Megakaryocyte
Encyclopedia
The megakaryocyte is a bone marrow
cell
responsible for the production of blood thrombocytes (platelets), which are necessary for normal blood clotting. Megakaryocytes normally account for 1 out of 10,000 bone marrow
cells but can increase in number nearly 10-fold during the course of certain diseases.
without cytokinesis
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
, just as the platelets that bud off from it, contains α-granula and Dense bodies
.
Megakaryocytes are derived from hematopoietic stem cell precursor cells in the bone marrow. They are primarily produced by the liver, kidney, spleen, and bone marrow. These multipotent 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
or TPO. TPO is sufficient but not absolutely necessary for inducing differentiation of progenitor cells in the bone marrow towards a final megakaryocyte phenotype
. Other molecular signals for megakaryocyte differentiation include GM-CSF, IL-3
, IL-6
, IL-11
, chemokines (SDF-1 ; FGF-4), and erythropoietin
. The megakaryocyte develops through the following lineage:
CFU-Me (pluripotential hemopoietic stem cell
or hemocytoblast) -> megakaryoblast
-> promegakaryocyte
-> megakaryocyte.
The cell eventually reaches megakaryoblast stage and loses its ability to divide. However, it is still able to replicate its DNA and continue development, becoming polyploid. The cytoplasm continues to expand and the DNA complement can increase up to 64N.
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. 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.
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
by alveolar macrophages.
s are signals used in the immune system
for intercellular communication. There are many cytokine
s which affect megakaryocytes. Certain cytokines such as IL-3
, IL-6
, IL-11
, LIF
, erythropoietin
, and thrombopoietin
all stimulate the maturation of megakaryocytic progenitor cells. Other signals such as PF4, CXCL5
, CXCL7
, and CCL5 inhibit platelet formation.
3p27. 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
. It is essential for the formation of an adequate quantity of platelets. Mice lacking TPO or the TPO receptor (Mpl) have a 90% reduction in circulating platelet number, although the platelets are normal in morphology and function.
, or blood clot. There are several diseases which are directly attributable to abnormal megakaryocyte function or abnormal platelet function.
(ET-Also known as Essential thrombocythemia) is a disorder characterized by extremely high numbers of circulating platelets. The disease occurs in 1-2 per 100,000 people. The current WHO requirements for diagnosis include > 600,000 platelets/μL of blood (normal 150,000-400,000) and a bone marrow
biopsy. Some of the consequences of having such high numbers of platelets include thrombosis
or clots throughout the body. Thrombi form more frequently in arteries than veins. Ironically, having platelet counts above 1,000,000 platelets/μL can lead to hemorrhagic events. Recent evidence suggests that the majority of ET cases are due to a mutation in the JAK2 protein, a member of the JAK-STAT pathway. Evidence suggests this mutation renders the megakaryocyte hypersensitive to thrombopoietin and causes clonal proliferation of megakaryocytes. There is a significant risk of transformation to leukemia
with this disorder. The primary treatment consists of anagrelide
or hydroxyurea
to lower platelet levels.
(CAMT) is a rare inherited
disorder. The primary manifestations are thrombocytopenia
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
including the cerebrum and cerebellum
which could cause symptoms. The primary treatment for CAMT is bone marrow transplantation.
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.
One of the few non-medical research related sources on the web with some information on CAMT is:
There appears to be no generic resource for CAMT patients on the web and this is potentially due to the rariety of the disease.
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...
cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
responsible for the production of blood thrombocytes (platelets), which are necessary for normal blood clotting. Megakaryocytes normally account for 1 out of 10,000 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...
cells but can increase in number nearly 10-fold during the course of certain diseases.
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 DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
without cytokinesis
Cytokinesis
Cytokinesis is the process in which the cytoplasm of a single eukaryotic cell is divided to form two daughter cells. It usually initiates during the late stages of mitosis, and sometimes meiosis, splitting a binucleate cell in two, to ensure that chromosome number is maintained from one generation...
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
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
, just as the platelets that bud off from it, contains α-granula and Dense bodies
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
.
Megakaryocyte development
Thrombopoietin
Thrombopoietin also known as megakaryocyte growth and development factor is a protein that in humans is encoded by the THPO gene....
or TPO. TPO is sufficient but not absolutely necessary for inducing differentiation of progenitor cells in the bone marrow towards a final megakaryocyte phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
. Other molecular signals for megakaryocyte differentiation include GM-CSF, IL-3
Interleukin 3
Interleukin 3, also known as IL-3, is a protein that in humans is encoded by the IL3 gene.-Function:Interleukin-3 is an interleukin, a type of biological signal that can improve the body's natural response to disease as part of the immune system...
, IL-6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
, IL-11
Interleukin 11
Interleukin 11 is a protein that in humans is encoded by the IL11 gene.IL-11 is a multifunctional cytokine first isolated in 1990 from bone marrow-derived stromal cells. It is a key regulator of multiple events in hematopoiesis, most notably the stimulation of megakaryocyte maturation...
, chemokines (SDF-1 ; FGF-4), and erythropoietin
Erythropoietin
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
. The megakaryocyte develops through the following lineage:
CFU-Me (pluripotential hemopoietic stem cell
Pluripotential hemopoietic stem cell
Hematopoietic stem cells , also spelled Hæmatopoietic stem cells, are multipotent stem cells that give rise to all the blood cell types from the myeloid , and lymphoid lineages...
or hemocytoblast) -> megakaryoblast
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....
-> promegakaryocyte
Promegakaryocyte
A promegakaryocyte is a precursor cell for a megakaryocyte, arising from a megakaryoblast.The developmental stages of the megakaryocyte are:CFU-Me → megakaryoblast → promegakaryocyte → megakaryocyte.-External links:* *...
-> megakaryocyte.
The cell eventually reaches megakaryoblast stage and loses its ability to divide. However, it is still able to replicate its DNA and continue development, becoming polyploid. The cytoplasm continues to expand and the DNA complement can increase up to 64N.
Platelet release
Once the cell has completed differentiation and become a mature megakaryocyte, it begins the process of producing platelets. ThrombopoietinThrombopoietin
Thrombopoietin also known as megakaryocyte growth and development factor is a protein that in humans is encoded by the THPO gene....
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. 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.
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
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
by alveolar macrophages.
Effects of cytokines
CytokineCytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s are signals used in the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
for intercellular communication. There are many cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s which affect megakaryocytes. Certain cytokines such as IL-3
Interleukin 3
Interleukin 3, also known as IL-3, is a protein that in humans is encoded by the IL3 gene.-Function:Interleukin-3 is an interleukin, a type of biological signal that can improve the body's natural response to disease as part of the immune system...
, IL-6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
, IL-11
Interleukin 11
Interleukin 11 is a protein that in humans is encoded by the IL11 gene.IL-11 is a multifunctional cytokine first isolated in 1990 from bone marrow-derived stromal cells. It is a key regulator of multiple events in hematopoiesis, most notably the stimulation of megakaryocyte maturation...
, LIF
Leukemia inhibitory factor
Leukemia inhibitory factor, or LIF, an interleukin 6 class cytokine, is a protein in cells that affects cell growth and development.-Function:LIF derives its name from its ability to induce the terminal differentiation of myeloid leukemic cells...
, erythropoietin
Erythropoietin
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
, and thrombopoietin
Thrombopoietin
Thrombopoietin also known as megakaryocyte growth and development factor is a protein that in humans is encoded by the THPO gene....
all stimulate the maturation of megakaryocytic progenitor cells. Other signals such as PF4, CXCL5
CXCL5
C-X-C motif chemokine 5 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-derived neutrophil-activating peptide 78...
, CXCL7
CXCL7
Chemokine ligand 7 is a human gene.The encoded protein, Chemokine 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 inhibit platelet formation.
Thrombopoietin
Thrombopoietin (TPO) is a 353-amino acid protein located on chromosomeChromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
3p27. 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
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
. It is essential for the formation of an adequate quantity of platelets. Mice lacking TPO or the TPO receptor (Mpl) have a 90% reduction in circulating platelet number, although the platelets are normal in morphology and function.
Disorders involving megakaryocytes
Megakaryocytes are directly responsible for producing platelets which are needed for the formation of a thrombusThrombus
A thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...
, or blood clot. There are several diseases which are directly attributable to abnormal megakaryocyte function or abnormal platelet function.
Essential Thrombocythemia
Essential thrombocytosisEssential thrombocytosis
Essential thrombocythemia is a rare chronic blood disorder characterized by the overproduction of platelets by megakaryocytes in the bone marrow in the absence of an alternative cause. In some cases this disorder may be progressive, and rarely may evolve into acute myeloid leukemia or myelofibrosis...
(ET-Also known as Essential thrombocythemia) is a disorder characterized by extremely high numbers of circulating platelets. The disease occurs in 1-2 per 100,000 people. The current WHO requirements for diagnosis include > 600,000 platelets/μL of blood (normal 150,000-400,000) and a 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...
biopsy. Some of the consequences of having such high numbers of platelets include thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
or clots throughout the body. Thrombi form more frequently in arteries than veins. Ironically, having platelet counts above 1,000,000 platelets/μL can lead to hemorrhagic events. Recent evidence suggests that the majority of ET cases are due to a mutation in the JAK2 protein, a member of the JAK-STAT pathway. Evidence suggests this mutation renders the megakaryocyte hypersensitive to thrombopoietin and causes clonal proliferation of megakaryocytes. There is a significant risk of transformation to leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
with this disorder. The primary treatment consists of anagrelide
Anagrelide
Anagrelide is a drug used for the treatment of essential thrombocytosis , or overproduction of blood platelets. It also has been used in the treatment of chronic myeloid leukemia. -Mechanism:...
or hydroxyurea
Hydroxyurea
Hydroxycarbamide or hydroxyurea is an antineoplastic drug, first synthesized in 1869, used in myeloproliferative disorders, specifically polycythemia vera and essential thrombocythemia...
to lower platelet levels.
Congenital amegakaryocytic thrombocytopenia (CAMT)
Congenital amegakaryocytic thrombocytopeniaThrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
(CAMT) is a rare inherited
Heredity
Heredity is the passing of traits to offspring . This is the process by which an offspring cell or organism acquires or becomes predisposed to the characteristics of its parent cell or organism. Through heredity, variations exhibited by individuals can accumulate and cause some species to evolve...
disorder. The primary manifestations are thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
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
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
including the cerebrum and cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
which could cause symptoms. The primary treatment for CAMT is bone marrow transplantation.
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.
One of the few non-medical research related sources on the web with some information on CAMT is:
There appears to be no generic resource for CAMT patients on the web and this is potentially due to the rariety of the disease.
External links
- Megakaryocytes: Mature Many microscopic images of mature megakaryocytes including in disease settings.
- Cell size comparison
- CAMT Specific Infant Bone Marrow Transplant Journal