Erythropoietin: function and therapeutic potential
https://doi.org/10.18699/SSMJ20230203
Abstract
Erythropoietin (EPO) exerts its effect on erythroid lineage cells through interaction with the EPO receptor (EPOR), the so-called canonical pathway, and through a complex consisting of EPOR and a common cytokine receptor beta subunit (CD131) – a non-canonical pathway for non-hematopoietic cells of the human and animal body. EPO realizes its effects through the launch of a signaling cascade, which begins with the phosphorylation of Janus kinase 2 (JAK2) and then with the involvement of phosphatidylinositol-3 kinase B (PI3K) or Ras-mitogen-activated protein kinase (MAPK) or signal transducers and transcription activators (STAT). EPO exhibits a direct cytoprotective effect through increased CD131 expression and subsequent development of anti-apoptotic and anti-inflammatory effects in target cells. In addition to its use in the treatment of anemia, EPO is increasingly being used in correction of inflammatory and degenerative processes, both in experimental and clinical studies. EPO promotes the engraftment of stem cells, differentiation of mesenchymal stem cells in the connective tissue direction, suppresses the inflammatory response and apoptosis of cells in the lesion. The article includes literature data concerning EPO and its clinical use in inflammatory and degenerative processes, based on data from eLibrary and the National Center for Biotechnological Information (NCBI) for the period 1998–2022.
About the Author
A. P. Lykov
Novosibirsk Research Institute of Tuberculosis of Minzdrav of Russia
Russian Federation
Russian Federation
Alexander P. Lykov, candidate of medical sciences
630040, Novosibirsk, Okhotskaya str., 81a
References
1. Jelkmann W. Molecular biology of erythropoietin. Intern. Med. 2004;43(8):649–659. doi:10.2169/internalmedicine.43.649
2. Ratcliffe P.J. HIF-1 and HIF-2: working alone or together in hypoxia? J. Clin. Invest. 2007;117(4):862–865. doi:10.1172/JCI31750
3. Percy M.J., Beer P.A., Campbell G., Dekker A.W., Green A.R., Oscier D., Rainey M.G., van Wijk R., Wood M., Lappin T.R., McMullin M.F., Lee F.S. Novel exon 12 mutations in the HIF2A gene associatedwith erythrocytosis. Blood. 2008;111(11):5400–5402. doi:10.1182/blood-2008-02-137703
4. Cantarelli C., Angeletti A., Cravedi P. Erythropoietin, a multifaceted protein with innate and adaptive immune modulatory activity. Am. J. Transplant. 2019;19(9):2407–2414. doi: 10.1111/ajt.15369
5. Ma Y., Zhou Z., Yang G.Y., Ding J., Wang X. The effect of erythropoietin and its derivatives on ischemic stroke therapy: a comprehensive review. Front. Pharmacol. 2022;13:743926. doi: 10.3389/fphar.2022.743926
6. Neubauer H., Cumano A., Müller M., Wu H., Huffstadt U., Pfeffer K. Jak2 defciency defnes an essential developmental checkpoint in defnitive hematopoiesis. Cell. 1998;93(3):397–409. doi:10.1016/s0092-8674(00)81168-x
7. Tefferi A., Barbui T. Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratifcation and management. Am. J. Hematol. 2020;95(12):1599–1613. doi:10.1002/ajh.26008
8. Jelkmann W. Erythropoietin. Front. Horm. Res. 2016;47:115–127. doi: 10.1159/000445174
9. Kimáková P., Solár P., Solárová Z., Komel R., Debeljak N. Erythropoietin and its angiogenic activity. Int. J. Mol. Sci. 2017;18(7):1519. doi: 10.3390/ijms18071519
10. Uversky V.N., Redwan E.M. Erythropoietin and co.: intrinsic structure and functional disorder. Mol. Biosyst. 2016;13(1):56–72. doi: 10.1039/c6mb00657d
11. Schiappacasse A., Maltaneri R.E., Chamorro M.E., Nesse A.B., Wetzler D.E., Vittori D.C. Modifcation of erythropoietin structure by N-homocysteinylation affects its antiapoptotic and proliferative functions. FEBS J. 2018;285(20):3801–3814. doi:10.1111/febs.14632
12. Chen Y., Xiang J., Qian F., Diwakar B.T., Ruan B., Hao S., Prabhu K.S., Paulson R.F. Epo receptor signaling in macrophages alters the splenic niche to promote erythroid differentiation. Blood. 2020;136(2):235–246. doi: 10.1182/blood.2019003480
13. Zafriou M.P., Noack C., Unsöld B., Didie M., Pavlova E., Fischer H.J., Reichardt H.M., Bergmann M.W., El-Armouche A., Zimmermann W.H., Zelarayan L.C. Erythropoietin responsive cardiomyogenic cells contribute to heart repair post myocardial infarction. Stem Cells. 2014;32(9):2480–2491. doi:10.1002/stem.1741
14. Bohr S., Patel S.J., Vasko R., Shen K., IrachetaVellve A., Lee J., Bale S.S., Chakraborty N., Brines M., Cerami A., Berthiaume F., Yarmush M.L. Modulation of cellular stress response via the erythropoietin/CD131 heteroreceptor complex in mouse mesenchymal-derived cells. J. Mol. Med. (Berl.). 2015;93(2):199–210. doi: 10.1007/s00109-014-1218-2
15. Lin H., Ling Y., Pan J., Gong H. Therapeutic effects of erythropoietin expressed in mesenchymal stem cells for dilated cardiomyopathy in rat. Biochem. Biophys. Res. Commun. 2019;517(4):575–580. doi: 10.1016/j.bbrc.2019.07.053
16. Kittur F.S., Lin Y., Arthur E., Hung C.Y., Li P.A., Sane D.C., Xie J. Recombinant asialoerythropoetin protects HL-1 cardiomyocytes from injury via suppression of Mst1 activation. Biochem. Biophys. Rep. 2019;17:157–168. doi: 10.1016/j.bbrep.2019.01.004
17. Wu S.H., Lu I.C., Lee S.S., Kwan A.L., Chai C.Y., Huang S.H. Erythropoietin attenuates motor neuron programmed cell death in a burn animal model. PLoS One. 2018;13(1):e0190039. doi: 10.1371/journal.pone.0190039
18. Eggold J.T., Rankin E.B. Erythropoiesis, EPO, macrophages, and bone. Bone. 2019;119:36–41. doi:10.1016/j.bone.2018.03.014
19. Perron-Deshaies G., St-Louis P., Romero H., Scorza T. Impact of erythropoietin production by erythroblastic island macrophages on homeostatic murine erythropoiesis. Int. J. Mol. Sci. 2020;21(23):8930. doi:10.3390/ijms21238930
20. Melashchenko O.V., Meniailo M.E., Malashchenko V.V., Gazatova N.D., Goncharov A.G., Seledtsova G.V., Seledtsov V.I. Erythropoietin directly affects human macrophage functionality. Curr. Pharm. Biotechnol. 2018;19(11):902–909. doi: 10.2174/1389201019666181031164520
21. Lisowska K.A., Dębska-Ślizień A., Jasiulewicz A., Daca A., Bryl E., Witkowski M. The influence of recombinant human erythropoietin on apoptosis and cytokine production of CD4+ lymphocytes from hemodialyzed patients. J. Clin. Immunol. 2013;33(3):661–665. doi: 10.1007/s10875-012-9835-4
22. Donadei C., Angeletti A., Cantarelli C., D’Agati V.D., la Manna G., Fiaccadori E., Horwitz J.K., Xiong H., Guglielmo C., Hartzell S., …Cravedi P. Erythropoietin inhibits SGK1-dependent TH17 induction and TH17-dependent kidney disease. JCI Insight. 2019;5(10):e127428. doi: 10.1172/jci.insight.127428
23. Purroy C., Fairchild R.L., Tanaka T., Baldwin W.M. 3rd, Manrique J., Madsen J.C., Colvin R.B., Alessandrini A., Blazar B.R., Fribourg M., …Cravedi P. Erythropoietin receptor-mediated molecular crosstalk promotes T cell immunoregulation and transplant survival. J. Am. Soc. Nephrol. 2017;28(8):2377–2392. doi: 10.1681/ASN.2016101100
24. Deshet-Unger N., Kolomansky A., Ben-Califa N., Hiram-Bab S., Gilboa D., Liron T., Ibrahim M., Awida Z., Gorodov A., Oster H.S., … Neumann D. Erythropoietin receptor in B cells plays a role in bone remodeling in mice. Theranostics. 2020;10(19):8744–8756. doi: 10.7150/thno.45845
25. Peng B., Kong G., Yang C., Ming Y. Erythropoietin and its derivatives: from tissue protection to immune regulation. Cell Death Dis. 2020;11(2):79. doi: 10.1038/s41419-020-2276-8
26. Kang J., Yun J.Y., Hur J., Kang J.A., Choi J.I., Ko S.B., Lee J., Kim J.Y., Hwang I.C., Park Y., Kim H.S. Erythropoietin priming improves the vasculogenic potential of G-CSF mobilized human peripheral blood mononuclear cells. Cardiovasc. Res. 2014;104(1):171–182. doi: 10.1093/cvr/cvu180
27. Lykov A.P., Surovtseva M.A., Poveshchenko O.V., Chernyavsky A.M., Fomichev A.V., Bondarenko N.A., Kim I.I. Effect of erythropoietin on bonemarrow mononuclear cells. Meditsinskaya immunologiya = Medical Immunology. 2020;22(1):135–142. [In Russian]. doi:10.15789/1563-0625-EEO-1807
28. Lykov A.P., Surovtseva M.A., Poveshchenko O.V., Bondarenko N.A., Kim I.I., Chernyavsky A.M., Fomichev A.V. Effect of erythropoietin on cytokine production by stem cells. Meditsinskaya immunologiya = Medical Immunology. 2019;21(5):861–868. [In Russian]. doi: 10.15789/1563-0625-2019-5-861-868
29. Rölfng J.H., Baatrup A., Stiehler M., Jensen J., Lysdahl H., Bünger C. The osteogenic effect of erythropoietin on human mesenchymal stromal cells is dosedependent and involves non-hematopoietic receptors and multiple intracellular signaling pathways. Stem. Cell Rev. Rep. 2014;10(1):69–78. doi: 10.1007/s12015-013-9476-x
30. Chang J.R., Sun N., Liu Y., Wei M., Zhao Y., Gan L., Zhu J.X., Su X.L. Erythropoietin attenuates vascular calcifcation by inhibiting endoplasmic reticulum stress in rats with chronic kidney disease. Peptides. 2020;123:170181. doi: 10.1016/j.peptides.2019.170181
31. Lykov A.P., Surovtseva M.A., Kim I.I., Bondarenko N.A., Poveshchenko O.V. Effect of erythropoietin on morphofunctional properties of mesenchymal stem cells. Bull. Exp. Biol. Med. 2020;170(1):164–170. doi: 10.1007/s10517-020-05024-z
32. Wang L., Wu F., Song Y., Duan Y., Jin Z. Erythropoietin induces the osteogenesis of periodontal mesenchymal stem cells from healthy and periodontitis sources via activation of the p38 MAPK pathway. Int. J. Mol. Med. 2018;41(2):829–835. doi: 10.3892/ijmm.2017.3294
33. Zhou J., Wei F., Ma Y. Inhibiting PPARγ by erythropoietin while upregulating TAZ by IGF1 synergistically promote osteogenic differentiation of mesenchymal stem cells. Biochem. Biophys. Res. Commun. 2016;478(1):349–355. doi: 10.1016/j.bbrc.2016.07.049
34. Tari K., Atashi A., Kaviani S., AkhavanRahnama M., Anbarlou A., Mossahebi-Mohammadi M. Erythropoietin induces production of hepatocyte growth factor from bone marrow mesenchymal stem cells in vitro. Biologicals. 2017;45:15–19. doi: 10.1016/j.biologicals.2016.10.010
35. Cui J., Liu X., Zhang Z., Xuan Y., Liu X., Zhang F. EPO protects mesenchymal stem cells from hyperglycaemic injury via activation of the Akt/FoxO3a pathway. Life Sci. 2019;222:158–167. doi: 10.1016/j.lfs.2018.12.045
36. Hu M.C., Shi M., Cho H.J., Zhang J., Pavlenco A., Liu S., Sidhu S., Huang L.J., Moe O.W. The erythropoietin receptor is a downstream effector of Klotho-induced cytoprotection. Kidney Int. 2013;84(3):468–481. doi: 10.1038/ki.2013.149
37. Tsai T.H., Lu C.H., Wallace C.G., Chang W.N., Chen S.F., Huang C., Tsai N.W., Lan M.Y., Sung P.H., Liu C.F., Yip H.K. Erythropoietin improves long-term neurological outcome in acute ischemic stroke patients: a randomized, prospective, placebo-controlled clinical trial. Crit. Care. 2015;19(1):49. doi: 10.1186/s13054-015-0761-8
38. Garrigue P., Hache G., Bennis Y., Brige P., Stalin J., Pellegrini L., Velly L., Orlandi F., Castaldi E., Dignat-George F., Sabatier F., Guillet B. Erythropoietin pretreatment of transplanted endothelial colony-forming cells enhances recovery in a cerebral ischemia model by increasing their homing ability: a SPECT/CT study. J. Nucl. Med. 2016;57(11):1798–1804. doi:10.2967/jnumed.115.170308
39. Zhang S., Shi B. Erythropoietin modifcation enhances the protection of mesenchymal stem cells on diabetic rat-derived schwann cells: implications for diabetic neuropathy. Biomed. Res. Int. 2017;2017:6352858. doi: 10.1155/2017/6352858
40. Li J., Guo W., Xiong M., Zhang S., Han H., Chen J., Mao D., Yu H., Zeng Y. Erythropoietin facilitates the recruitment of bone marrow mesenchymal stem cells to sites of spinal cord injury. Exp. Ther. Med. 2017;13(5):1806–1812. doi: 10.3892/etm.2017.4182
41. Zhang H., Fang X., Huang D., Luo Q., Zheng M., Wang K., Cao L., Yin Z. Erythropoietin signaling increases neurogenesis and oligodendrogenesis of endogenous neural stem cells following spinal cord injury both in vivo and in vitro. Mol. Med. Rep. 2018;17(1):264–272. doi: 10.3892/mmr.2017.7873
42. Si W., Wang J., Li M., Qu H., Gu R., Liu R., Wang L., Li S., Hu X. Erythropoietin protects neurons from apoptosis via activating PI3K/AKT and inhibiting Erk1/2 signaling pathway. 3 Biotech. 2019;9(4):131. doi: 10.1007/s13205-019-1667-y
43. Chen S.J., Wang Y.L., Lo W.T., Wu C.C., Hsieh C.W., Huang,C.F., Lan Y.H., Wang C.C., Chang D.M., Sytwu H.K. Erythropoietin enhances endogenous haem oxygenase-1 and represses immune responses to ameliorate experimental autoimmune encephalomyelitis. Clin. Exp. Immunol. 2010; 162(2):210–223. doi: 10.1111/j.1365-2249.2010.04238.x
44. Zhong L., Zhang H., Ding Z.F., Li J., Lv J.W., Pan Z.J., Xu D.X., Yin Z.S. Erythropoietin-induced autophagy protects against spinal cord injury and improves neurological function via the extracellular-regulated protein kinase signaling pathway. Mol. Neurobiol. 2020;57(10):3993–4006. doi: 10.1007/s12035-020-01997-0
45. Huang R., Zhang J., Ren C., Zhang X., Gu L., Dong Y., Zhang J., Zhang J. Effect of erythropoietin on Fas/FasL expression in brain tissues of neonatal rats with hypoxic-ischemic brain damage. Neuroreport. 2019;30(4):262–268. doi: 10.1097/WNR.0000000000001194
46. Jasiulewicz A., Lisowska K.A., Dębska-Ślizień A., Witkowski J.M. Phenotype, proliferation and apoptosis of B lymphocytes in hemodialysis patients treated with recombinant human erythropoietin. Int. Immunol. 2016;28(11):523–532. doi: 10.1093/intimm/dxw032
47. Cakiroglu F., Enders-Comberg S.M., Pagel H., Rohwedel J., Lehnert H., Kramer J. Erythropoietin-enhanced endothelial progenitor cell recruitment in peripheral blood and renal vessels during experimental acute kidney injury in rats. Cell. Biol. Int. 2016;40(3):298–307. doi: 10.1002/cbin.10566
48. Li J.P., Wang D.W., Song Q.H. Transplantation of erythropoietin gene-transfected umbilical cord mesenchymal stem cells as a treatment for limb ischemia in rats. Genet. Mol. Res. 2015;14(4):19005–19015. doi:10.4238/2015.December.29.8
49. Lykov A.P., Bondarenko N.A., Poveshchenko O.V., Kabakov A.V., Surovtseva M.A., Kim I.I., Kazakov O.V., Poveshchenko A.F., Yankaite E.V. Therapeutic potential of a biomedical cellular product in rats with lower limb ischaemia. Angiol. Sosud. Khir. 2020;26(3):37–43. doi: 10.33529/ANGIO2020315
50. Hu R., Cheng Y., Jing H., Wu H. Erythropoietin promotes the protective properties of transplanted endothelial progenitor cells against acute lung injury via PI3K/Akt pathway. Shock. 2014;42(4):327–336. doi:10.1097/SHK.0000000000000216
51. Zhang Z., Sun C.., Wang J., Jiang W., Xin Q., Luan Y. Timing of erythropoietin modifed mesenchymal stromal cell transplantation for the treatment of experimental bronchopulmonary dysplasia. J. Cell Mol. Med. 2018;22(11):5759–5763. doi: 10.1111/jcmm.13843
52. Luan Y., Zhang L., Chao S., Liu X., Li K., Wang Y., Zhang Z. Mesenchymal stem cells in combination with erythropoietin repair hyperoxia-induced alveoli dysplasia injury in neonatal mice via inhibition of TGF-β1 signaling. Oncotarget. 2016;7(30):47082–47094. doi: 10.18632/oncotarget.9314
53. Imam R.A., Rizk A.A. Efcacy of erythropoietin-pretreated mesenchymal stem cells in murine burn wound healing: possible in vivo transdifferentiation into keratinocytes. Folia Morphol. (Warsz). 2019;78(4):798–808. doi: 10.5603/FM.a2019.0038
54. Lykov A.P., Bondarenko N.A., Poveshchenko O.V., Kim I.I., Surovtseva M.A., Sadykova J.B., Semin P.A., Zavjalov E.L., Krivoshapkin A.L., Konenkov V.I. Treatment of intervertebral disc degeneration in Wistar rats with mesenchymal stem cells. Bull. Exp. Biol. Med. 2020;168(4):578–582. doi: 10.1007/s10517-020-04756-2
55. Fomichev A.V., Chernyavsky A.M., Gulyaeva K.K., Poveshchenko O.V., Lykov A.P., Kareva Yu.E., Minin S.M., Nikitin N.A. The results of intramiocardial implantation of autologous bone marrow cells treated with erythropoietin in surgical treatment of coronary artery disease with sever lesion of vessels. Rossiyskiy kardiologicheskiy zhurnal = Russian Journal of Cardiology. 2019;24(1):62–69. [In Russian]. doi: 10.15829/1560-4071-2019-1-62-69
56. Lagrèze W.A., Küchlin S., Ihorst G., Grotejohann B., Beisse F., Volkmann M., Heinrich S.P., Albrecht P., Ungewiss J., Wörner M., …TONE study group. Safety and efcacy of erythropoietin for the treatment of patients with optic neuritis (TONE): a randomised, double-blind, multicentre, placebo-controlled study. Lancet Neurol. 2021;20(12):991–1000. doi: 10.1016/S1474-4422(21)00322-7
57. Juul S.E., Comstock B.A., Wadhawan R., Mayock D.E., Courtney S.E., Robinson T., Ahmad K.A., Bendel-Stenzel E., Baserga M., LaGamma E.F., … PENUT Trial Consortium. A randomized trial of erythropoietin for neuroprotection in preterm infants. N. Engl. J. Med. 2020;382(3):233–243. doi: 10.1056/NEJMoa1907423
58. Wellmann S., Hagmann C.F., von Felten S., Held L., Klebermass-Schrehof K., Truttmann A.C., Knöpfli C., Fauchère J.C., Bührer C., Bucher H.U., Rüegger C.M.; Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants (EpoRepair) Investigators. Safety and short-term outcomes of high-dose erythropoietin in preterm infants with intraventricular hemorrhage: the EpoRepair randomized clinical trial. JAMA Netw. Open. 2022;5(12):e2244744. doi: 10.1001/jamanetworkopen.2022.44744
59. Hong J.M., Choi M.H., Park G.H., Shin H.S., Lee S.J., Lee J.S., Lim Y.C. Transdural revascularization by multiple burrhole after erythropoietin in stroke patients with cerebral hypoperfusion: a randomized controlled trial. Stroke. 2022;53(9):2739–2748. doi: 10.1161/STROKEAHA.122.038650
60. Minamino T., Higo S., Araki R., Hikoso S., Nakatani D., Suzuki H., Yamada T., Okutsu M., Yamamoto K., Fujio Y., … EPO-AMI-II Investigators. Low-Dose Erythropoietin in Patients With ST-Segment Elevation Myocardial Infarction (EPO-AMI-II). A randomized controlled clinical trial. Circ. J. 2018;82(4):1083–1091. doi: 10.1253/circj.CJ-17-0889
Review
For citations:
Lykov A.P. Erythropoietin: function and therapeutic potential. Сибирский научный медицинский журнал. 2023;43(2):29-39. (In Russ.) https://doi.org/10.18699/SSMJ20230203
Views:
1503
Email this article 