myofibroblasts
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A myofibroblast is a cell
phenotype right , Here the relation between genotype and phenotype is illustrated, using a Punnett square, for the character of petal color in pea plants. The letters B and b represent genes for color, and the pictures show the resultant phenotypes. Thi ...

phenotype
that was first described as being in a state between a
fibroblast A fibroblast is a type of biological cell The cell (from Latin ''cella'', meaning "small room") is the basic structural, functional, and biological unit of all known organisms. Cells are the smallest units of life, and hence are often referred ...

fibroblast
and a
smooth muscle Smooth muscle is an involuntary non-striated muscle. It is divided into two subgroups; the single-unit smooth muscle, single-unit (unitary) and multiunit smooth muscle. Within single-unit cells, the whole bundle or sheet Muscle contraction, contra ...

smooth muscle
cell.


Structure

Myofibroblasts are contractile web-like fusiform cells that are identifiable by their expression of α-smooth muscle actin within their cytoplasmic stress fibers. In the gastrointestinal and genitourinary tracts, myofibroblasts are found subepithelially in mucosal surfaces. Here they not only act as a regulator of the shape of the crypts and villi, but also act as stem-niche cells in the intestinal crypts and as parts of atypical antigen-presenting cells. They have both support as well as paracrine function in most places.


Location

Myofibroblasts were first identified in granulation tissue during skin wound healing. Typically, these cells are found in granulation tissue, scar tissue (fibrosis) and the stroma of tumours. They also line the gastrointestinal tract, wherein they regulate the shapes of crypts and villi.


Markers

Myofibroblasts usually stain for the intermediate filament
vimentin Vimentin is a structural protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, incl ...

vimentin
, which is a general mesenchymal marker, α-smooth muscle actin (human gene = ''
ACTA2 ACTA2 (actin alpha 2) is an actin Actin is a family In human society, family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity (by marriage or other relationship). The purpose of ...
''), and for palladin, which is a cytoskeletal actin
scaffold protein 300px, Function of scaffold proteins In biology, scaffold proteins are crucial regulators of many key signalling pathways. Although scaffolds are not strictly defined in function, they are known to interact and/or bind with multiple members of a s ...
. They are positive for other smooth muscle markers, such as intermediate filament type
desmin Desmin is a protein that in humans is encoded by the ''DES'' gene. Desmin is a muscle-specific, type III intermediate filament that integrates the sarcolemma, sarcomere#Bands, Z disk, and nuclear membrane in sarcomeres and regulates sarcomere archit ...
in some tissues, but may be negative for desmin in other tissues. Similar heterogeneous positivity may exist for almost every smooth muscle marker except probably a few which are positive only in contractile smooth muscles like metavinculin and smoothelin. Myofibroblasts upregulate the expression of
fibronectin Fibronectin is a high- molecular weight (~500 kDa) glycoprotein Glycoproteins are protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid residue (biochemistry), residues. Prote ...

fibronectin
,
collagen Collagen () is the main structural in the found in the body's various s. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole-body protein content. Collagen consists of ...

collagen
s, and
hyaluronic acid Hyaluronic acid (; abbreviated HA; conjugate base A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid donates a proton ( H+) to a base—in other words, it is a base with a hydrogen ...

hyaluronic acid
during and after their differentiation from fibroblasts. Among these, the EDA isoform of fibronectin (EDA-FN), and collagen type I (Collagen, type I, alpha 1, COL1A1/Collagen, type I, alpha 2, COL1A2) are typical markers of myofibroblast-dependent synthesis of pro-fibrotic extracellular matrix. Some myofibroblasts (especially if they have a stellate form) may also be positive for glial fibrillary acidic protein, GFAP.


Development

There are many possible ways of myofibroblast development: #Partial smooth muscle Cellular differentiation, differentiation of a fibroblastic cell #Activation of a stellate cell (e.g. Hepatic stellate cell, hepatic Ito cells or pancreatic stellate cells). #Loss of contractile phenotype (or acquisition of "synthetic phenotype") of a smooth muscle cell. #Direct myofibroblastic differentiation of a progenitor cell resident in a stromal tissue. #Homing and recruitment of a circulating mesenchymal precursor which can directly differentiate as above or indirectly differentiate through the other cell types as intermediates. #Epithelial to mesenchymal transdifferentiation (Epithelial–mesenchymal transition, EMT) of an epithelial cell. Perhaps the most well studied pathway of myofibroblast formation, is TGF beta 1, TGF-beta1 dependent differentiation from
fibroblast A fibroblast is a type of biological cell The cell (from Latin ''cella'', meaning "small room") is the basic structural, functional, and biological unit of all known organisms. Cells are the smallest units of life, and hence are often referred ...

fibroblast
cells. Activation of the TGF beta receptor 1, TGF-beta receptor 1 and TGF beta receptor 2, TGF-beta receptor 2 leads to induction of the canonical SMAD2/Smad3, SMAD3 pathway. Together with the co-activation of the non-canonical EGFR (gene), EGFR pathway, these events lead to upregulation of the ''
ACTA2 ACTA2 (actin alpha 2) is an actin Actin is a family In human society, family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity (by marriage or other relationship). The purpose of ...
'' gene and subsequent alpha smooth muscle actin protein production. Several regulators of the myofibroblast differentiation pathway have been described, including Hyaluronic acid, hyaluronan and CD44 co-receptor activation of EGFR.


Function

In many organs like liver, lung, and kidney they are primarily involved in fibrosis. In the wound tissue they are implicated in wound strengthening by extracellular collagen fiber deposition and then wound contraction by intracellular contraction and concomitant alignment of the collagen fibers by integrin-mediated pulling on to the collagen bundles. Pericytes and renal mesangial cells are some examples of modified myofibroblast-like cells. Myofibroblasts may interfere with the propagation of electrical signals controlling heart rhythm, leading to Heart arrhythmia, arrhythmia in both patients who have suffered a heart attack and in foetuses. Ursodiol is a promising drug for this condition.BBC News
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Wound healing

Myofibroblasts can contract by using smooth muscle type actin-myosin complex, rich in a form of actin called alpha-smooth muscle actin. These cells are then capable of speeding wound repair by contracting the edges of the wound. Early work on wound healing showed that granulation tissue taken from a wound could contract ''in vitro'' (or in an organ bath) in a similar fashion to smooth muscle, when exposed to substances that cause smooth muscle to contract, such as adrenaline or angiotensin. More recently it has been shown that fibroblasts can transform into myofibroblasts with photobiomodulation. After healing is complete, these cells are lost through apoptosis and it has been suggested that in several fibrotic diseases (for example liver cirrhosis, kidney fibrosis, retroperitoneal fibrosis) that this mechanism fails to work, leading to persistence of the myofibroblasts, and consequently expansion of the extracellular matrix (fibrosis) with contraction. Similarly, in wounds that fail to resolve and become keloids or hypertrophic scars, myofibroblasts may persist, rather than disappearing by apoptosis.


See also

*List of human cell types derived from the germ layers


References


External links

* {{Authority control Animal cells Contractile cells