Haematopoiesis
Encyclopedia
Haematopoiesis (or hematopoiesis in the United States; 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.
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. HSCs are self renewing: when they proliferate, at least some of their daughter cells remain as HSCs, so the pool of stem cells does not become depleted. The other daughters of HSCs (myeloid and lymphoid progenitor cells), however can each 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. This is one of the vital processes in the body.
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All blood cells are divided into three lineages.
Granulopoiesis
(or granulocytopoiesis) is haematopoiesis of granulocytes.
Megakaryocytopoiesis
is haematopoiesis of megakaryocytes.
, liver
and lymph node
s. 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 secondary lymphoid organs (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.
. 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 haematopoetic organ. Therefore, the liver is enlarged during development.
s, haematopoiesis can occur wherever there is a loose stroma
of connective tissue and slow blood supply, such as the gut
, spleen
, kidney
or ovaries.
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.
provides an ideal environment for thymocytes to differentiate into a variety of different functional T cells. 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 fact, however, it is not really true. The ability of the bone marrow to regulate the quantity of different cell types to be produced is more accurately explained by a 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.
(SCF).
Glycoprotein
growth factors regulate the proliferation and maturation of the cells that enter the blood from the marrow, and cause cells in one or more committed cell lines to proliferate and mature.
Three more factors that stimulate the production of committed stem cells are called colony-stimulating factors (CSFs) and include granulocyte-macrophage CSF (GM-CSF), granulocyte CSF (G-CSF) and macrophage CSF (M-CSF).
These stimulate much 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. On the other hand, thrombopoietin
makes myeloid progenitor cells differentiate to megakaryocytes (thrombocyte-forming cells).
Examples of cytokines and the blood cells they give rise to, is shown in the picture to the right.
pathways, altering transcription factors, that, in turn activate genes that determine the differentiation of blood cells.
The early committed progenitors express low levels of transcription factors that may commit them to discrete cell lineages. Which cell lineage is selected for differentiation may depend both on chance and on the external signals received by progenitor cells.
Several transcription factors have been isolated that regulate differentiation along the major cell lineages. For instance, PU.1 commits cells to the myeloid lineage whereas GATA-1
has an essential role in erythropoietic and megakaryocytic differentiation. The Ikaros, Aiolos and Helios transcription factors play a major role in lymphoid development.
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
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.
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. HSCs are self renewing: when they proliferate, at least some of their daughter cells remain as HSCs, so the pool of stem cells does not become depleted. The other daughters of HSCs (myeloid and lymphoid progenitor cells), however can each 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. This is one of the vital processes in the body.
Lineages
- Erythroid cells are the oxygen carrying red blood cells. Both reticulocytes and erythrocytes are functional and are released into the blood. In fact, a reticulocyte count estimates the rate of erythropoiesisErythropoiesisErythropoiesis is the process by which red blood cells are produced. It is stimulated by decreased O2 in circulation, which is detected by the kidneys, which then secrete the hormone erythropoietin...
. - Lymphocytes are the cornerstone of the adaptive immune system. They are derived from common lymphoid progenitors. The lymphoid lineage is primarily composed of T-cells and B-cells (types of white blood cells). This is lymphopoiesisLymphopoiesisLymphopoiesis refers to the generation of lymphocytes, one of the five different types of white blood cells , and is also more formally called lymphoid hematopoiesis.-The name Lymphopoiesis:...
. - MyelocyteMyelocyteA myelocyte is a young cell of the granulocytic series, occurring normally in bone marrow, but not in circulating blood .-Histology:...
s, which include granulocyteGranulocyteGranulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes because of the varying shapes of the nucleus, which is usually lobed into three segments...
s, megakaryocyteMegakaryocyteThe megakaryocyte is a bone marrow cell responsible for the production of blood thrombocytes , which are necessary for normal blood clotting...
s and macrophageMacrophageMacrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s and are derived from common myeloid progenitors, are involved in such diverse roles as innate immunity, adaptive immunity, and blood clotting. This is myelopoiesisMyelopoiesisMyelopoiesis is the regulated formation of myeloid cells, including eosinophilic granulocytes, basophilic granulocytes, neutrophilic granulocytes, and monocytes...
.
Granulopoiesis
Granulopoiesis
Granulopoiesis is hematopoiesis of granulocytes.It occurs primarily within bone marrow and involves the following stages:* Pluripotential hemopoietic stem cell* Myeloblast* Promyelocyte* Eosino/neutro/basophilic myelocyte...
(or granulocytopoiesis) is haematopoiesis of granulocytes.
Megakaryocytopoiesis
Megakaryocytopoiesis
Megakaryocytopoiesis is the process by which bone marrow progenitor cells develop into mature megakaryocytes, which in turn produce platelets required for normal hemostasis....
is haematopoiesis of megakaryocytes.
Locations
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 spleenSpleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
, liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
s. When bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
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 secondary lymphoid organs (spleen, thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
, 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 haematopoiesisExtramedullary hematopoiesis
Extramedullary hematopoiesis refers to hematopoiesis occurring outside of the medulla of the bone.In some cases, it may be physiologic. For example, during fetal development, hematopoiesis occurs at many different locations, such as the liver and spleen....
. 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 haematopoetic organ. Therefore, the liver is enlarged during development.
Other vertebrates
In some vertebrateVertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
s, haematopoiesis can occur wherever there is a loose stroma
Stromal cell
In cell biology, stromal cells are connective tissue cells of any organ, for example in the uterine mucosa , prostate, bone marrow, and the ovary. They are cells that support the function of the parenchymal cells of that organ...
of connective tissue and slow blood supply, such as the gut
Gut (zoology)
In zoology, the gut, also known as the alimentary canal or alimentary tract, is a tube by which bilaterian animals transfer food to the digestion organs. In large bilaterians the gut generally also has an exit, the anus, by which the animal disposes of solid wastes...
, spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
, kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
or ovaries.
Maturation
As a stem cell matures it undergoes changes in gene expressionGene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
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.
Determination
Cell determination appears to be dictated by the location of differentiation. For instance, the thymusThymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
provides an ideal environment for thymocytes to differentiate into a variety of different functional T cells. 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 fact, however, it is not really true. The ability of the bone marrow to regulate the quantity of different cell types to be produced is more accurately explained by a 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
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
and die. By regulating this balance between different cell types, the bone marrow can alter the quantity of different cells to ultimately be produced.
Haematopoietic growth factors
Red and white blood cell production is regulated with great precision in healthy humans, and the production of granulocytes is rapidly increased during infection. The proliferation and self-renewal of these cells depend on stem cell factorStem cell factor
Stem Cell Factor is a cytokine that binds to the c-Kit receptor . SCF can exist both as a transmembrane protein and a soluble protein...
(SCF).
Glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
growth factors regulate the proliferation and maturation of the cells that enter the blood from the marrow, and cause cells in one or more committed cell lines to proliferate and mature.
Three more factors that stimulate the production of committed stem cells are called colony-stimulating factors (CSFs) and include granulocyte-macrophage CSF (GM-CSF), granulocyte CSF (G-CSF) and macrophage CSF (M-CSF).
These stimulate much granulocyte
Granulocyte
Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes because of the varying shapes of the nucleus, which is usually lobed into three segments...
formation and are active on either progenitor cells or end product cells.
Erythropoietin
Erythropoietin
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
is required for a myeloid progenitor cell to become an erythrocyte. On the other hand, thrombopoietin
Thrombopoietin
Thrombopoietin also known as megakaryocyte growth and development factor is a protein that in humans is encoded by the THPO gene....
makes myeloid progenitor cells differentiate to megakaryocytes (thrombocyte-forming cells).
Examples of cytokines and the blood cells they give rise to, is shown in the picture to the right.
Transcription factors
Growth factors initiate signal transductionSignal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
pathways, altering transcription factors, that, in turn activate genes that determine the differentiation of blood cells.
The early committed progenitors express low levels of transcription factors that may commit them to discrete cell lineages. Which cell lineage is selected for differentiation may depend both on chance and on the external signals received by progenitor cells.
Several transcription factors have been isolated that regulate differentiation along the major cell lineages. For instance, PU.1 commits cells to the myeloid lineage whereas GATA-1
GATA1
Erythroid transcription factor also known as GATA-binding factor 1 or GATA-1 is a protein that in humans is encoded by the GATA1 gene....
has an essential role in erythropoietic and megakaryocytic differentiation. The Ikaros, Aiolos and Helios transcription factors play a major role in lymphoid development.
The myeloid-based model
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.See also
- HaematonHematonThe hematon was first defined in 1988 as the primary fundamental unit of haematopoiesis, the formation of blood cells.The hematon is believed to be a low density multicellular spheroid approximately 100-500 micrometres in diameter...
- Haematopoietic stimulants:
- Granulocyte colony-stimulating factorGranulocyte colony-stimulating factorGranulocyte colony-stimulating factor is a colony-stimulating factor hormone. G-CSF is also known as colony-stimulating factor 3 ....
- Granulocyte macrophage colony-stimulating factor
- Granulocyte colony-stimulating factor
- Erythropoiesis-stimulating agents