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Title: Haematopoiesis  
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Subject: Acute myeloid leukemia, Hemogenic endothelium, Immunology, Amniotic stem cells, ATC code B
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Diagram showing the development of different blood cells from haematopoietic stem cell to mature cells

Haematopoiesis (from Greek αἷμα, "blood" and ποιεῖν "to make"; also hematopoiesis in American English; sometimes also haemopoiesis or hemopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult person, approximately 1011–1012 new blood cells are produced daily in order to maintain steady state levels in the peripheral circulation.[1][2]


  • Haematopoietic stem cells (HSCs) 1
  • Locations 2
    • Extramedullary 2.1
    • Other vertebrates 2.2
  • Maturation 3
    • Determination 3.1
    • Haematopoietic growth factors 3.2
    • Transcription factors in hematopoiesis 3.3
    • The myeloid-based model 3.4
  • See also 4
  • References 5
  • Further reading 6
  • External links 7

Haematopoietic stem cells (HSCs)

Haematopoietic stem cells (HSCs) reside in the medulla of the bone (bone marrow) and have the unique ability to give rise to all of the different mature blood cell types and tissues. HSCs are self-renewing cells: when they proliferate, at least some of their daughter cells remain as HSCs, so the pool of stem cells does not become depleted.This phenomenon is called asymmetric division.[3] The other daughters of HSCs (myeloid and lymphoid progenitor cells), however can commit to any of the alternative differentiation pathways that lead to the production of one or more specific types of blood cells, but cannot self-renew. The pool of progenitors is heterogeneous and can be divided into two groups, long-term self-renewing HSC and only transiently self-renewing HSC, also called short-terms.[4] This is one of the main vital processes in the body.

All blood cells are divided into three lineages.[5]

Granulopoiesis (or granulocytopoiesis) is haematopoiesis of granulocytes.

Megakaryocytopoiesis is haematopoiesis of megakaryocytes.


Sites of haematopoesis (human) in pre- and postnatal periods

In developing embryos, blood formation occurs in aggregates of blood cells in the yolk sac, called thymus, and lymph nodes). In children, haematopoiesis occurs in the marrow of the long bones such as the femur and tibia. In adults, it occurs mainly in the pelvis, cranium, vertebrae, and sternum.[6]


In some cases, the liver, thymus, and spleen may resume their haematopoietic function, if necessary. This is called

  • Granulopoiesis from

External links

  • Godin, Isabelle & Cumano, Ana, ed. (2006). Hematopoietic stem cell development. Springer.  

Further reading

  1. ^ Semester 4 medical lectures at Uppsala University 2008 by Leif Jansson
  2. ^ Parslow,T G.;Stites, DP.; Terr, AI.; and Imboden JB. Medical Immunology (1 ed.).  
  3. ^ Morrison, J.; Judith Kimble (2006). "Asymmetric and symmetric stem-cell divisions in development and cancer". Nature 441 (7097): 1068–74.  
  4. ^ Morrison, SJ; Weissman, IL (Nov 1994). "The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype.". Immunity 1 (8): 661–73.  
  5. ^ "". Retrieved 3 February 2014. 
  6. ^ Fernández, KS; de Alarcón, PA (Dec 2013). "Development of the hematopoietic system and disorders of hematopoiesis that present during infancy and early childhood.". Pediatric clinics of North America 60 (6): 1273–89.  
  7. ^ Georgiades, CS; Neyman, EG; Francis, IR; Sneider, MB; Fishman, EK (Nov 2002). "Typical and atypical presentations of extramedullary hemopoiesis.". AJR. American journal of roentgenology 179 (5): 1239–43.  
  8. ^ Zon, LI (Oct 15, 1995). "Developmental biology of hematopoiesis.". Blood 86 (8): 2876–91.  
  9. ^ Alenzi, FQ; Alenazi, BQ; Ahmad, SY; Salem, ML; Al-Jabri, AA; Wyse, RK (Mar 2009). "The haemopoietic stem cell: between apoptosis and self renewal.". The Yale journal of biology and medicine 82 (1): 7–18.  
  10. ^ a b c Molecular cell biology. Lodish, Harvey F. 5. ed. : - New York : W. H. Freeman and Co., 2003, 973 s. b ill. ISBN 0-7167-4366-3
  11. ^
    • For the growth factors also mentioned in previous version File:Hematopoiesis (human) cytokines.jpg: Molecular cell biology. Lodish, Harvey F. 5. ed. : - New York : W. H. Freeman and Co., 2003, 973 s. b ill. ISBN 0-7167-4366-3
    • The rest: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone.  
  12. ^ Broudy, VC (Aug 15, 1997). "Stem cell factor and hematopoiesis.". Blood 90 (4): 1345–64.  
  13. ^ Ketley, N. J.; A. C. Newland. "Haemopoietic growth factors.". Postgrad Med J. 
  14. ^ Hauke, Ralph; Stefano R. Tarantolo (November 2000). "Hematopoietic Growth Factors". Laboratory Medicine. 
  15. ^ Engel, I; Murre, C (Oct 1999). "Transcription factors in hematopoiesis.". Current opinion in genetics & development 9 (5): 575–9.  
  16. ^ O’Connell, R; Rao, D.; Baltimore, D (2012). "microRNA Regulation of Inflammatory Responses". Annual Review of Immunology 30: 295–312.  
  17. ^ Ho, PA; Alonzo, TA; Gerbing, RB; Pollard, J; Stirewalt, DL; Hurwitz, C; Heerema, NA; Hirsch, B; Raimondi, SC; Lange, B; Franklin, JL; Radich, JP; Meshinchi, S (Jun 25, 2009). "Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group.". Blood 113 (26): 6558–66.  
  18. ^ Fiedler, Katja; Cornelia Brunner. "Mechanisms Controlling Hematopoiesis". 
  19. ^ O'Brien, P; Morin P, Jr; Ouellette, RJ; Robichaud, GA (Dec 15, 2011). "The Pax-5 gene: a pluripotent regulator of B-cell differentiation and cancer disease.". Cancer Research 71 (24): 7345–50.  
  20. ^ Cobaleda, C; Jochum, W; Busslinger, M (Sep 27, 2007). "Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors". Nature 449 (7161): 473–7.  
  21. ^ Wang, JH; Nichogiannopoulou, A; Wu, L; Sun, L; Sharpe, AH; Bigby, M; Georgopoulos, K (Dec 1996). "Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation.". Immunity 5 (6): 537–49.  
  22. ^ Sun, L; Liu, A; Georgopoulos, K (Oct 1, 1996). "Zinc finger-mediated protein interactions modulate Ikaros activity, a molecular control of lymphocyte development.". The EMBO Journal 15 (19): 5358–69.  
  23. ^ Schjerven, H; McLaughlin, J; Arenzana, TL; Frietze, S; Cheng, D; Wadsworth, SE; Lawson, GW; Bensinger, SJ; Farnham, PJ; Witte, ON; Smale, ST (Oct 2013). "Selective regulation of lymphopoiesis and leukemogenesis by individual zinc fingers of Ikaros.". Nature immunology 14 (10): 1073–83.  
  24. ^ Kawamoto, Wada, Katsura. A revised scheme for developmental pathways of haematopoietic cells: the myeloid-based model. International Immunology 2010.


See also

For a decade now, the evidence is growing that HSC maturation follows a myeloid-based model instead of the 'classical' schoolbook dichotomy model. In the latter model, the HSC first generates a common myeloid-erythroid progenitor (CMEP) and a common lymphoid progenitor (CLP). The CLP produces only T or B cells. The myeloid-based model postulates that HSCs first diverge into the CMEP and a common myelo-lymphoid progenitor (CMLP), which generates T and B cell progenitors through a bipotential myeloid-T progenitor and a myeloid-B progenitor stage. The main difference is that in this new model, all erythroid, T and B lineage branches retain the potential to generate myeloid cells (even after the segregation of T and B cell lineages). The model proposes the idea of erythroid, T and B cells as specialized types of a prototypic myeloid HSC. Read more in Kawamoto et al. 2010.[24]

The myeloid-based model

Mutations in transtription factors are tightly connected to blood cancers, as acute myeloid leukaemia or acute lymphoblastic leukemia (All). For example Ikaros is known to be regulator of numerous biological events. Mice with no Ikaros lack B cells, Natural killer and T cells.[21] Ikaros has six zinc fingers domains, four are conserved DNA-binding domain and two are for dimerization.[22] Very important finding is, that different zinc fingers are involved in binding to different place in DNA and this is the reason for pleiotropic effect of Ikaros and different involvement in cancer, but mainly are mutations associated with BCR-Abl patients and it is bad prognostic marker.[23]

An example is PAX5 factor, which is important in B-cell development and associated with lymphomas.[19] Surprisingly, pax5 conditional knock out mice allowed peripheral mature B cells to dedifferentiate to early bone marrow progenitors. These findings show that transcription factors act as caretakers of differentiation level and not only as initiators.[20]

Other factors include Ikaros, and Gfi1 or IRF8. What is of great significance is the occurrence of the same factors multiple times in the haematopoiesis tree. For example, CEBP alfa in neutrophil development or Pu.1. in monocytes and dendritic cell development. It is important to note that processes are not unidirectional.

The first key player of differentiation from HSC to a multipotent progenitor (MPP) is transcription factor CCAAT-enhancer binding protein alfa (C/EBP alfa). Mutations in C/EBP alfa are associated with acute myeloid leukaemia.[17] Than the way is divided to Erythroid-megakaryocyte lineage or lymphoid and myeloid lineage, which have common progenitor, called lymphoid-primed multipotent progenitor. There are two main transcription factors. Pu.1 for Erythroid-megakaryocyte lineage and GATA-1, which leads to a lymphoid-primed multipotent progenitor.[18]

Growth factors initiate signal transduction pathways, which lead to activation of transcription factors. Signal, which is received by cells, is not digital. This means that cells can distinguish time, amount, and frequency. For example, long-term expression of PU.1 resulted in myeloid commitment, and short-term induction of PU.1 activity led to the formation of immature eosinophils.[15] Recently, it was reported that transcription factors such as NF-κB could be regulated by microRNAs (e.g., miR-125b) in hematopoiesis.[16]

Transcription factors in hematopoiesis

Erythropoietin is required for a myeloid progenitor cell to become an erythrocyte.[10] On the other hand, thrombopoietin makes myeloid progenitor cells differentiate to megakaryocytes (thrombocyte-forming cells).[10] Examples of cytokines and the blood cells they give rise to, is shown in the picture to the right.[14]

Red and white blood cell production is regulated with great precision in healthy humans, and the production of leukocytes is rapidly increased during infection. The proliferation and self-renewal of these cells depend on Growth factors. One of the key player in self-renewal and development of haematopoietics cells is stem cell factor (SCF).[12] Absence of this factor is lethal. But there are other important Glycoprotein growth factors, which regulate the proliferation and maturation, these are for example IL-2,3,6,7. There are three more examples of factors that stimulate the production of committed stem cells. So called colony-stimulating factors (CSFs) and include granulocyte-macrophage CSF (GM-CSF), granulocyte CSF (G-CSF) and macrophage CSF (M-CSF).[13] These stimulate granulocyte formation and are active on either progenitor cells or end product cells.

Diagram including some of the important cytokines that determine which type of blood cell will be created.[10] SCF= Stem Cell Factor Tpo= Thrombopoietin IL= Interleukin GM-CSF= Granulocyte Macrophage-colony stimulating factor Epo= Erythropoietin M-CSF= Macrophage-colony stimulating factor G-CSF= Granulocyte-colony stimulating factor SDF-1= Stromal cell-derived factor-1 FLT-3 ligand= FMS-like tyrosine kinase 3 ligand TNF-a = Tumour necrosis factor-alpha TGFβ = Transforming growth factor beta [11]

Haematopoietic growth factors

There are two points of view. For the stem cells and other undifferentiated blood cells in the bone marrow, the determination is generally explained by the determinism theory of haematopoiesis, saying that colony stimulating factors and other factors of the haematopoietic microenvironment determine the cells to follow a certain path of cell differentiation. This is the classical way of describing haematopoiesis. The other point of view is stochastic theory: Undifferentiated blood cells are determined to specific cell types by randomness. The haematopoietic microenvironment prevails upon some of the cells to survive and some, on the other hand, to perform apoptosis and die. By regulating this balance between different cell types, the bone marrow can alter the quantity of different cells to ultimately be produced.[9]


As a stem cell matures it undergoes changes in gene expression that limit the cell types that it can become and moves it closer to a specific cell type. These changes can often be tracked by monitoring the presence of proteins on the surface of the cell. Each successive change moves the cell closer to the final cell type and further limits its potential to become a different cell type.


In some vertebrates, haematopoiesis can occur wherever there is a loose stroma of connective tissue and slow blood supply, such as the gut, spleen or kidney.[8]

Other vertebrates


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