Extracellular matrix- Composition

Composition of the ECM

Fibrous structural proteins.

Glycosaminoglycans (Gags) and proteoglycans.

Cell adhesion proteins.



Fibrous structural proteins
Ex. Collagens and elastins that provide tensile strength and recoil.
Collagen
Collagen is the most common protein providing the extracellular framework for all multicellular organisms.

There are 27 different types of collagens encoded by 41 genes dispersed on at least 14 chromosomes are known.






Types I, II, III and V, and XI; these proteins are found in extracellular fibrillar structures.

Type IV collagens; they are the main components of the basement membrane, together with laminin.

Another collagen with a long interrupted triple-helical domain (type VII) forms the anchoring fibrils between some epithelial and mesenchymal structures, such as epidermis and dermis.


Vitamin C is required for the hydroxylation of procollagen, a requirement that explains the inadequate wound healing in scurvy.

Genetic defects in collagen production cause many inherited syndromes, including various forms of the Ehlers-Danlos syndrome and osteogenesis imperfecta

Elastin, fibrillin, and elastic fibers
Tissues such as blood vessels, skin, uterus, and lung require elasticity for their function. Proteins of the collagen family provide tensile strength, but the ability of these tissues to expand and recoil (compliance) depends on the elastic fibers.

Morphologically, elastic fibers consist of a central core made of elastin, surrounded by a peripheral network of microfibrils.
Substantial amounts of elastin are found in the walls of large blood vessels, such as the aorta, and in the uterus, skin, and ligaments.

2. Cell adhesion proteins

Most adhesion proteins, also called CAMs (cell adhesion molecules), can be classified into four main families:
Immunoglobulin family CAMs.
Cadherins.
Integrins.
Selectins.

Fibronectin

is a large protein that binds to many molecules, such as collagen, fibrin, proteoglycans, and cell surface receptors.

Fibronectin two forms, tissue fibronectin and plasma fibronectin.

The plasma form binds to fibrin, helping to stabilize the blood clot that fills the gaps created by wounds, and serves as a substratum for ECM deposition and formation of the provisional matrix during wound healing.


3. Glycosaminoglycans (gags) and proteoglycans

ECM, besides the fibrous structural proteins and cell adhesion proteins.

Most of GAGs are linked to a core protein, forming molecules called proteoglycans.

Four structurally distinct families of GAGs:

Heparan sulfate.
Chondroitin/dermatan sulfate.
Keratan sulfate.
Hyaluronan (HA).



Repair by connective tissue deposition includes the following basic features:

Inflammation
Angiogenesis
Migration and proliferation of fibroblasts
Scar formation
Connective tissue remodeling.


Mechanisms of angiogenesis
Angiogenesis is a fundamental process that affects physiologic reactions (e.g. wound healing, regeneration, the vascularization of ischemic tissues, and menstruation), and pathologic processes, such as tumor development and metastasis, diabetic retinopathy, and chronic inflammation.


Blood vessels are assembled during embryonic development by vasculogenesis, in which a primitive vascular network is established from endothelial cell precursors (angioblasts), or from dual hemopoietic/endothelial cell precursors called hemangioblasts.
Blood vessel formation in adults, known as angiogenesis or neovascularization, involves the branching and extension of adjacent pre-existing vessels, but it can also occur by recruitment of endothelial progenitor cells (EPCs) from the bone marrow.

Vasodilation in response to nitric oxide, and VEGF-induced increased permeability of the preexisting vessel
Proteolytic degradation of the basement membrane of the parent vessel by matrix metalloproteinases (MMPs) and disruption of cell-to-cell contact between endothelial cells by plasminogen activator
Migration of endothelial cells toward the angiogenic stimulus
Proliferation of endothelial cells, just behind the leading front of migrating cells
Maturation of endothelial cells, which includes inhibition of growth and remodeling into capillary tubes
Recruitment of periendothelial cells (pericytes and vascular smooth muscle cells) to form the mature vessel


Angiogenesis from Endothelial Precursor Cells (EPCs).
EPCs can be recruited from the bone marrow into tissues to initiate angiogenesis. The nature of the homing mechanism is uncertain.
These cells express some markers of hematopoietic stem cells as well as VEGFR-2, and vascular endothelial–cadherin (VE-cadherin).
EPCs may contribute to the re-endothelization of vascular implants and the neovascularization of ischemic organs, cutaneous wounds, and tumors.
The number of circulating EPCs increases greatly in patients with ischemic conditions, suggesting that EPCs may influence vascular function and determine the risk of cardiovascular diseases.


Provisional Matrix
Provisional matrix is a term that describes the temporary extracellular organization of plasma-derived matrix proteins and tissue-derived components that accumulate at sites of injury.

They also support the migration of monocytes, endothelial cells, epidermal cells, and fibroblasts to the wound site. Plasma-derived provisional matrix proteins include fibrinogen, fibronectin, and vitronectin.
These proteins become insoluble by binding to the stromal matrix and by forming cross-links via the action of tissue- and plasma-derived transglutaminases.


Granulation Tissue
Granulation tissue is the transient, specialized tissue of repair, which replaces the provisional matrix.
On gross examination, it is simple, with a glistening appearance.
Microscopically, a mixture of fibroblasts and red blood cells first appears, followed by the development of provisional matrix and patent single cell-lined capillaries, which are surrounded by fibroblasts and inflammatory cells.


Summary of the healing process.
The initial phase of the repair reaction, which typically begins with hemorrhage into the tissues.
A fibrin clot forms and fills the gap created by the wound.
Macrophages recruited to the wound area process cell remnants and damaged extracellular matrix.
Fibronectin, cell debris, and bacterial products are chemoattractants for a variety of cells that are recruited to the wound site (2 to 4 days).
As a new extracellular matrix is deposited at the wound site, the initial fibrin clot is lysed by a combination of extracellular proteolytic enzymes and phagocytosis (2 to 4 days).
Concurrent with fibrin removal, there is deposition of a temporary matrix formed by proteoglycans, glycoproteins, and type III collagen (2 to 5 days).
Final phase of the repair reaction. Eventually, the temporary matrix is removed by a combination of extracellular and intracellular digestion, and the definitive matrix, rich in type I collagen, is deposited (5 days to weeks).