A megakaryocyte (''
mega-
Mega is a metric prefix, unit prefix in metric systems of units denoting a factor of one million (106 or 1000000 (number), ). It has the unit symbol M. It was confirmed for use in the International System of Units (SI) in 1960. ''Mega'' comes fro ...
'' + ''
karyo-'' + ''
-cyte'', "large-nucleus cell") is a large
bone marrow
Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...
cell
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
with a
lobated nucleus responsible for the production of blood
thrombocyte
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby in ...
s (
platelets
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
), which are necessary for normal blood
clot
A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cr ...
ting. In humans, megakaryocytes usually account for 1 out of 10,000
bone marrow
Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...
cells, but can increase in number nearly 10-fold during the course of certain diseases.
Owing to variations in
combining forms and spelling, synonyms include megalokaryocyte and megacaryocyte.
Structure
In general, megakaryocytes are 10 to 15 times larger than a typical red blood cell, averaging 50–100 μm in diameter. During its maturation, the megakaryocyte grows in size and replicates its
DNA without
cytokinesis
Cytokinesis () is the part of the cell division process during which the cytoplasm of a single eukaryotic cell divides into two daughter cells. Cytoplasmic division begins during or after the late stages of nuclear division in mitosis and meios ...
in a process called
endomitosis. As a result, the nucleus of the megakaryocyte can become very large and lobulated, which, under a light microscope, can give the false impression that there are several nuclei. In some cases, the nucleus may contain up to 64N DNA, or 32 copies of the normal complement of DNA in a human cell.
The
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
, just as the platelets that bud off from it, contains
α-granula and
dense bodies.
Development
Megakaryocytes are derived from
hematopoietic stem cell
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...
precursor cells in the bone marrow. They are produced primarily by the liver, kidney, spleen, and bone marrow. These
multipotent Pluripotency: These are the cells that can generate into any of the three Germ layers which imply Endodermal, Mesodermal, and Ectodermal cells except tissues like the placenta.
According to Latin terms, Pluripotentia means the ability for many thin ...
stem cells live in the marrow sinusoids and are capable of producing all types of blood cells depending on the signals they receive. The primary signal for megakaryocyte production is
thrombopoietin
Thrombopoietin (THPO) also known as megakaryocyte growth and development factor (MGDF) is a protein that in humans is encoded by the ''THPO'' gene.
Thrombopoietin is a glycoprotein hormone produced by the liver and kidney which regulates the pro ...
or TPO. TPO is sufficient but not absolutely necessary
for inducing differentiation of progenitor cells in the bone marrow towards a final megakaryocyte
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
. Other molecular signals for megakaryocyte differentiation include
GM-CSF
Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that ...
,
IL-3,
IL-6,
IL-11,
chemokines
Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition ...
(
SDF-1,
FGF-4
Fibroblast growth factor 4 is a protein that in humans is encoded by the ''FGF4'' gene.
The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activi ...
)
and
erythropoietin
Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bo ...
.
The megakaryocyte develops through the following lineage:
CFU-Me (
pluripotential hemopoietic stem cell
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...
or hemocytoblast) →
megakaryoblast
A megakaryoblast is a precursor cell to a promegakaryocyte, which in turn becomes a megakaryocyte during haematopoiesis. It is the beginning of the thrombocytic series.
Development
The megakaryoblast derives from a CFU-Meg colony unit of pluripot ...
→
promegakaryocyte
A promegakaryocyte is a precursor cell for a megakaryocyte. It arises from a megakaryoblast, into a promegakaryocyte and then into a megakaryocyte, which will eventually break off and become a platelet.
The developmental stages of the megakaryoc ...
→ megakaryocyte.
The cell eventually reaches megakaryocyte stage and loses its ability to divide. However, it is still able to replicate its DNA and continue development, becoming
polyploid
Polyploidy is a condition in which the cells of an organism have more than one pair of ( homologous) chromosomes. Most species whose cells have nuclei ( eukaryotes) are diploid, meaning they have two sets of chromosomes, where each set contain ...
.
[ The cytoplasm continues to expand and the DNA amount can increase up to 64n in humans and 256n in mice. Many of the morphological features of megakaryocyte differentiation can be recapitulated in non-hematopoietic cells by the expression of Class VI β-tubulin (β6) and they provide a mechanistic basis for understanding these changes.
]
Function
Platelet release
Once the cell has completed differentiation and become a mature megakaryocyte, it begins the process of producing platelets. The maturation process occurs via endomitotic synchronous replication whereby the cytoplasmic volume enlarges as the number of chromosomes multiplies without cellular division. The cell ceases its growth at 4N, 8N or 16N, becomes granular, and begins to produce platelets. Thrombopoietin
Thrombopoietin (THPO) also known as megakaryocyte growth and development factor (MGDF) is a protein that in humans is encoded by the ''THPO'' gene.
Thrombopoietin is a glycoprotein hormone produced by the liver and kidney which regulates the pro ...
plays a role in inducing the megakaryocyte to form small proto-platelet processes. Platelets are held within these internal membranes within the cytoplasm of megakaryocytes. There are two proposed mechanisms for platelet release. In one scenario, these proto-platelet processes break up explosively to become platelets. It is possible to visualize the spontaneous release of platelets using holotomographic live cell imaging
Live-cell imaging is the study of living cells using time-lapse microscopy. It is used by scientists to obtain a better understanding of biological function through the study of cellular dynamics. Live-cell imaging was pioneered in the first de ...
. Alternatively, the cell may form platelet ribbons into blood vessels. The ribbons are formed via pseudopodia and they are able to continuously emit platelets into circulation. In either scenario, each of these proto-platelet processes can give rise to 2000–5000 new platelets upon breakup. Overall, 2/3 of these newly produced platelets will remain in circulation while 1/3 will be sequestered by the spleen.
Thrombopoietin (TPO) is a 353-amino acid protein encoded on chromosome 3
Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans almost 200 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA in ...
p27. TPO is primarily synthesized in the liver but can be made by kidneys, testes, brain, and even bone marrow stromal cells. It has high homology with erythropoietin
Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bo ...
. It is essential for the formation of an adequate quantity of platelets.
After budding off platelets, what remains is mainly the cell nucleus. This crosses the bone marrow barrier to the blood and is consumed in the lung
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...
by alveolar macrophage
An alveolar macrophage, pulmonary macrophage, (or dust cell) is a type of macrophage, a professional phagocyte, found in the airways and at the level of the alveoli in the lungs, but separated from their walls.
Activity of the alveolar macropha ...
s.
Effects of cytokines
Cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s are signals used in the immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
for intercellular communication. There are many cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s that affect megakaryocytes. Certain cytokines such as IL-3, IL-6, IL-11, LIF
Lithium fluoride is an inorganic compound with the chemical formula LiF. It is a colorless solid, that transitions to white with decreasing crystal size. Although odorless, lithium fluoride has a bitter-saline taste. Its structure is analogous to ...
, erythropoietin
Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bo ...
, and thrombopoietin
Thrombopoietin (THPO) also known as megakaryocyte growth and development factor (MGDF) is a protein that in humans is encoded by the ''THPO'' gene.
Thrombopoietin is a glycoprotein hormone produced by the liver and kidney which regulates the pro ...
all stimulate the maturation of megakaryocytic progenitor cells. Other signals such as PF4
Platelet factor 4 (PF4) is a small cytokine belonging to the CXC chemokine family that is also known as chemokine (C-X-C motif) ligand 4 (CXCL4) . This chemokine is released from alpha-granules of activated platelets during platelet aggregation, ...
, CXCL5
C-X-C motif chemokine 5 (CXCL5 or ENA78) is a protein that in humans is encoded by the ''CXCL5'' gene.
Function
The protein encoded by this gene, CXCL5 is a small cytokine belonging to the CXC chemokine family that is also known as epithelial- ...
, CXCL7
Chemokine (C-X-C motif) ligand 7 (CXCL7) is a human gene.
The encoded protein, Chemokine (C-X-C motif) ligand is a small cytokine belonging to the CXC chemokine family. It is an isoform of Beta-Thromboglobulin or ''Pro-Platelet basic protein'' ( ...
, and CCL5
Chemokine (C-C motif) ligand 5 (also CCL5) is a protein which in humans is encoded by the ''CCL5'' gene. The gene has been discovered in 1990 by ''in situ'' hybridisation and it is localised on 17q11.2-q12 chromosome. It is also known as RANTE ...
inhibit platelet formation.
Clinical significance
Megakaryocytes are directly responsible for producing platelets, which are needed for the formation of a thrombus
A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of ...
, or blood clot. There are several diseases that are directly attributable to abnormal megakaryocyte function or abnormal platelet function.
Essential thrombocythemia
Essential thrombocythemia
Essential thrombocythemia (ET) is a rare chronic blood cancer (myeloproliferative neoplasm) characterised by the thrombocythemia, overproduction of platelets (thrombocytes) by megakaryocytes in the bone marrow. It may, albeit rarely, develop into a ...
(ET) is a disorder characterized by elevated numbers of circulating platelets. The disease occurs in 1–2 per 100,000 people. The 2016 WHO requirements for diagnosis include > 450,000 platelets/μL of blood (normal 150,000–400,000) and characteristic findings in a bone marrow
Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...
biopsy. Some of the consequences of having such high numbers of platelets include thrombosis
Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thro ...
or clots in blood vessels. Thrombi form more frequently in arteries than veins. It seems ironic that having platelet counts above 1,000,000 platelets/μL can lead to hemorrhagic
Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...
events. Approximately half ET cases are due to a mutation in the JAK2
Janus kinase 2 (commonly called JAK2) is a non-receptor tyrosine kinase. It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor family (e.g. interferon receptors), the GM-CSF rece ...
protein, a member of the JAK-STAT pathway
The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumour formation. The pathway communicates information from chemical signals out ...
. This mutation induces an unregulated proliferative signal from the thrombopoietin (TPO) receptor in the absence of TPO causing clonal expansion of bone marrow cells, especially megakaryocytes. There is a low risk of transformation to leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
with this disorder. The primary treatment consists of anagrelide
Anagrelide (Agrylin/Xagrid, Shire and Thromboreductin, AOP Orphan Pharmaceuticals AG) is a drug used for the treatment of essential thrombocytosis (also known as essential thrombocythemia), or overproduction of blood platelets. It also has been u ...
or hydroxyurea
Hydroxycarbamide, also known as hydroxyurea, is a medication used in sickle-cell disease, essential thrombocythemia, chronic myelogenous leukemia, polycythemia vera, and cervical cancer. In sickle-cell disease it increases fetal hemoglobin and d ...
to lower platelet levels.
Congenital amegakaryocytic thrombocytopenia
Congenital amegakaryocytic thrombocytopenia
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited disorder.
Presentation
The primary manifestations are thrombocytopenia and megakaryocytopenia, or low numbers of platelets and megakaryocytes. There is an absence of megakaryo ...
(CAMT) is a rare inherited disorder. The primary manifestations are thrombocytopenia
Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...
and megakaryocytopenia, i.e. low numbers of platelets and megakaryocytes. There is an absence of megakaryocytes in the bone marrow with no associated physical abnormalities. The cause for this disorder appears to be a mutation in the gene for the TPO receptor, ''c-mpl'', despite high levels of serum TPO. In addition, there may be abnormalities with the central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
including the cerebrum
The cerebrum, telencephalon or endbrain is the largest part of the brain containing the cerebral cortex (of the two cerebral hemispheres), as well as several subcortical structures, including the hippocampus, basal ganglia, and olfactory bulb. In ...
and cerebellum
The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...
that could cause symptoms.[ The primary treatment for CAMT is ]bone marrow transplantation
Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce ...
.
Bone marrow/stem cell transplant is the only remedy for this genetic disease. Frequent platelet transfusions are required to keep the patient from bleeding to death until transplant has been completed, although this is not always the case.
There appears to be no generic resource for CAMT patients on the web and this is potentially due to the rarity of the disease.
History
In 1906, James Homer Wright provided evidence that megakaryocytes give rise to blood platelets.
Kelemen first coined the term "thrombopoietin
Thrombopoietin (THPO) also known as megakaryocyte growth and development factor (MGDF) is a protein that in humans is encoded by the ''THPO'' gene.
Thrombopoietin is a glycoprotein hormone produced by the liver and kidney which regulates the pro ...
" to describe the humoral substance responsible for the production of platelets.
References
External links
''Megakaryocytes: Mature''
Many microscopic images of mature megakaryocytes including in disease settings.
''Megakaryocytes''
''Cell size comparison''
CAMT Specific Infant Bone Marrow Transplant Journal
{{Authority control
Leukocytes
Human cells