Haematopoiesis

Abstract

Haematopoiesis generates a variety of distinct blood cell types from a common stem cell. Secreted signalling molecules called cytokines modulate the survival, proliferation and differentiation of all the blood cell lineages, mediated by defined sets of transcription factors. Haematopoiesis is also influenced by external cues such as oxygen concentration. Haematopoiesis is an ongoing process continuing throughout lifetime, although the location of stem cells, and the specific cell types derived from them, changes during embryonic, foetal and early postnatal development. In the adult, haematopoiesis occurs primarily in the bone marrow, in association with a supportive niche. Haematopoietic stem cells are derived from cells bipotential for blood and endothelial cells, or directly from specialised endothelium. Blood lineages have a hierarchical relationship, but there is some flexibility among progenitors for deriving specific fates. Defects in haematopoiesis result in common and serious human diseases including anaemia and leukaemia.

Key Concepts

  • Haematopoiesis is the process of forming blood cells, which occurs during embryogenesis and throughout life.
  • Defects in haematopoiesis can result in some of the most common and serious human diseases, including anaemia and leukaemia.
  • Blood consists of many different kinds of cells with a diverse range of functions, controlling gaseous exchange and clotting and comprising the immune system.
  • All blood cells are derived from a common progenitor, the haematopoietic stem cell.
  • The sites where haematopoiesis occurs change during embryonic development, but in adult mammals, the bone marrow is the major site of haematopoiesis.
  • Haematopoietic stem cells in the bone marrow reside in a specialised microenvironment known as the haematopoietic stem cell niche, composed of osteoblasts, mesenchymal cells and sinusoidal vessels.
  • Growth factors called cytokines control the survival, self‐renewal and differentiation of haematopoietic stem cells and their progeny.
  • Blood cells have a close developmental relationship with endothelial cells, and haematopoietic stem cells appear to derive from ‘haemogenic endothelium’.
  • Haematopoiesis is also regulated by external factors. For example, hypoxia results in a compensatory increase in the number of erythrocytes.
  • Much effort is currently focused on generating and manipulating haematopoietic stem cells in vitro, to develop new regenerative therapies.

Keywords: blood; stem cell; cell lineage; cytokines; niche; haemoglobin

Figure 1. Schematic illustrating a generally accepted hierarchical relationship among haematopoietic stem cells and adult‐stage blood cells. The long‐term reconstituting haematopoietic stem cell (LTRC) maintains itself, and gives rise to myeloid and lymphoid cells through several intermediate progenitor stages. Short‐term reconstituting haematopoietic stem cells (STRC) have limited self‐renewal capacity and give rise to multipotent progenitors (MPPs) that lack self‐renewal capacity but have strong proliferative capacity. Common myeloid progenitors (CMPs) are the earliest committed myeloid progenitor and eventually differentiate into mature cells through the intermediate stages of megakaryocyte‐erythroid progenitors (MEPs) and granulocyte‐monocyte progenitors (GMPs). Common lymphoid progenitors (CLPs) have the capacity to differentiate into a B cell, NK cell or T cell, but whether they represent a physiological T‐cell progenitor is controversial. It has been hypothesised that early thymic progenitors (ETPs) bypass the stage of CLPs, and are the physiological T‐cell progenitors, although further studies are needed to clarify the pathways (indicated by question marks).
Figure 2. A schematised view of the haematopoietic niche. Haematopoietic stem cells (HSCs) in the bone marrow cavity lay in perivascular niches very close to blood vessels, where endothelial cells (ECs) and mesenchymal stromal cells (MSCs) provide signals for HSC maintenance. Osteoblasts in the endosteal niche promote the maintenance and most likely differentiation of haematopoietic stem and progenitor (HSP) cells.
Figure 3. Organisation of the human β‐like globin genes on chromosome 11. The black line represents the deoxyribonucleic acid of the chromosome and the boxes represent individual globin genes (the illustration is not drawn to scale). Each gene is transcribed in the same direction (arrow) and in the same developmental order as arranged on the chromosome. Erythroid cells that develop in a different location express distinct globin genes. Although not shown here, each gene has its own regulatory elements (promoters and enhancers) and the entire locus is regulated in addition by a sequence located far upstream, distal to the ϵ gene (the locus control region or LCR). The pseudo‐gene is not expressed; it is thought to be an evolutionary remnant. ‘Switching’ occurs for the embryonic and adult α‐like globin genes on chromosome 16, although the mechanism may differ.
Figure 4. Potential plasticity of haematopoietic progenitors. As schematised here, mature haematopoietic cells or progenitors may be diverted from their normal developmental potential and redirected to new cell fates by ectopic cytokine signalling or forced expression of regulatory genes. Mature B cells and T‐cell progenitors (ETPs) can be trans‐differentiated into macrophages by forced expression of C/EBPα. Downregulation of Pax5 (Pax5‐) results in dedifferentiation of mature B cells into uncommitted progenitors that can be differentiated to mature T cells. Forced expression of the transcription factors Oct3/4, Sox2, Klf4 and cMyc can induce dedifferentiation of B cells (coupled with downregulation of Pax5) and T cells into ESC‐like cells known as induced pluripotent stem cells (iPSCs). B‐cell and myeloid cell progenitors can be reprogrammed into transplantable HSC‐like cells by induction of six transcription factors: Run1t1, Hlf, Lmo2, Prdm5, Pbx1 and Zfp37.
close

References

Balazs AB, Fabian AJ, Esmon CT and Mulligan RC (2006) Endothelial protein C receptor (CD201) explicitly identifies hematopoietic stem cells in murine bone marrow. Blood 107: 2317–2321.

Bauer DE, Kamran SC and Orkin SH (2012) Reawakening fetal hemoglobin: prospects for new therapies for the beta‐globin disorders. Blood 120: 2945–2953.

Baum CM, Weissman IL, Tsukamoto AS, Buckle AM and Peault B (1992) Isolation of a candidate human hematopoietic stem‐cell population. Proceedings of the National Academy of Sciences of the United States of America 89: 2804–2808.

Bhandoola A and Sambandam A (2006) From stem cell to T cell: one route or many? Nature Reviews Immunology 6: 117–126.

Boitano AE, Wang J, Romeo R, et al. (2010) Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 329: 1345–1348.

Bradley TR and Metcalf D (1966) The growth of mouse bone marrow cells in vitro. The Australian Journal of Experimental Biology and Medical Science 44: 287–299.

Butler JM, Gars EJ, James DJ, et al. (2012) Development of a vascular niche platform for expansion of repopulating human cord blood stem and progenitor cells. Blood 120: 1344–1347.

Chanda B, Ditadi A, Iscove NN and Keller G (2013) Retinoic acid signaling is essential for embryonic hematopoietic stem cell development. Cell 155: 215–227.

Charbord P, Pouget C, Binder H, et al. (2014) A systems biology approach for defining the molecular framework of the hematopoietic stem cell niche. Cell Stem Cell 15: 376–391.

Choi K, Kennedy M, Kazarov A, Papadimitriou JC and Keller G (1998) A common precursor for hematopoietic and endothelial cells. Development 125: 725–732.

Delaney C, Heimfeld S, Brashem‐Stein C, et al. (2010) Notch‐mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nature Medicine 16: 232–236.

Di Stefano B, Sardina JL, van Oevelen C, et al. (2014) C/EBPalpha poises B cells for rapid reprogramming into induced pluripotent stem cells. Nature 506: 235–239.

Doulatov S, Notta F, Laurenti E and Dick JE (2012) Hematopoiesis: a human perspective. Cell Stem Cell 10: 120–136.

Espin‐Palazon R, Stachura DL, Campbell CA, et al. (2014) Proinflammatory signaling regulates hematopoietic stem cell emergence. Cell 159: 1070–1085.

Fairbairn LJ, Cowling GJ, Reipert BM and Dexter TM (1993) Suppression of apoptosis allows differentiation and development of a multipotent hemopoietic cell line in the absence of added growth factors. Cell 74: 823–832.

Galloway JL and Zon LI (2003) Ontogeny of hematopoiesis: examining the emergence of hematopoietic cells in the vertebrate embryo. Current Topics in Developmental Biology 53: 139–158.

Gazit R, Mandal PK, Ebina W, et al. (2014) Fgd5 identifies hematopoietic stem cells in the murine bone marrow. The Journal of Experimental Medicine 211: 1315–1331.

Gleadle JM and Ratcliffe PJ (1998) Hypoxia and the regulation of gene expression. Molecular Medicine Today 4: 122–129.

Goessling W, Allen RS, Guan X, et al. (2011) Prostaglandin E2 enhances human cord blood stem cell xenotransplants and shows long‐term safety in preclinical nonhuman primate transplant models. Cell Stem Cell 8: 445–458.

Graf T and Enver T (2009) Forcing cells to change lineages. Nature 462: 587–594.

Grover A, Mancini E, Moore S, et al. (2014) Erythropoietin guides multipotent hematopoietic progenitor cells toward an erythroid fate. The Journal of Experimental Medicine 211: 181–188.

Hanna J, Markoulaki S, Schorderet P, et al. (2008) Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell 133: 250–264.

Hirschi KK (2012) Hemogenic endothelium during development and beyond. Blood 119: 4823–4827.

Jeong M and Goodell MA (2014) New answers to old questions from genome‐wide maps of DNA methylation in hematopoietic cells. Experimental Hematology 42: 609–617.

Kiel MJ, Yilmaz OH, Iwashita T, et al. (2005) SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121: 1109–1121.

Kim AD, Stachura DL and Traver D (2014) Cell signaling pathways involved in hematopoietic stem cell specification. Experimental Cell Research 329: 227–233.

Krause DS, Theise ND, Collector MI, et al. (2001) Multi‐organ, multi‐lineage engraftment by a single bone marrow‐derived stem cell. Cell 105: 369–377.

Logan AC, Weissman IL and Shizuru JA (2012) The road to purified hematopoietic stem cell transplants is paved with antibodies. Current Opinion in Immunology 24: 640–648.

Loh YH, Hartung O, Li H, et al. (2010) Reprogramming of T cells from human peripheral blood. Cell Stem Cell 7: 15–19.

Luc S, Luis TC, Boukarabila H, et al. (2012) The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential. Nature Immunology 13: 412–419.

Mendelson A and Frenette PS (2014) Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nature Medicine 20: 833–846.

Morrison SJ, Wandycz AM, Hemmati HD, Wright DE and Weissman IL (1997) Identification of a lineage of multipotent hematopoietic progenitors. Development 124: 1929–1939.

Morrison SJ and Scadden DT (2014) The bone marrow niche for haematopoietic stem cells. Nature 505: 327–334.

Mossadegh‐Keller N, Sarrazin S, Kandalla PK, et al. (2013) M‐CSF instructs myeloid lineage fate in single haematopoietic stem cells. Nature 497: 239–243.

Murayama E, Kissa K, Zapata A, et al. (2006) Tracing hematopoietic precursor migration to successive hematopoietic organs during zebrafish development. Immunity 25: 963–975.

Orkin SH and Zon LI (2008) Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132: 631–644.

Paulson RF, Shi L and Wu DC (2011) Stress erythropoiesis: new signals and new stress progenitor cells. Current Opinion in Hematology 18: 139–145.

Riddell J, Gazit R, Garrison BS, et al. (2014) Reprogramming committed murine blood cells to induced hematopoietic stem cells with defined factors. Cell 157: 549–564.

Rieger MA, Hoppe PS, Smejkal BM, Eitelhuber AC and Schroeder T (2009) Hematopoietic cytokines can instruct lineage choice. Science 325: 217–218.

Sandler VM, Lis R, Liu Y, et al. (2014) Reprogramming human endothelial cells to haematopoietic cells requires vascular induction. Nature 511: 312–318.

Sankaran VG, Xu J and Orkin SH (2010) Advances in the understanding of haemoglobin switching. British Journal of Haematology 149: 181–194.

Sieweke MH and Graf T (1998) A transcription factor party during blood cell differentiation. Current Opinion in Genetics & Development 8: 545–551.

Sturgeon CM, Ditadi A, Clarke RL and Keller G (2013) Defining the path to hematopoietic stem cells. Nature Biotechnology 31: 416–418.

Sun J, Ramos A, Chapman B, et al. (2014) Clonal dynamics of native haematopoiesis. Nature 514: 322–327.

Suzuki N, Yamazaki S, Yamaguchi T, et al. (2013) Generation of engraftable hematopoietic stem cells from induced pluripotent stem cells by way of teratoma formation. Molecular Therapy: The Journal of the American Society of Gene Therapy 21: 1424–1431.

Takahashi K and Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663–676.

Till JE and McCulloch (1961) A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiation Research 14: 213–222.

Yamamoto R, Morita Y, Ooehara J, et al. (2013) Clonal analysis unveils self‐renewing lineage‐restricted progenitors generated directly from hematopoietic stem cells. Cell 154: 1112–1126.

Yoder MC (2014) Cord blood banking and transplantation: advances and controversies. Current Opinion in Pediatrics 26: 163–168.

Zhen F, Lan Y, Yan B, Zhang W and Wen Z (2013) Hemogenic endothelium specification and hematopoietic stem cell maintenance employ distinct Scl isoforms. Development 140: 3977–3985.

Further Reading

Kondo M (2009) Hematopoietic Stem Cell Biology (Stem Cell Biology and Regenerative Medicine). New York: Humana Press.

Metcalf D and Moore MAS (1971) Haemopoietic Cells. Amsterdam: North‐Holland.

Orkin SH, Nathan DG, Ginsburg D, et al. (2008) Nathan and Oski's Hematology of Infancy and Childhood, 7th edn. Philadelphia: WB Saunders.

Thompson AW and Lotze MT (2003) The Cytokine Handbook, 4th edn. San Diego: Academic Press.

Zon L (2001) Hematopoiesis: A Developmental Approach. Oxford: University Press.

For Images

Thompson AW and Lotze MT (2003) The Cytokine Handbook, 4th edn. San Diego: Academic Press.

American Society of Hematology, Image Bank [http://imagebank.hematology.org/]

National Institutes of Health, Stem Cell Information Page, Hematopoietic Stem Cells [http://stemcells.nih.gov/info/Regenerative_Medicine/Pages/2006Chapter2.aspx]

Slideshare [http://www.slideshare.net/balsan/normal‐hematopoiesis]

University of Nebraska at Omaha, Blood Cell Histology [http://www.unomaha.edu/hpa/blood.html]

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Kumar, Ritu, and Evans, Todd(Jun 2015) Haematopoiesis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000518.pub4]