Multi-scale Modelling of Erythropoiesis and Hemoglobin Production

  • A. Bouchnita
  • A. Rocca
  • E. Fanchon
  • M. J. Koury
  • J. M. Moulis
  • V. Volpert


The paper is devoted to multi-scale modelling of erythropoiesis and hemoglobin production. Red blood cells, which carry oxygen from the lungs to the other body tissues, are produced in the bone marrow of adult humans in cell units called erythroblastic islands. Erythroblastic islands are composed by a central macrophage surrounded by erythroid cells in different stages of maturation. Immature cells, the colony-forming units-erythroid, make a choice between self-renewal, differentiation and apoptosis determined by the intracellular proteins and extracellular substances. Moreover, this choice is regulated by erythropoietin and other hormones. Erythropoietin is produced in the kidney in response to hypoxia from decreased numbers of red blood cells, and it is delivered in the plasma to the bone marrow. Erythropoietin stimulates differentiation of erythroid cells and increases their proliferation by downregulating apoptosis. The rate of erythropoietin production depends on the level of hemoglobin in blood which is function of the number of circulating red blood cells. Hemoglobin is produced in the erythroid cells within the bone marrow in the process of their terminal differentiation. Thus, there is a feedback between production of red blood cells by the bone marrow, the level of hemoglobin contained in these cells and the level of erythropoietin. The multi-scale model developed in this work includes erythroid cells in the bone marrow, their intracellular and extracellular regulations, hemoglobin production, and the feedback by erythropoietin. This model describes normal functioning of erythropoiesis and its response to anemia resulting from the loss of red blood cells.


Erythropoiesis Hemoglobin Multi-scale model 

List of Abbreviations


α-Hemoglobin stabilizing protein


Mitochondrial enzyme amino-levulinate synthetase 2


Bone morphogenetic protein 4


Colony-forming units-erythroid/Proerythroblasts


Erythroblastic island




Hypoxia-inducible factor


Heme oxygenase-1


Heme regulated inhibitor


Hematopoietic stem cell


Iron regulatory proteins


Kit ligand/stem cell factor


Transferrin receptor


Red blood cell


  1. 1.
    T. Papayannopoulou, A.R. Migliaccio, J.L. Abkowitz, A.D. D’Andrea, Biology of erythropoiesis, erythroid differentiation, and maturation, in Hematology: basic Principles and Practice, 5th edn., ed. by R. Hoffman, E.J. Benz Jr., S.J. Shattil, B. Furie, L.E. Silberstein, P. McGlave, H.E. Heslop (Churchill Livingstone, Elsevier, Inc., Philadelphia, 2009), pp. 276–294Google Scholar
  2. 2.
    J.A. Chasis, N. Mohandas, Erythroblastic islands: niches for erythropoiesis. Blood 112, 470–478 (2008)CrossRefGoogle Scholar
  3. 3.
    C.J. Eaves, R.K. Humphries, A.C. Eaves, In vitro characterization of erythroid precursor cells and erythropoietic differentiation, in Cellular and Molecular Regulation of Hemoglobin Switching, ed. by G. Stamatoyannopoulos, A.W. Nienhuis (Grune and Stratton, New York, 1979), pp. 251–273Google Scholar
  4. 4.
    W. Nijhof, Wierenga PK Isolation and characterization of the erythroid progenitor cell: CFU-E. J Cell Biol. 96, 386–392 (1983)CrossRefGoogle Scholar
  5. 5.
    K. Sawada, S.B. Krantz, J.S. Kans, E.N. Dessypris, S. Sawyer, A.D. Glick, Civin CI Purification of human erythroid colony-forming units and demonstration of specific binding of erythropoietin. J. Clin. Invest. 80, 357–366 (1987)CrossRefGoogle Scholar
  6. 6.
    M. Socolovsky, H. Nam, M.D. Fleming, V.H. Haase, C. Brugnara, H.F. Lodish, Ineffective erythropoiesis in Stat5a(-/-)5b(-/-) mice due to decreased survival of early erythroblasts. Blood 98, 3261–3273 (2001)CrossRefGoogle Scholar
  7. 7.
    K. Chen, J. Liu, S. Heck, J.A. Chasis, X. An, N. Mohandas, Resolving the distinct stages in erythroid differentiation based on dynamic changes in membrane protein expression during erythropoiesis. Proc. Natl. Acad. Sci. USA. 106, 17413–17418 (2009)CrossRefGoogle Scholar
  8. 8.
    J. Hu, J. Liu, F. Xue et al., Isolation and functional characterization of human erythroblasts at distinct stages: implications for understanding of normal and disordered erythropoiesis in vivo. Blood 121, 3246–3253 (2013)CrossRefGoogle Scholar
  9. 9.
    R. De Maria, U. Testa, L. Luchetti, A. Zeuner, G. Stassi, E. Pelosi, R. Riccioni, N. Felli, P. Samoggia, C. Peschle, Apoptotic role of Fas/Fas ligand system in the regulation of erythropoiesis. Blood 93, 796–803 (1999)Google Scholar
  10. 10.
    Y. Liu, R. Pop, C. Sadegh, C. Brugnara, V.H. Haase, M. Socolovsky, Suppression of Fas-FasL coexpression by erythropoietin mediates erythroblast expansion during the erythropoietic stress response in vivo. Blood 108, 123–133 (2006)CrossRefGoogle Scholar
  11. 11.
    C.H. Dai, S.B. Krantz, K.M. Zsebo, Human burst-forming units-erythroid need direct interaction with stem cell factor for further development. Blood 78, 2493–4977 (1991)Google Scholar
  12. 12.
    M.J. Koury, M.C. Bondurant, Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells. Science 248, 378–381 (1990)CrossRefGoogle Scholar
  13. 13.
    H. Wu, X. Liu, R. Jaenisch, H.F. Lodish, Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell 83, 59–67 (1995)CrossRefGoogle Scholar
  14. 14.
    M.J. Koury, Erythropoietin: the story of hypoxia and a finely regulated hematopoietic hormone. Exp. Hematol. 33, 1263–1270 (2005)CrossRefGoogle Scholar
  15. 15.
    T. Gregory, C. Yu, A. Ma, S.H. Orkin, G.A. Blobel, M.J. Weiss, GATA-1 and erythropoietin cooperate to promote erythroid cell survival by regulating bcl-xL expression. Blood 94, 87–96 (1999)Google Scholar
  16. 16.
    J. Xiang, D.C. Wu, Y. Chen, R.F. Paulson, In vitro culture of stress erythroid progenitors identifies distinct progenitor populations and analogous human progenitors. Blood 125, 1803–1812 (2015)CrossRefGoogle Scholar
  17. 17.
    A.B. Cantor, S.H. Orkin, Transcriptional regulation of erythropoiesis: an affair involving multiple partners. Oncogene 21, 3368–3376 (2002)CrossRefGoogle Scholar
  18. 18.
    M.J. Koury, V.H. Haase, Anaemia in kidney disease: harnessing hypoxia responses for therapy. Nat. Rev. Nephrol. 11, 394–410 (2015)CrossRefGoogle Scholar
  19. 19.
    P. Ponka, M.J. Koury, A.D. Sheftel, Erythropoiesis, hemoglobin synthesis, and erythroid mitochondrial iron homeostasis, in Handbook of Porphyrin Science: erythropoiesis, Heme, and Applications to Biomedicine, vol. 27, ed. by G. Ferreira (World Scientific Publishing, Hackensack, 2013), pp. 41–84Google Scholar
  20. 20.
    M.C. Ghosh, D.L. Zhang, S.Y. Jeong, G. Kovtunovych, H. Ollivierre-Wilson, A. Noguchi, T. Tu, T. Senecal, G. Robinson, D.R. Crooks, W.H. Tong, K. Ramaswamy, A. Singh, B.B. Graham, R.M. Tuder, Z.X. Yu, M. Eckhaus, J. Lee, D.A. Springer, T.A. Rouault, Deletion of iron regulatory protein 1 causes polycythemia and pulmonary hypertension in mice through translational derepression of HIF2alpha. Cell Metab. 17, 271–281 (2013)CrossRefGoogle Scholar
  21. 21.
    A. Nai, M.R. Lidonnici, M. Rausa, G. Mandelli, A. Pagani, L. Silvestri, G. Ferrari, C. Camaschella, The second transferrin receptor regulates red blood cell production in mice. Blood 125, 1170–1179 (2015)CrossRefGoogle Scholar
  22. 22.
    L. Cianetti, M. Gabbianelli, N.M. Sposi, Ferroportin and erythroid cells: an update. Adv Hematol. 2010, 404173 (2010)Google Scholar
  23. 23.
    J. Sun, M. Brand, Y. Zenke, S. Tashiro, M. Groudine, K. Igarashi, Heme regulates the dynamic exchange of Bach1 and NF-E2-related factors in the Maf transcription factor network. Proc. Natl. Acad. Sci. USA 101, 1461–1466 (2004)CrossRefGoogle Scholar
  24. 24.
    J.J. Chen, Regulation of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to anemias. Blood 109, 2693–2699 (2007)Google Scholar
  25. 25.
    J.G. Quigley, Z. Yang, M.T. Worthington, J.D. Phillips, K.M. Sabo, D.E. Sabath, C.L. Berg, S. Sassa, B.L. Wood, J.L. Abkowitz, Identification of a human heme exporter that is essential for erythropoiesis. Cell 118, 757–766 (2004)CrossRefGoogle Scholar
  26. 26.
    M.D. Fleming, I. Hamza, Mitochondrial heme: an exit strategy at last. J. Clin. Invest. 122, 4328–4330 (2012)CrossRefGoogle Scholar
  27. 27.
    T.L. Mollan, X. Yu, M.J. Weiss, J.S. Olson, The role of alpha—hemoglobin stabilizing protein in redox chemistry, denaturation, and hemoglobin assembly. Antioxid. Redox Signal. 12, 219–231 (2010)CrossRefGoogle Scholar
  28. 28.
    M. Vidal, Exosomes in erythropoiesis. Transfus. Clin. Biol. 17, 131–137 (2010)CrossRefGoogle Scholar
  29. 29.
    F.L.A. Willekens, J.M. Werre, Y.A.M. Groenen-Dopp, B. Roerdinkholder-Stoelwinder, B. de Pauw, G.J.C.G.M. Bosman, Erythrocyte vesiculation: a self-protective mechanism? Br. J. Haematol. 141, 549–556 (2008)CrossRefGoogle Scholar
  30. 30.
    F. Crauste, I. Demin, O. Gandrillon, V. Volpert, Mathematical study of feedback control roles and relevance in stress erythropoiesis. J. Theor. Biol. 263, 303–316 (2010)CrossRefGoogle Scholar
  31. 31.
    I. Demin, F. Crauste, O. Gandrillon, V. Volpert, A multi-scale model of erythropoiesis. J. Biol. Dyn. 4, 59–70 (2010)CrossRefGoogle Scholar
  32. 32.
    N. Bessonov, L. Pujo-Menjouet, V. Volpert, Cell modelling of hematopoiesis. Math. Model Nat. Phenom. 1, 81–103 (2006)CrossRefGoogle Scholar
  33. 33.
    N. Bessonov, F. Crauste, I. Demin, V. Volpert, Dynamics of erythroid progenitors and erythroleukemia. Math. Model. Nat. Phenom. 4, 210–232 (2009)CrossRefGoogle Scholar
  34. 34.
    N. Bessonov, I. Demin, L. Pujo-Menjouet, V. Volpert, A multi-agent model describing self-renewal of differentiation effects on the blood cell population. Math. Comput. Model. 49, 2116–2127 (2009)CrossRefGoogle Scholar
  35. 35.
    N. Bessonov, F. Crauste, S. Fischer, P. Kurbatova, V. Volpert, Application of hybrid models to blood cell production in the bone marrow. Math. Model. Nat. Phenom. 6, 2–12 (2011)CrossRefGoogle Scholar
  36. 36.
    S. Fischer, P. Kurbatova, N. Bessonov, O. Gandrillon, V. Volpert, F. Crauste, Modeling erythroblastic islands: using a hybrid model to assess the function of central macrophage. J. Theor. Biol. 298, 92–106 (2012)CrossRefGoogle Scholar
  37. 37.
    N. Eymard, N. Bessonov, O. Gandrillon, M.J. Koury, V. Volpert, The role of spatial organization of cells in erythropoiesis. J. Math. Biol. 70, 71–97 (2015)CrossRefGoogle Scholar
  38. 38.
    A. Bouchnita, N. Eymard, T.K. Moyo, M.J. Koury, V. Volpert, Bone marrow infiltration by multiple myeloma causes anemia by reversible disruption of erythropoiesis. Am. J. Hematol. 91, 371–378 (2016)CrossRefGoogle Scholar
  39. 39.
    R.S. Hillman, E.R. Giblett, Red cell membrane alteration associated with “marrow stress”. J. Clin. Invest. 44, 1730–1736 (1965)CrossRefGoogle Scholar
  40. 40.
    R.S. Hillman, Characteristics of marrow production and reticulocyte maturation in normal man in response to anemia. J. Clin. Invest. 48, 443–453 (1969)CrossRefGoogle Scholar
  41. 41.
    M.J. Koury, S.T. Sawyer, M.C. Bondurant, Splenic erythroblasts in anemia-inducing friend disease: a source of cells for studies of erythropoietin-mediated differentiation. J. Cell Physiol. 121, 526–532 (1984)CrossRefGoogle Scholar
  42. 42.
    S.T. Sawyer, S.B. Krantz, Transferrin receptor number, synthesis, and endocytosis during erythropoietin-induced maturation of Friend virus-infected erythroid cells. J. Biol. Chem. 261, 9187–9195 (1986)Google Scholar
  43. 43.
    M.J. Koury, M.C. Bondurant, Maintenance by erythropoietin of viability, proliferation and maturation of murine erythroid precursor cells. J. Cell Physiol. 137, 65–74 (1988)CrossRefGoogle Scholar
  44. 44.
    H.D. Kim, M.J. Koury, S.J. Lee, J.H. Im, S.T. Sawyer, Metabolic adaptation during erythropoietin mediated terminal differentiation of mouse erythroid cells. Blood 77, 387–392 (1991)Google Scholar
  45. 45.
    M. Schranzhofer, M. Schifrer, J.A. Cabrera, S. Kopp, P. Chiba, H. Beug, E.W. Müllner, Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis. Blood 107(10), 4159–4167 (2006)CrossRefGoogle Scholar
  46. 46.
    E. Pourcelot, M. Lenon, N. Mobilia, J.-Y. Cahn, J. Arnaud, E. Fanchon, J.-M. Moulis, P. Mossuz, Iron for proliferation of cell lines and hematopoietic progenitors: nailing down the intracellular functional iron concentration. Biochimica et Biophysica Acta 1853, 1596–1605 (2015)Google Scholar
  47. 47.
    H. Niederreiter, Random number generation and quasi-Monte Carlo methods. in 63 in CBMS-NSF Regional Conference Series in Applied Mathematics, Society for Industrial and Applied Mathematics (1992)Google Scholar
  48. 48.
    S.A. Anderson, C.P. Nizzi, Y.I. Chang, K.M. Deck, P.J. Schmidt, B. Galy, A. Damnernsawad, A.T. Broman, C. Kendziorski, M.W. Hentze, M.D. Fleming, J. Zhang, R.S. Eisenstein, The IRP1-HIF-2alpha axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption. Cell Metab. 17, 282–290 (2013)CrossRefGoogle Scholar
  49. 49.
    N. Wilkinson, K. Pantopoulos, IRP1 regulates erythropoiesis and systemic iron homeostasis by controlling HIF2alpha mRNA translation. Blood 122, 1658–1668 (2013)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • A. Bouchnita
    • 1
    • 2
  • A. Rocca
    • 3
  • E. Fanchon
    • 3
  • M. J. Koury
    • 4
  • J. M. Moulis
    • 5
    • 6
    • 7
  • V. Volpert
    • 1
    • 8
    • 9
  1. 1.Institut Camille Jordan, UMR 5208 CNRSUniversity Lyon 1VilleurbanneFrance
  2. 2.LERMA, Mohammadia School of EngineersUniversity Mohamed VRabatMorocco
  3. 3.Université Grenoble AlpesCNRS UMR 5525, TIMC-IMAG laboratoryGrenobleFrance
  4. 4.Vanderbilt University Medical CenterNashvilleUSA
  5. 5.Université Grenoble Alpes, Laboratoire de Bioénergétique Fondamentale et Appliquée and Biologie Environmentale et Systémique (BEeSy)GrenobleFrance
  6. 6.InsermGrenobleFrance
  7. 7.Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA) Institut de Biosciences and Biotechnologies de Grenoble (BIG)GrenobleFrance
  8. 8.INRIA Team Dracula, INRIA Antenne Lyon la DouaVilleurbanneFrance
  9. 9.Laboratoire PonceletUMI 2615 CNRSMoscowRussia

Personalised recommendations