Erythroid Enucleation: a Gateway into a "bloody" World

Overview

Journal Exp Hematol

Specialty Hematology

Date 2021 Jan 13

PMID 33440185

Citations 25

Authors

Vijay Menon

Saghi Ghaffari

Affiliations

Soon will be listed here.

Abstract

Erythropoiesis is an intricate process starting in hematopoietic stem cells and leading to the daily production of 200 billion red blood cells (RBCs). Enucleation is a greatly complex and rate-limiting step during terminal maturation of mammalian RBC production involving expulsion of the nucleus from the orthochromatic erythroblasts, resulting in the formation of reticulocytes. The dynamic enucleation process involves many factors ranging from cytoskeletal proteins to transcription factors to microRNAs. Lack of optimum terminal erythroid maturation and enucleation has been an impediment to optimum RBC production ex vivo. Major efforts in the past two decades have exposed some of the mechanisms that govern the enucleation process. This review focuses in detail on mechanisms implicated in enucleation and discusses the future perspectives of this fascinating process.

Citing Articles

Cell death signaling in human erythron: erythrocytes lose the complexity of cell death machinery upon maturation.

Tkachenko A, Havranek O Apoptosis. 2025; .

PMID: 39924584 DOI: 10.1007/s10495-025-02081-5.

New insights into the mechanisms of red blood cell enucleation: From basics to clinical applications.

Zhuo Q, Zhang Z, Fang X EJHaem. 2024; 5(6):1301-1311.

PMID: 39691252 PMC: 11647694. DOI: 10.1002/jha2.1051.

Erythroblast enucleation at a glance.

Newton L, Fowler V, Humbert P J Cell Sci. 2024; 137(19).

PMID: 39397781 PMC: 11529606. DOI: 10.1242/jcs.261673.

PROTAC-mediated vimentin degradation promotes terminal erythroid differentiation of pluripotent stem cells.

Yan H, Zang R, Cui T, Liu Y, Zhang B, Zhao L Stem Cell Res Ther. 2024; 15(1):310.

PMID: 39294765 PMC: 11412063. DOI: 10.1186/s13287-024-03910-1.

Mononuclear Phagocytes, Cellular Immunity, and Nobel Prizes: A Historic Perspective.

Gordon S, Roberti A, Kaufmann S Cells. 2024; 13(16).

PMID: 39195266 PMC: 11352343. DOI: 10.3390/cells13161378.

References

Wu H, Liu X, Jaenisch R, Lodish H . Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell. 1995; 83(1):59-67. DOI: 10.1016/0092-8674(95)90234-1. View

Logdberg L, Reid M, Zelinski T . Human blood group genes 2010: chromosomal locations and cloning strategies revisited. Transfus Med Rev. 2010; 25(1):36-46. DOI: 10.1016/j.tmrv.2010.08.005. View

Wu H, Zhang Y . Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev. 2011; 25(23):2436-52. PMC: 3243055. DOI: 10.1101/gad.179184.111. View

Vegiopoulos A, Garcia P, Emambokus N, Frampton J . Coordination of erythropoiesis by the transcription factor c-Myb. Blood. 2006; 107(12):4703-10. PMC: 1895806. DOI: 10.1182/blood-2005-07-2968. View

Gnanapragasam M, McGrath K, Catherman S, Xue L, Palis J, Bieker J . EKLF/KLF1-regulated cell cycle exit is essential for erythroblast enucleation. Blood. 2016; 128(12):1631-41. PMC: 5034741. DOI: 10.1182/blood-2016-03-706671. View

Yan H, Wang Y, Qu X, Li J, Hale J, Huang Y . Distinct roles for TET family proteins in regulating human erythropoiesis. Blood. 2017; 129(14):2002-2012. PMC: 5383871. DOI: 10.1182/blood-2016-08-736587. View

Li X, Mei Y, Yan B, Vitriol E, Huang S, Ji P . Histone deacetylase 6 regulates cytokinesis and erythrocyte enucleation through deacetylation of formin protein mDia2. Haematologica. 2017; 102(6):984-994. PMC: 5451330. DOI: 10.3324/haematol.2016.161513. View

McGrath K, Kingsley P, Koniski A, Porter R, Bushnell T, Palis J . Enucleation of primitive erythroid cells generates a transient population of "pyrenocytes" in the mammalian fetus. Blood. 2007; 111(4):2409-17. PMC: 2234067. DOI: 10.1182/blood-2007-08-107581. View

Zermati Y, Garrido C, Amsellem S, Fishelson S, Bouscary D, Valensi F . Caspase activation is required for terminal erythroid differentiation. J Exp Med. 2001; 193(2):247-54. PMC: 2193347. DOI: 10.1084/jem.193.2.247. View

10.

Naughton B, Kolks G, Arce J, Liu P, PILIERO S, Gordon A . The regenerating liver: a site of erythropoiesis in the adult Long-Evans rat. Am J Anat. 1979; 156(1):159-67. DOI: 10.1002/aja.1001560117. View

11.

Cantu C, Bose F, Bianchi P, Reali E, Colzani M, Cantu I . Defective erythroid maturation in gelsolin mutant mice. Haematologica. 2012; 97(7):980-8. PMC: 3396666. DOI: 10.3324/haematol.2011.052522. View

12.

Wolwer C, Pase L, Russell S, Humbert P . Calcium Signaling Is Required for Erythroid Enucleation. PLoS One. 2016; 11(1):e0146201. PMC: 4701494. DOI: 10.1371/journal.pone.0146201. View

13.

Bakker W, van Dijk T, Parren-van Amelsvoort M, Kolbus A, Yamamoto K, Steinlein P . Differential regulation of Foxo3a target genes in erythropoiesis. Mol Cell Biol. 2007; 27(10):3839-3854. PMC: 1900006. DOI: 10.1128/MCB.01662-06. View

14.

Zhang L, Flygare J, Wong P, Lim B, Lodish H . miR-191 regulates mouse erythroblast enucleation by down-regulating Riok3 and Mxi1. Genes Dev. 2011; 25(2):119-24. PMC: 3022257. DOI: 10.1101/gad.1998711. View

15.

Goto T, Ubukawa K, Kobayashi I, Sugawara K, Asanuma K, Sasaki Y . ATP produced by anaerobic glycolysis is essential for enucleation of human erythroblasts. Exp Hematol. 2019; 72:14-26.e1. DOI: 10.1016/j.exphem.2019.02.004. View

16.

Dore L, Amigo J, Dos Santos C, Zhang Z, Gai X, Tobias J . A GATA-1-regulated microRNA locus essential for erythropoiesis. Proc Natl Acad Sci U S A. 2008; 105(9):3333-8. PMC: 2265118. DOI: 10.1073/pnas.0712312105. View

17.

Konstantinidis D, Pushkaran S, Johnson J, Cancelas J, Manganaris S, Harris C . Signaling and cytoskeletal requirements in erythroblast enucleation. Blood. 2012; 119(25):6118-27. PMC: 3383020. DOI: 10.1182/blood-2011-09-379263. View

18.

Jayapal S, Lee K, Ji P, Kaldis P, Lim B, Lodish H . Down-regulation of Myc is essential for terminal erythroid maturation. J Biol Chem. 2010; 285(51):40252-65. PMC: 3001006. DOI: 10.1074/jbc.M110.181073. View

19.

Carlile G, Smith D, Wiedmann M . Caspase-3 has a nonapoptotic function in erythroid maturation. Blood. 2004; 103(11):4310-6. DOI: 10.1182/blood-2003-09-3362. View

20.

Mei Y, Liu Y, Ji P . Understanding terminal erythropoiesis: An update on chromatin condensation, enucleation, and reticulocyte maturation. Blood Rev. 2020; 46:100740. DOI: 10.1016/j.blre.2020.100740. View