/well. These results suggest that the profile of detectable stem/progenitors can be altered by retrovirus-mediated expression of the hEpoR gene.

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