Haematopoiesis (;[Semester 4 medical lectures at Uppsala University 2008 by Leif Jansson]
Process
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 differentiate, at least some of their daughter cells remain as HSCs so the pool of stem cells is not depleted.
This phenomenon is called asymmetric division.
The other daughters of HSCs (
myeloid and
Lymphatic system progenitor cells) can follow any of the other differentiation pathways that lead to the production of one or more specific types of blood cell, but cannot renew themselves. 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.
This is one of the main vital processes in the body.
Cell types
All blood cells are divided into three lineages.
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Red blood cells, which are also called erythrocytes, are the oxygen-carrying cells. Erythrocytes are functional, and are released into the blood. The number of reticulocytes, which are immature red blood cells, gives an estimate of the rate of erythropoiesis.
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are the cornerstone of the adaptive immune system. They are derived from common lymphoid progenitors. The lymphoid lineage is composed of , , and natural killer cells. This is lymphopoiesis.
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Cells of the myeloid lineage, which include , , monocytes, and , are derived from common myeloid progenitors, and are involved in such diverse roles as innate immunity and blood clotting. This is myelopoiesis.
Granulopoiesis (or granulocytopoiesis) is haematopoiesis of granulocytes, except which are granulocytes but with an extramedullar maturation.
Thrombopoiesis is haematopoiesis of Platelet.
Terminology
Between 1948 and 1950, the Committee for Clarification of the Nomenclature of Cells and Diseases of the Blood and Blood-forming Organs issued reports on the nomenclature of blood cells.
An overview of the terminology is shown below, from earliest to final stage of development:
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rootblast
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prorootcyte
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rootcyte
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metarootcyte
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mature cell name
The root for erythrocyte colony-forming units (CFU-E) is "rubri", for granulocyte-monocyte colony-forming units (CFU-GM) is "granulo" or "myelo" and "mono", for lymphocyte colony-forming units (CFU-L) is "lympho" and for megakaryocyte colony-forming units (CFU-Meg) is "megakaryo". According to this terminology, the stages of red blood cell formation would be: rubriblast, prorubricyte, rubricyte, metarubricyte, and erythrocyte. However, the following nomenclature seems to be, at present, the most prevalent:
also arise from hemopoietic cells of the monocyte/neutrophil lineage, specifically CFU-GM.
Location
In developing embryos, blood formation occurs in aggregates of blood cells in the yolk sac, called
blood islands. As development progresses, blood formation occurs in the
spleen,
liver and
lymph nodes.
When
bone marrow develops, it eventually assumes the task of forming most of the blood cells for the entire organism.
However, maturation, activation, and some proliferation of lymphoid cells occurs in the spleen,
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.
Extramedullary
In some cases, the liver, thymus, and spleen may resume their haematopoietic function, if necessary. This is called
extramedullary haematopoiesis. It may cause these organs to increase in size substantially. During fetal development, since bones and thus the bone marrow develop later, the liver functions as the main haematopoietic organ. Therefore, the liver is enlarged during development.
Extramedullary haematopoiesis and myelopoiesis may supply
leukocytes in cardiovascular disease and inflammation during adulthood.
Splenic
macrophages and adhesion molecules may be involved in regulation of extramedullary myeloid cell generation in cardiovascular disease.
Maturation
[[File:Hematopoiesis (human) diagram en.svg|thumb|400px|More detailed and comprehensive diagram that shows the development of different blood cells in humans:
]]
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 (cellular differentiation). 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.
Cell fate determination
Two models for haematopoiesis have been proposed: determinism and stochastic theory.
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. In
stochastic theory, undifferentiated blood cells differentiate to specific cell types by randomness. This theory has been supported by experiments showing that within a population of mouse haematopoietic progenitor cells, underlying stochastic variability in the distribution of Sca-1, a
stem cell factor, subdivides the population into groups exhibiting variable rates of cellular differentiation. For example, under the influence of
erythropoietin (an erythrocyte-differentiation factor), a subpopulation of cells (as defined by the levels of Sca-1) differentiated into erythrocytes at a sevenfold higher rate than the rest of the population.
Furthermore, it was shown that if allowed to grow, this subpopulation re-established the original subpopulation of cells, supporting the theory that this is a stochastic, reversible process. Another level at which stochasticity may be important is in the process of apoptosis and self-renewal. In this case, 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.
Growth factors
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 players in self-renewal and development of haematopoietic cells is stem cell factor (SCF),
which binds to the c-kit receptor on the HSC. Absence of SCF is lethal. There are other important
glycoprotein growth factors which regulate the proliferation and maturation, such as
IL-2, IL-3, IL-6, IL-7. Other factors, termed colony-stimulating factors (CSFs), specifically stimulate the production of committed cells. Three CSFs are granulocyte-macrophage CSF (GM-CSF),
granulocyte CSF (G-CSF) and
macrophage CSF (M-CSF).
These stimulate
granulocyte formation and are active on either
progenitor cells or end product cells.
Erythropoietin is required for a myeloid progenitor cell to become an erythrocyte.[Molecular cell biology. Lodish, Harvey F. 5. ed. : – New York : W. H. Freeman and Co., 2003, 973 s. b ill.
----] On the other hand, thrombopoietin makes myeloid progenitor cells differentiate to (thrombocyte-forming cells).[ The diagram to the right provides examples of cytokines and the differentiated blood cells they give rise to.]
Transcription factors
Growth factors initiate signal transduction pathways, which lead to activation of transcription factors. Growth factors elicit different outcomes depending on the combination of factors and the cell's stage of differentiation. For example, long-term expression of PU.1 results in myeloid commitment, and short-term induction of PU.1 activity leads to the formation of immature eosinophils.
The first key player of differentiation from HSC to a multipotent progenitor (MPP) is transcription factor CCAAT-enhancer binding protein α (C/EBPα). Mutations in C/EBPα are associated with acute myeloid leukaemia.
Other transcription factors include Ikaros
An example is PAX5 factor, which is important in B cell development and associated with lymphomas.
Mutations in transcription factors are tightly connected to blood cancers, as acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). For example, Ikaros is known to be regulator of numerous biological events. Mice with no Ikaros lack , Natural killer and .
Other animals
In some , haematopoiesis can occur wherever there is a loose Stromal cell of connective tissue and slow blood supply, such as the gut, spleen or kidney.
Unlike eutherian mammals, the liver of newborn marsupials is actively haematopoietic.[Old JM (2016). Haematopoiesis in marsupials. Developmental and Comparative Immunology. 58, 40-46. DOI: 10.1016/j.dci.2015.11.009][Old JM, Deane EM (2000). Development of the immune system and immunological protection in marsupial pouch young. Developmental and Comparative Immunology. 24(5), 445-454. DOI: 10.1016/S0145-305X(00)00008-2][Old JM, Deane EM (2003). The lymphoid and immunohaematopoietic tissues of the embryonic brushtail possum ( Trichosurus vulpecula). Anatomy and Embryology (now called Brain Structure and Function). 206(3), 193-197. DOI: 10.1007/s00429-002-0285-2][Old JM, Lynne Selwood, Deane EM (2003). A histological investigation of the lymphoid and immunohaematopoietic tissues of the adult stripe-faced dunnart ( Sminthopsis macroura). Cells Tissues Organs. 173(2), 115-121. DOI: 10.1159/000068946]
See also
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Clonal hematopoiesis
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Erythropoiesis-stimulating agents
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Haematopoietic stimulants:
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Granulocyte colony-stimulating factor
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Granulocyte macrophage colony-stimulating factor
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Leukocyte extravasation
Further reading
External links
