8. The Extracellular Matrix PDF

Cytoskeleton summary Watch: https://www.youtube.com/watch?v=YTv9ItGd050  Lecture 8. The Extracellular Matrix 8. The Extracellular Matrix The Extracellular Matrix. a. Structure and Function. b. Glycosaminoglycans. c. Collagen. Elastin d. Fibronectin. Basal Lamina...

Cytoskeleton summary Watch: https://www.youtube.com/watch?v=YTv9ItGd050  Lecture 8. The Extracellular Matrix 8. The Extracellular Matrix The Extracellular Matrix. a. Structure and Function. b. Glycosaminoglycans. c. Collagen. Elastin d. Fibronectin. Basal Lamina and Laminins. e. Integrins.  8. The Extracellular Matrix Structure o The cells in tissues of multicellular organisms are embedded in an extracellular matrix consisting of secreted proteins and polysaccharides. o The extracellular matrix fills the spaces between cells and binds cells and tissues together.  8. The Extracellular Matrix Structure o The extracellular matrix differs between tissues.  8. The Extracellular Matrix Structure o In epithelial tissues, o EM is less pronounced, cells are tightly bound together, cell-cell junctions. o Basal lamina: thin, sheetlike extracellular matrix, upon which layers of epithelial cells rest. It also surrounds muscle cells, adipose cells, and peripheral nerves.  8. The Extracellular Matrix Structure o In connective tissues, o EM is more abundant, beneath epithelial cell layers. o In bone, tendon, and cartilage EM is principally responsible for their structure and function.  8. The Extracellular Matrix Structure  8. The Extracellular Matrix Function o The extracellular matrix regulates a number of cellular functions such as: o Adhesion o Migration o Proliferation o Differentiation o Shape o Survival o Structural support  8. The Extracellular Matrix Structure o The extracellular matrix regulates a number of cellular functions such as: 1. Adhesion 2. Migration  8. The Extracellular Matrix Neutrophil chemotaxis https://www.youtube.com/watch?v=ZUUfdP87Ssg  8. The Extracellular Matrix Neutrophil phagocytosis https://www.youtube.com/watch?v=Z_mXDvZQ6dU  8. The Extracellular Matrix Wound repair and fibroblast migration https://www.youtube.com/watch?v=GF78ZhE5Fy8  8. The Extracellular Matrix Structure o The extracellular matrix regulates a number of cellular functions such as: 1. Adhesion 2. Migration 3. Proliferation 4. Differentiation 5. Shape 6. Survival 7. Structural support  8. The Extracellular Matrix Macromolecules  Glycosaminoglycans (GAG) and proteoglycan  Fibrous structural proteins:  Collagen  Elastin  Adhesion proteins:  Fibronectin  Laminin  8. The Extracellular Matrix Glycosaminoglycans o GAGs consist of polysaccharide chains composed of repeating units of disaccharides, forming gels. 1. N-acetylglucosamine or N-acetylgalactosamine (in most cases is sulfated). 2. Acid (either glucuronic acid or iduronic acid).  8. The Extracellular Matrix Glycosaminoglycans Major types of glycosaminoglycans: - Hyaluronic acid - Chondroitin sulfate and dermatan sulfate - Heparan sulfate and heparin - Keratan sulfate  8. The Extracellular Matrix Glycosaminoglycans o GAGs are highly negatively charged and bind positively charged ions and trap water molecules to form hydrated gels, thereby providing mechanical support to the extracellular matrix.  8. The Extracellular Matrix Glycosaminoglycans Hyaluronic acid o It’s a high-molecular-mass polysaccharide found in the extracellular matrix, especially of soft connective tissues. o It’s a single long polysaccharide chain, with no sulfated sugars and not attached to proteins.  8. The Extracellular Matrix Glycosaminoglycans Hyaluronic acid Homeostasis, any self- regulating process by o Physiological functions: which biological systems tend to maintain stability o Role in resisting compressive while adjusting to forces in joints and tissues conditions that are optimal o Water and plasma protein for survival. homeostasis HA provides an open o Mitosis hydrated matrix, a cell-free o Locomotion space, that facilitates o Cell migration these processes. o Development and differentiation  8. The Extracellular Matrix Glycosaminoglycans o GAGs (except hyaluronic acid) are linked to proteins to form proteoglycans. o Proteoglycans can contain as few as one or as many as more than a hundred GAGs chains attached to serine residues of a core protein. o The proteoglycans are a diverse group of macromolecules. o Some proteoglycans are cell surface proteins that function in cell adhesion.  8. The Extracellular Matrix Proteoglycans  8. The Extracellular Matrix Proteoglycans o Aggrecan is the major proteoglycan of cartilage. Bovine Cartilage Aggrecan  8. The Extracellular Matrix Glycosaminoglycans  8. The Extracellular Matrix Macromolecules  Glycosaminoglycans (GAG) and proteoglycan  Fibrous structural proteins:  Collagen  Elastin  Adhesion proteins:  Fibronectin  Laminin  8. The Extracellular Matrix Collagen o Is the most abundant protein in animal tissues. o The major structural protein of the extracellular matrix. o Provides strength. o Structure: - three polypeptide chains are wound tightly around one another in a ropelike structure (triple helices). - repeats of the amino acid sequence Gly-X-Y, in which X is frequently proline and Y is frequently hydroxyproline (Hyp).  8. The Extracellular Matrix Collagen Types of collagen: o Fibril-forming collagens. o Fibril-associated collagens, which bind to the surface of collagen fibrils and link them both to one another and to other matrix components. o Network-forming collagen (Basal lamina). o Anchoring fibrils, which link some basal lamina to underlying connective tissues.  8. The Extracellular Matrix o The collagens are a large family of proteins. o The most abundant is type I collagen, one of the fibril-forming collagens that are the basic structural components of connective tissues.  8. The Extracellular Matrix Fibril-forming collagens o Three polypeptide chains coil around one another in a characteristic triple helix structure. o Collagen molecules assemble in a regular staggered array to form fibrils.  8. The Extracellular Matrix Fibril-forming collagens  8. The Extracellular Matrix Fibril-forming collagens o After being secreted from the cell, these collagens assemble into collagen fibrils in which the triple helical molecules are associated in regular staggered arrays.  8. The Extracellular Matrix Fibril-forming collagens o This reaction places stable crosslinks within (intramolecular crosslinks) and between the molecules (intermolecular crosslinks). o Gives the collagen fibers such tremendous strength.  8. The Extracellular Matrix Collagen IX (fibril-associated) o The location of collagen IX molecules on fibril surfaces represent macromolecular bridges between fibrils and other matrix components in cartilage. o Collagen IX is important for the cohesive and compressive properties of cartilage.  8. The Extracellular Matrix Network-forming collagen o Collagen IV is a type of collagen found primarily in the basal lamina.  8. The Extracellular Matrix Collagen-related diseases o Wide spectrum of diseases caused by the more than 1,000 mutations in collagen genes  Critical role of collagens  8. The Extracellular Matrix Elastin o Elastic fibers are composed principally of a protein called elastin. o It’s crosslinked into a network by covalent bonds formed between the side chains of lysine residues. o It’s formed as a highly disordered polypeptide, which is essential for its function.  8. The Extracellular Matrix Elastin o This network of crosslinked elastin chains behaves like a rubber band, stretching under tension and then snapping back when the tension is released.  8. The Extracellular Matrix Elastin o Connective tissues contain elastic fibers, which are particularly abundant in organs that regularly stretch and then return to their original shape. Elastin is the dominant extracellular matrix protein in arteries.  8. The Extracellular Matrix Elastin o The lungs, for example, stretch each time a breath is inhaled and return to their original shape with each exhalation.  8. The Extracellular Matrix Fibrous structural proteins o Collagen fibers are present to prevent elastic tissue breakdown. Strength Resilience  8. The Extracellular Matrix Macromolecules  Glycosaminoglycans (GAG) and proteoglycan  Fibrous structural proteins:  Collagen  Elastin  Adhesion proteins:  Fibronectin  Laminin  8. The Extracellular Matrix Cell adhesion proteins The role of cell adhesion proteins o Establishing the architecture of extracellular matrices o Attaching to the surface of cells o Cell motility o Cell growth o Cell differentiation  8. The Extracellular Matrix Fibronectin o Fibronectin is the principal adhesion protein of connective tissues. o Fibronectin is a dimeric glycoprotein consisting of two polypeptide chains. attachment of cells to the extracellular disulfide matrix bonds  8. The Extracellular Matrix Fibronectin Fibronectin regulates: Morphology Cell organization The orientation of the fibronectin will cause: Alignment of the actin cytoskeleton A reorientation of the cell itself The interaction between the EM and the cytoskeleton is reciprocal.  8. The Extracellular Matrix Fibronectin o Tension exerted by cells regulates the assembly of fibronectin fibrils. Fibronectin Actin (EM) (intracellular)  8. The Extracellular Matrix Basal lamina o Basal lamina, a specialized form of extracellular matrix, contains a distinct adhesion protein called laminin.  8. The Extracellular Matrix Basal lamina o The basal lamina can be organized in three ways: 1. It can surround cells. 2. It lies underneath sheets of epithelial cells. 3. It separates two sheets of cells. This type of arrangement is found in the kidney glomerulus, where the basal lamina acts as a selective permeable barrier.  8. The Extracellular Matrix Basal lamina Mechanical barrier Filtration function  8. The Extracellular Matrix Basal lamina o Laminin consists of three polypeptide chains. Binding sites for nidogen, type IV collagen, proteoglycans, and cell surface receptors.  8. The Extracellular Matrix Basal lamina. Laminin. 1. Can self-assemble into meshlike polymers. 2. Have binding sites for cell surface receptors, type IV collagen, and the proteoglycan perlecan. 3. Are tightly associated with another glycoprotein, called entactin or nidogen, which also binds to type IV collagen. 4. These multiple interactions form crosslinked networks in the basal lamina.  8. The Extracellular Matrix Basal lamina A highly crosslinked network  8. The Extracellular Matrix Basal lamina o In some multilayered epithelia, such as the stratified squamous epithelium that forms the epidermis of the skin, the basal lamina is attached to the underlying connective tissue by specialized anchoring fibrils made of type VII collagen molecules. o The term basement membrane is often used to describe the composite of the basal lamina and this layer of collagen fibrils.  8. The Extracellular Matrix Basal lamina o The basement membrane acts as a mechanical barrier, preventing malignant cells from invading the deeper tissues.  8. The Extracellular Matrix Basal lamina Tissue regeneration  8. The Extracellular Matrix The Extracellular matrix: degradation and remodeling o Is a highly dynamic structure, constantly undergoing a remodeling process where ECM components are deposited, degraded, or otherwise modified. o ECM dynamics are indispensible during restructuring of tissue architecture. o Regulates cell differentiation, the establishment and maintenance of stem cell niches, morphogenesis, angiogenesis, bone remodeling, and wound repair. o Abnormal ECM dynamics lead to deregulated cell proliferation and invasion, failure of cell death, and loss of cell differentiation, resulting in congenital defects and pathological processes including tissue fibrosis and cancer.