Understanding Erythropoiesis

Erythropoiesis is defined as the process through which the body produces red blood cells (RBCs). On average, the body produces 2 million RBCs per second and each RBC will remain in the circulation for ~120 days.1

Normal erythropoiesis is a dynamic differentiation pathway that starts with proliferation and ends with maturation

  • Proliferation (increasing number of cells) is characterized by the early development and expansion of hematopoietic stem cells (HSCs) to erythroid-committed progenitor cells2,3
    • Burst-forming unit–erythroids (BFU-Es) are the first progenitor cells exclusively committed to erythroid differentiation and progress further into colony-forming unit–erythroids (CFU-Es)1
    • CFU-Es will differentiate into the first morphologically identifiable cell of the erythrocyte lineage, the proerythroblast1
  • Differentiation is the process through which less specialized cells, such as HSCs, become more specialized4
  • Maturation is characterized by differentiation of erythroblasts into functional RBCs1
    • Synthesis of hemoglobin (the predominant protein in RBCs responsible for transporting oxygen) begins in the early basophilic erythroblast; iron uptake increases and is involved in hemoglobin synthesis and regulation
    • Enucleation (extrusion of nuclei) of the erythroblast gives rise to the reticulocyte, which matures finally into the RBC

Normal Erythropoiesis1

BFU-E, burst-forming unit–erythroid progenitor; CFU-E, colony-forming unit–erythroid progenitor; HSC, hematopoietic stem cell; RBC, red blood cell.

Erythropoiesis is a tightly regulated process5,6

Erythropoiesis is regulated by transcription factors and cytokines, including transforming growth factor beta (TGF-β) superfamily ligands, whose roles vary throughout the process. The balance of these different transcription factors and cytokines is essential to ensure the proliferation and differentiation of erythroid precursors to complete the maturation process of RBCs.5,6

Regulation of proliferation and differentiation of erythroid precursors1,5-16

BFU-E, burst-forming unit–erythroid progenitor; BMP2, bone morphogenetic protein 2; CFU-E, colony-forming unit–erythroid progenitor; GATA-1, GATA-binding factor 1; GATA-2, GATA-binding factor 2; GDF11, growth differentiation factor 11; GDF15, growth differentiation factor 15; HSC, hematopoietic stem cell; RBC, red blood cell; TGF-β, transforming growth factor beta.

Cytokines

  • Proliferation is characterized by the activity of erythropoietin (EPO, an endogenous hormone made by the kidneys), which stimulates production of erythroid precursors; CFU-Es, specifically, are highly dependent on EPO1,7
  • The TGF-β superfamily is another key regulator of erythroid progenitor cell development. Excessive signaling by select members of the TGF-β superfamily is hypothesized to inhibit erythrocyte maturation6,10,12,14,16
    • Within the TGF-β superfamily, some key regulators of erythropoiesis include TGF-β, activin A, bone morphogenetic protein 2 (BMP2), growth differentiation factor 11 (GDF11), and growth differentiation factor 15 (GDF15)12,14,15
    • Other cytokine regulators of erythropoiesis include stem cell factor (SCF), interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), insulin-like growth factor 1 (IGF-1), and death receptor FAS ligand (FasL)5,12,15

Transcription factors

  • GATA-2 is essential for erythroid progenitor differentiation, whereas GATA-1 promotes the maturation of erythroid precursors to RBCs. GATA-1 and GATA-2 act antagonistically to each other and are expressed in proliferation and maturation phases, respectively5,8,9

Ineffective erythropoiesis, due to defective RBC maturation, is an underlying cause of chronic anemia in patients with MDS.17

References: 1. Ponka P, Koury MJ, Sheftel AD. Erythropoiesis, hemoglobin synthesis, and erythroid mitochondrial iron homeostasis. In: Ferreira GC, Kadish KM, Smith KM, Guilard R, eds. Handbook of Porphyrin Science. Toh Tuck Link, Singapore: World Scientific Publishers; 2014:41-84. 2. Oikonomidou PR, Rivella S. What can we learn from ineffective erythropoiesis in thalassemia? Blood Rev. 2018;32(2):130-143. 3. Jelkmann W. Physiology and pharmacology of erythropoietin. Transfus Med Hemother. 2013;40(5):302-309. 4. Betts JG, Desaix P, Johnson E, et al. Anatomy and Physiology. 2nd ed. Houston, TX: OpenStax, Rice University; 2017. https://openstax.org/details/books/anatomy-and-physiology. Accessed July 5, 2019. 5. Hattangadi SM, Wong P, Zhang L, et al. From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications. Blood. 2011;118(24):6258-6268. 6. Blank U, Karlsson S. TGF-β signaling in the control of hematopoietic stem cells. Blood. 2015;125(23):3542-3550. 7. Lodish H, Flygare J, Chou S. From stem cell to erythroblast: regulation of red cell production at multiple levels by multiple hormones. IUBMB Life. 2010;62(7):492-496. 8. Bresnick EH, Hewitt KJ, Mehta C, et al. Mechanisms of erythrocyte development and regeneration: implications for regenerative medicine and beyond. Development. 2018;145(1). 9. Suzuki N, Suwabe N, Ohneda O, et al. Identification and characterization of 2 types of erythroid progenitors that express GATA-1 at distinct levels. Blood. 2003;102(10):3575-3583. 10. Maguer-Satta V, Bartholin L, Jeanpierre S, et al. Regulation of human erythropoiesis by activin A, BMP2, and BMP4, members of the TGFβ family. Exp Cell Res. 2003;282(2):110-120. 11. Singh VK, Saini A, Kalsan M, et al. Stage-specific regulation of erythropoiesis and its implications in ex-vivo RBCs generation. J Stem Cells. 2016;11(3):149-169. 12. Valent P, Büsche G, Theurl I, et al. Normal and pathological erythropoiesis in adults: from gene regulation to targeted treatment concepts. Haematologica. 2018;103(10):1593-1603. 13. Jelkmann W. Regulation of erythropoietin production. J Physiol. 2011;589(Pt 6):1251-1258. 14. Zhou L, Nguyen AN, Sohal D, et al. Inhibition of the TGF-β receptor I kinase promotes hematopoiesis in MDS. Blood. 2008;112(8):3434-3443. 15. Tanno T, Noel P, Miller JL. Growth differentiation factor 15 in erythroid health and disease. Curr Opin Hematol. 2010;17(3):184-190. 16. Zermati Y, Fichelson S, Valensi F, et al. Transforming growth factor inhibits erythropoiesis by blocking proliferation and accelerating differentiation of erythroid progenitors. Exp Hematol. 2000;28(8):885-894. 17. Oliva EN, Schey C, Hutchings AS. A review of anemia as a cardiovascular risk factor in patients with myelodysplastic syndromes. Am J Blood Res. 2011;1(2):160-166.