Mast cell

A mast cell is a resident cell that develops and lives in connective tissue and contains many small secretory granules for the storage and release of histamine, heparin and other chemicals. A part of the immune and neuroimmune systems, a mast cell is a type of granulocyte derived from myeloid progenitor cells. Mast cells were discovered by Friedrich von Recklinghausen in 1863 and later rediscovered by Paul Ehrlich in 1877. Mast cells are best known for their roles in allergy, anaphylaxis, and atopic dermatitis. They also play an important protective role in the defense and repair of cells through wound healing, angiogenesis, vascular permeability, and responses to bacteria, other pathogens, and venoms.

Development

Mast cells are considered to have originated nearly 500 million years ago, in urochordates, making them one of the most ancient types of immune cells.
Mast cells are specialized immune cells derived through hematopoiesis, the formation of blood cell components. Mast cells develop from circulating mast cell progenitors. Once they are recruited to a given type of connective tissue, they specialize and become resident mast cells. Mature MCs exhibit context-specific modifications in their effector properties related to local tissue types and diseases.
Mast cells may have dual methods of origin in the hematopoietic system. In 1989, Leonore Herzenberg and Leonard Herzenberg proposed that different types of stem cells produce specific types of immune cells through multiple waves of development. Specific types of immune cells have been shown to arise sequentially at different points in embryonic development. The original layered immune theory proposed that hematopoietic stem cells were the basis for such development. In the classical sequence of hematopoiesis, hematopoietic stem cells were described as becoming multipotent progenitors, then differentiating into common myeloid progenitors, followed by granulocyte/monocyte progenitors. GMPs then differentiate into mast cells and basophils.
However, lineage relationships in human hematopoiesis have been hotly debated. Subsequent research suggests that multiple waves of immune cells develop through hematopoiesis from hemogenic endothelial cells, in an HSC-independent manner with HSCs arising in a final hematopoietic wave. Tissue-resident immune cells either may be fetal-derived or be the progeny of adult HSCs.
In vertebrates, the earliest source of mast cells is the extraembryonic yolk sac, where blood and immune cells first develop. However, there are differences in the embryonic development of vertebrates such as mice compared to primates. In primates, yolk sac formation involves a transient primary yolk sac, and the formation of extraembryonic mesoderm, prior to generation of a secondary yolk sac where the first blood cells of the embryo develop.
During embryonic development, mast cell progenitors form in a series of developmentally discrete waves. The first wave of mast cells in the embryo is derived from erythro-myeloid progenitors in the yolk sac, before hematopoietic stem cells emerge.
In mouse models, the earliest mast cell progenitors originate in the embryo around embryonic day 7. Transient erythro-myeloid progenitors develop in the yolk sac between E8.5-E10.5 and in fetal liver between E11.5-E13.5. Embryonic multipotent progenitors and hematopoietic stem cells emerge around E10.5. Mast cell differentiation in the fetal liver starts from E11, along with a peak in the number of mast cell progenitors. Mast cell progenitors then enter the circulation and seed other tissues including the brain, heart, lung, peritoneal cavity, skin, and, spleen, where they complete their maturation.
eMPPs and HSCs start producing mature hematopoietic cells in in the fetal liver around E12.5 and E14.5 respectively. HSCs can produce mast cells within a limited time window which declines after embryonic day E14.5.
Whether mast cell origination is mostly independent of HSCs, or "adult" mast cells originate in bone marrow from HSCs is debated. MC precursors of myeloid origin are found in bone marrow, but mature MCs are absent. Mast cells are easily generated from adult BM cells in vitro, but this has been less successful following HSC transplantation in vivo. It is unclear whether fetal-derived immune cells may be produced by HSCs during the fetal to neonatal period.
In humans, the first yolk sac-derived MCs originate from mesodermal precursors that form in blood islands of the yolk sac, starting around three weeks into gestation. From there, circulating progenitors migrate into peripheral tissues for complete differentiation and maturation. Hematopoietic progenitors subsequently differentiate into multiple lineages, including erythroid, lymphoid, megakaryocytic, and myeloid precursors, which emerge in the fetal liver. Immature MCs are activated by antigens and cytokines and become specialized in response to their resident environment. MCs become widely distributed throughout all tissues.
Sizeable populations of fetal‐derived MCs persist in connective tissue into adulthood, and appear to self‐maintain mostly independent of bone marrow.

Structure

Mast cells are highly versatile immune cells that first appear during fetal development. Individual mast cells likely reflect the processes by which they originally develop as well as the microenvironments where they mature.
Mast cell progenitors, sometimes referred to as "immature" mast cells, circulate in the bloodstream as undifferentiated mononuclear cells. Circulating progenitors are similar in size to lymphocytes, and have fewer granules than mature mast cells.
Circulating MC progenitors in human blood and in human bone marrow have been identified using the expression of the c-Kit marker and the CD34 marker. CD34 is a widely expressed cell surface antigen found in cells with both progenitor-like and mature properties, making it difficult to distinquish between origins.
Once mast cell progenitors reach a destination tissue, they mature into resident granulated mast cells. Mature mast cells are also mononuclear.
Mast cells are present in most tissues. and characteristically surround blood vessels, nerves and lymphatic vessels. They are especially prominent near the boundaries between the outside world and the internal milieu, such as the skin, mucosa of the lungs, and digestive tract, as well as the mouth, conjunctiva, and nose.
Mature resident mast cells are categorized based on their tissue location, granule protease content, and functional characteristics. In rodents, the two major categories of mature mast cells are connective tissue-resident mast cells and mucosal mast cells. Connective tissue mast cells contain heparin and large amounts of histamine and carboxypeptidase in their granules, and are distributed in the skin, peritoneal cavity, intestinal submucosa, and perivascular space around blood vessels. Mucosal mast cells predominantly contain chondroitin sulfate with small amounts of histamine and carboxypeptidase and are distributed in the mucosa of the lung and gastrointestinal tract.
In humans, three main categories of MCs have been identified based on the proteases they express.
MC_T expresses tryptase and resides primarily in mucosa of the lung and small intestine.
MC_TC expresses tryptase, chymase, and carboxypeptidase and resides primarily in the skin, lymph nodes, and lung and gut submucosa. ∼98% of all mast cells in the mucosa of the human small intestine are MC_T, while only ∼13% of MCs in submucosa are MC_T. A third form, MC_C, expresses chymase but not tryptase. MC_T somewhat resembles rodent MMC, while MC_TC somewhat resembles rodent CTMC. Mast cells are still heterogenous within these main categories. In humans, at least six possible subsets of MCs with consistently expressed genes have been observed across twelve organs. Some of these appear to be preferentially distributed.

Function

Mast cells are best known for their roles in allergy, anaphylaxis, and atopic dermatitis. They also play an important protective role in the defense and repair of cells through wound healing, angiogenesis, vascular permeability, and
responses to bacteria, other pathogens, and venoms.
Mast cells are seen as "first responders" that deal with pathogens by alerting other immune cells and coordinating immune responses in the innate and acquired immune systems. When activated, a mast cell can either selectively release or rapidly release compounds or "mediators" from storage granules into the local microenvironment. Mast cells can be stimulated to degranulate by allergens through cross-linking with immunoglobulin E receptors, physical injury through pattern recognition receptors for damage-associated molecular patterns, microbial pathogens through pattern recognition receptors for pathogen-associated molecular patterns, and various compounds through their associated G-protein coupled receptors or ligand-gated ion channels. Complement proteins can activate membrane receptors on mast cells to exert various functions as well.
Mast cells express a high-affinity receptor for the Fc region of IgE, the least-abundant member of the antibodies. This receptor is of such high affinity that binding of IgE molecules is in essence irreversible. As a result, mast cells are coated with IgE, which is produced by plasma cells. IgE antibodies are typically specific to one particular antigen.
In allergic reactions, mast cells remain inactive until an allergen binds to IgE already coated upon the cell. Other membrane activation events can either prime mast cells for subsequent degranulation or act in synergy with FcεRI signal transduction. In general, allergens are proteins or polysaccharides. The allergen binds to the antigen-binding sites, which are situated on the variable regions of the IgE molecules bound to the mast cell surface. It appears that binding of two or more IgE molecules is required to activate the mast cell. The clustering of the intracellular domains of the cell-bound Fc receptors, which are associated with the cross-linked IgE molecules, causes a complex sequence of reactions inside the mast cell that lead to its activation. Although this reaction is most well understood in terms of allergy, it appears to have evolved as a defense system against parasites and bacteria.
Mast cells have been shown to form mast cell extracellular traps to entrap and kill microbes. In a multistage process, MCs become activated, the nuclear membrane disintegrates, chromatin is released into the cytoplasm, cytoplasmic granules adhere to an emerging DNA web, and the complex is released into the extracellular space.