EXTRACELLULAR MATRIX AND ITS COMPONENTS

ECM AND ITS COMPONENTS

1. Extracellular Matrix and Its Components ECM

2. Extracellular matrix (ECM) Extracellular matrix (ECM) is a network of extracellular macromolecules, such as collagen, enzymes, and glycoproteins, that provide structural and biochemical support to surrounding cells ECM includes the interstitial matrix and the basement membrane Gels of polysaccharides and fibrous proteins fill the interstitial space This gel act as a compression buffer against the stress placed on the ECM

3. General Structure of Extracellular Matrix Animal cells embedded in an extracellular matrix Basal laminae: thin layer on which epithelial cells rest. Also surrounds muscle cells, adipose cells, and peripheral nerves most abundant in connective tissues Connective tissue loose connective tissue Bone tendon cartilage

4. Extracellular matrix (ECM) Extracellular matrix (ECM) is a network of interstitial proteins that constitutes a significant proportion of any tissue. ilIustration depicting extracellular matrix in relation to epithelium, endothelium and connective tissue

5. FUNCTIONS OF ECM Mechanical support- For cell anchorage and cell migration, and maintenance of cell polarity. Control of cell proliferation- By acting as a depot of latent growth factors, binding and displaying growth factors, and signaling through cellular receptors. Scaffolding for tissue renewal- Integrity of ECM is critical for the organized regeneration of tissues. So ECM disruption results in defective tissue regeneration and repair ( eg . Cirrhosis of Liver).

6. FUNCTIONS OF ECM Establishment of tissue microenvironments- Basement membrane acts as boundary between epithelium and connective tissue, and is also functional. Cellular interaction- For maintaining normal tissue architecture.

7. ECM is important for cell adhesion and serve as a reservoir for growth factors, thus, ECM regulates the proliferation, movement, and differentiation of the cells living within it. Synthesis and degradation of ECM accompanies morphogenesis, wound healing, chronic fibrotic processes, and tumor invasion and metastasis

8. TWO BASIC FORMS OF ECM ECM occurs in two basic forms: interstitial matrix and basement membrane 1- Interstitial Matrix: present in the spaces between cells in connective tissue; it is synthesized by mesenchymal cells (e.g., fibroblasts) and tends to form a three-dimensional, amorphous gel. Its major constituents are fibrillar and nonfibrillar collagens, as well as fibronectin , elastin, proteoglycans, hyaluronate , and other elements

9. The basement membrane: lies beneath the epithelium It is synthesized by overlying epithelium and underlying mesenchymal cells Its major constituents are amorphous nonfibrillar type IV collagen and laminin

10. COMPONENTS OF ECM Components of ECM are categorized into 3 groups of proteins; 1) Fibrous structural proteins- Collagens, Elastins & Fibrillin . Confer tensile strength and recoil. 2) Water-hydrated gels- Proteagylcans & Hyaluronan Permit compressive resistance and lubrication. 3) Adhesive gl roteins & r y- F bronectin , Laminin & integan Connect ECM elements to one another and to cells. 4) Water - 65%

11. Collagens Collagens are fibrous structural proteins that confer tensile strength. Collagens are composed of three separate polypeptide chains braided into a ropelike triple helix. About 30 collagen types have been identified Some collagen types (e.g., types I, II, III, and V) form fibrils by virtue of lateral cross-linking of the triple helices. These are called the fibrillarcollagens , and form a major proportion of the connective tissue in healing wounds and particularly in scars Other collagens are nonfibrillar and present in basement membrane (type IV) The tensile strength of the fibrillar collagens derives from their cross-linking, which is the result of covalent bonds. This process is dependent on vitamin C; therefore, children with vitamin C deficiencyhave skeletal deformities, bleed easily because of weak vascular wall basement membrane, and heal poorly

12. Elastin   the ability of tissues to recoil and return to a baseline structure after physical stress is conferred by elastic tissue. This is especially important in the walls of: vessels , the uterus, skin, and ligaments.

13. Proteoglycans and Hyaluronan   Proteoglycans form highly hydrated compressible gels conferring resilience and lubrication (such as in the cartilage in joints). They consist of long polysaccharides called glycosaminoglycans (examples are dermatan sulfate and heparan sulfate) linked to a protein backbone. Hyaluronan a huge molecule composed of many disaccharide repeats without a protein core, is also an important constituent of the ECM. Because of its ability to bind water, it forms a viscous, gelatin-like matrix

14. Adhesive glycoproteins and adhesion receptors  Adhesive glycoproteins and adhesion receptors  are structurally diverse molecules involved in cell-to-cell adhesion, the linkage between cells and ECM, and binding between ECM components. The adhesive glycoproteins include fibronectin (major component of the interstitial ECM) and laminin (major constituent of basement membrane). The adhesion receptors, also known as cell adhesion molecules (CAMs), are grouped into four families: immunoglobulins , cadherins , selectins , and integrins

15. Fibronectin   Fibronectin is a large disulfide-linked heterodimer synthesized by a variety of cells, including fibroblasts, monocytes, and endothelium. Main adhesion protein of connective tissue Fibronectins can bind to a wide spectrum of ECM components (e.g., collagen, fibrin, heparin, and proteoglycans) and can also attach to cell integrins . Fibronectin mRNA has two splice forms, which generate: 1- tissue fibronectin forms fibrillar aggregates at wound healing sites 2- plasma fibronectin binds to fibrin to form the provisional blood clot of a wound, which serves as a base for ECM deposition and re-epithelialization

16. Laminin  Laminin is the most abundant glycoprotein in basement membrane. Adhesion protein of basal laminae connects cells to underlying ECM components such as type IV collagen and heparan sulfate, mediating attachment to basement membrane. laminin can also modulate cell proliferation, differentiation, and motility.

17. Cell-Matrix Interactions   Integrins : major cell surface receptors, involved in attachment of cells to the extracellular matrix Transmembrane proteins, heterodimer of α and β subunits (18 α, 8β) Bind to short aa in, Collagen Fibronectin laminin also anchor the cytoskeleton to the extracellular matrix

18. Cell-Matrix Junctions   Two types of cell-matrix junction Focal adhesions: bundles of actin filaments are anchored to β subunits of integrins via α- actinin Vinculin via talin Assembly of focal adhesions Focal complex: small group of integrins RecruiteTalin , Vinculin , α- actinin and Formin Formin initiates actin bundles

19. Focal adhesions are reversible   Integrins can reversibly bind matrix components change conformation between active and inactive states Inactive state: integrin heads turned close to cell surface Cell signaling extends heads to matrix Migrating cells: focal adhesions form at the leading edge

20. Cell-Matrix Junctions: Hemidesmosomes Hemidesmosomes anchor epithelial cells to the basal lamina α6 β4 integrins bind to lamins long cytoplasmic tail of β subunit binds to intermediate filaments via Plectin and BP230 and BP180 (similar to transmembrane collagens)