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As a Key Regulator of Erythropoiesis, Bone Remodeling and Endothelial

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cells Review Erythropoietin (EPO) as a Key Regulator of Erythropoiesis, Bone Remodeling and Endothelial Transdifferentiation of Multipotent Mesenchymal Stem Cells (MSCs): Implications in Regenerative Medicine Asterios S. Tsiftsoglou Laboratory of Pharmacology, Department of Pharmaceutical Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; [email protected] Abstract: Human erythropoietin (EPO) is an N-linked glycoprotein consisting of 166 aa that is pro- duced 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 mat- uration 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 Citation: Tsiftsoglou, A.S. and the production of hemoglobin. The detection of a heterodimeric complex of EPO-R (consist- Erythropoietin (EPO) as a Key ing of one EPO-R chain and the CSF2RB β-chain, CD131) in several tissues (brain, heart, skeletal Regulator of Erythropoiesis, Bone muscle) explains the EPO pleotropic action as a protection factor for several cells, including the Remodeling and Endothelial multipotent MSCs as well as cells modulating the innate and adaptive immunity arms. EPO induces Transdifferentiation of Multipotent the osteogenic and endothelial transdifferentiation of the multipotent MSCs via the activation of Mesenchymal Stem Cells (MSCs): EPO-R signaling pathways, leading to bone remodeling, induction of angiogenesis and secretion Implications in Regenerative of a large number of trophic factors (secretome). These diversely unique properties of EPO, taken Medicine. Cells 2021, 10, 2140. together with its clinical use to treat anemias associated with chronic renal failure and other blood https://doi.org/10.3390/ disorders, make it a valuable biologic agent in regenerative medicine for the treatment/cure of tissue cells10082140 de-regeneration disorders. Academic Editors: Claudia Spits and Alexander E. Kalyuzhny Keywords: erythropoietin-alpha; bone marrow erythropoiesis; bone remodeling; endothelial transd- ifferentiation (angiogenesis); mesenchymal stem cells; regenerative medicine Received: 22 July 2021 Accepted: 17 August 2021 Published: 20 August 2021 1. Introduction into Human Erythropoietin (EPO): Brief History and Structure Publisher’s Note: MDPI stays neutral Human erythropoietin (EPO) is a peptide hormone produced in the fetal liver during with regard to jurisdictional claims in early development and the kidneys in the human adult body. As a major hematopoietic published maps and institutional affil- growth factor (HGF), it regulates bone marrow erythropoiesis by promoting the daily iations. massive production (200 billion) of RBCs full of hemoglobin A (α2β2), that carry oxygen and transfer it from the lungs to tissues [1–6] (Figure1). In terms of structure, EPO is a glycoprotein consisting initially of 193 aa that include an N-terminal 27 aa signaling peptide. This premature polypeptide is post-translationally cleaved to yield the mature Copyright: © 2021 by the author. form of EPO (UniProt P01588). Licensee MDPI, Basel, Switzerland. The primary structure of the full-length human erythropoietin contains 166 aa, with an This article is an open access article approximate MW of 30.4 kDa. It is an acidic glycoprotein and exhibits two disulfide (-S-S-) distributed under the terms and bonds, supporting the overall molecular structure between Cys29 and Cyst33 and Cys7 and conditions of the Creative Commons Cys161. There are three N-linked carbohydrates at the Asparagine residues 24, 38 and 83, Attribution (CC BY) license (https:// and one O-linked carbohydrate at Serine 126. The 3D structure of EPO is composed of four creativecommons.org/licenses/by/ alpha-helices. Helix A is connected to Helix D through Cys7 and Cys171, while Helices A 4.0/). Cells 2021, 10, 2140. https://doi.org/10.3390/cells10082140 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 14 Cells 2021, 10, 2140 2 of 14 38 and 83, and one O-linked carbohydrate at Serine 126. The 3D structure of EPO is com- posed of four alpha-helices. Helix A is connected to Helix D through Cys7 and Cys171, while Helices A and B are connected through Cys29 and Cys33. Over the years, various andrecombinant B are connected human through erythropoietins Cys29 and (rhEPOetins) Cys33. Over have the years, been synthesized various recombinant in several human gene- erythropoietinscloning-expression (rhEPOetins) platforms. haveThese been includ synthesizede genetically in severalmodified gene-cloning-expression mammalian CHO [7,8] platforms.and HEK293 These cells, include as well genetically as yeast- and modified baculovirus-infected mammalian CHO insect [7 ,cell8] and systems. HEK293 The cells, bio- assimilar well epoetins as yeast- exhibit and baculovirus-infected some differences attrib insectuted cell to variations systems. Thein the biosimilar glycosylation epoetins pat- exhibitterns. rhEPO some differenceshas been commer attributedcially to available variations since in the 1989 glycosylation after gaining patterns. authorization rhEPO hasap- been commercially available sinceR 1989 after gaining authorization approval by the FDA proval by Rthe FDA (EPOGEN ) for use as a valuable biologic medicinal product in the (EPOGENreplacement) forprotein use astherapy a valuable (RPT) biologic of chronic medicinal renal failure product (CRF), in the that replacement is characterized protein by therapy (RPT) of chronic renal failure (CRF), that is characterized by insufficient production insufficient production of EPO. of EPO. FigureFigure 1. IllustrationIllustration of of the the human human bone bone marrow marrow cell cell restricted restricted pathways pathways of the of thediffere differentiationntiation of hematopoietic of hematopoietic stem stem cells cellsinto mature into mature blood blood cells. cells.In the Inlower the lowerright box, right the box, erythroid the erythroid cell restricted cell restricted lineage lineagedifferentia differentiationtion is shown. is HSCs shown. give HSCs rise giveto common rise to commonmyeloid progenitors myeloid progenitors (CMP) and (CMP) common and megakaryocyte common megakaryocyte erythroid erythroidprogenitors progenitors (MEP). The (MEP). latter Theare differ- latter areentiated differentiated into erythropoietin-responsiv into erythropoietin-responsivee BFU-E and BFU-E CFU-E and clones, CFU-E clones,shown shownby the byarrows the arrows where wherehuman human EPO acts EPO upon acts uponthem. them.Interactions Interactions of EPO ofwith EPO its withhomodimeric its homodimeric EPO-R lead EPO-R to cell lead signaling to cell signalingactivation activationpathways that pathways increase that the increase biosyn- thethesis biosynthesis of hemoglobin. of hemoglobin. The levels Theof hemoglobins levels of hemoglobins increase as increase erythropoiesis as erythropoiesis continues continuesin the proerythroblasts, in the proerythroblasts, in the or- inthochomatic the orthochomatic normoblasts normoblasts (ON) and (ON) finally and in finally the reticulocyte in the reticulocytess and mature and red mature blood red cells blood (RBCs) cells following (RBCs) following the extrusion the of the nucleus. Erythropoiesis is homeostatically regulated by low-oxygen conditions (hypoxia) and the final end produc- extrusion of the nucleus. Erythropoiesis is homeostatically regulated by low-oxygen conditions (hypoxia) and the final tion via a feedback action loop. The original figure was published by Tsiftsoglou et al. [4] and has been lightly modified end production via a feedback action loop. The original figure was published by Tsiftsoglou et al. [4] and has been lightly accordingly to indicate where EPO acts upon in the proerythroid cells. The initial commitment to the erythroid cell lineage modifiedrestricted accordinglypathway of todifferentiation indicate where begi EPOns at acts the upon level in of the BM proerythroid HSCs and leads cells. to The theinitial formation commitment of MEPs tothat the yield erythroid BFU- cellEs and lineage CFU-Es. restricted The most pathway recently of differentiationpublished work begins by Eisele at the et levelal. [9] of provided BM HSCs direct and evidence leads to theindicating formation that of EPO MEPs indeed that yieldacts upon BFU-Es the andBM CFU-Es.HSCs to promote The most commi recentlytment published towards work the erythroid by Eisele etmaturation. al. [9] provided direct evidence indicating that EPO indeed acts upon the BM HSCs to promote commitment towards the erythroid maturation. Historically, the search for EPO began as early as 1875, when anemia-like symptoms wereHistorically, diagnosed in the patients search living for EPO at beganlow altitude as early and as characterized 1875, when anemia-like by low blood symptoms oxygen werelevels. diagnosed Moreover, in it patients took intensive living atresearch low altitude work over and characterizedthe past 50 years by lowto identify blood oxygenEPO as levels.the major Moreover, driver of it tookBM erythropoiesis, intensive research purify work it from over urine the past derived 50 years
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  • Erythropoietin and Cancer: the Unintended Consequences of Anemia Correction

    Erythropoietin and Cancer: the Unintended Consequences of Anemia Correction

    REVIEW ARTICLE published: 11 November 2014 doi: 10.3389/fimmu.2014.00563 Erythropoietin and cancer: the unintended consequences of anemia correction Nataša Debeljak 1*, Peter Solár 2 and Arthur J. Sytkowski 3 1 Faculty of Medicine, Institute of Biochemistry, University of Ljubljana, Ljubljana, Slovenia 2 Department of Cell and Molecular Biology, Institute of Biology and Ecology, Faculty of Sciences, Pavol Jozef Šafárik University, Košice, Slovakia 3 Oncology Therapeutic Area, Quintiles Transnational, Arlington, MA, USA Edited by: Until 1990, erythropoietin (EPO) was considered to have a single biological purpose and Pietro Ghezzi, Brighton and Sussex action, the stimulation of red blood cell growth and differentiation. Slowly, scientific and Medical School, UK medical opinion evolved, beginning with the discovery of an effect on endothelial cell Reviewed by: Ralf Schindler, Charité, Germany growth in vitro and the identification of EPO receptors (EPORs) on neuronal cells. We Domenico Ribatti, University of Bari now know that EPO is a pleiotropic growth factor that exhibits an anti-apoptotic action on Medical School, Italy numerous cells and tissues, including malignant ones. In this article, we present a short Chris Thiemermann, Queen Mary discussion of EPO, receptors involved in EPO signal transduction, and their action on non- University of London, UK hematopoietic cells. This is followed by a more detailed presentation of both pre-clinical *Correspondence: Nataša Debeljak, Faculty of Medicine, and clinical data that demonstrate EPO’s action on cancer cells, as well as tumor angio- Institute of Biochemistry, University genesis and lymphangiogenesis. Clinical trials with reported adverse effects of chronic of Ljubljana, Vrazov trg 2, SI-1000 erythropoiesis-stimulating agents (ESAs) treatment as well as clinical studies exploring Ljubljana, Slovenia the prognostic significance of EPO and EPOR expression in cancer patients are reviewed.