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MIT 20 441J - Structure and function of naturally occurring extracellular matrices

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2.79J/3.96J/20.441J/HST522J Biomaterials-Tissue Interactions Phenotype change: fibroblast α2β1 integrin binds to collagen ligand GFOGER (hexapeptide)The Extracellular Matrices (ECMs) (summary of structure and function)The Extracellular Matrices… (summary of structure and function)The major ECM molecules in tissuesThe Extracellular Matrices. Part I. CollagensHierarchy of structural order in proteinsHierarchy of structural order in proteins (cont.)Collagens Collagens (cont.) (most fibrous collagens) Collagen structure-function relations Collagen structure-function relations (cont.)The Extracellular Matrices Part II.Elastin fibersThe Hydrophobic bondProteoglycans (PGs) and glycosaminoglycans (GAGs)Cell-adhesion molecules12.79J/3.96J/20.441J/HST522JBiomaterials-Tissue InteractionsStructure and function of naturally occurring extracellular matrices (ECMs).2The insoluble regulator in a unit cell process is part of an ECM macromoleculeCell +InsolubleRegulatorProductSolubleRegulator ASolubleRegulator BControl volume dVUnit cell process confined conceptually in a control volume dV3100 μm 100 μm A biologically active model of ECMacts as an insoluble regulator of cell function4Integrin adhesion to collagen at the GFOGER ligandEmsley et al., 2000Knight et al., 2000Phenotype change: fibroblast α2β1 integrin binds to collagen ligand GFOGER (hexapeptide)Courtesy of Elsevier, Inc., http://www.sciencedirect.com.Used with permission.5The Extracellular Matrices (ECMs) (summary of structure and function) Insoluble macromolecular networks.  Structure varies with organ; but different ECMs comprise few types of macromolecules (mostly collagen, elastin, proteoglycans) plus water (65%). ECM does not migrate, proliferate, synthesize proteins or contain DNA! Give and take of signals with cells. Ligands on ECM surface interact specifically with cell receptors (integrins).  Partly determine the state of differentiation of cells.6The Extracellular Matrices…(summary of structure and function) Possibly play role of memory storage device which is used to record events (e.g., a recent cell migration), thereby informing cells of what has already been done and acting as “arrow” in a kinetic process.  Often bind cytokines and growth factors and act as reservoirs of such molecules. Loss of cell-matrix contact characterizes tumor cells just prior to spreading of cancer from one organ to another (metastasis). Determines the shape of animals and maintains positional homeostasis of organs. Recently, certain synthetic ECM models have induced organ regeneration in adults.7The major ECM molecules in tissues1. Collagens.2. Elastin.3. Proteoglycans and glycosaminoglycans (GAGs).4. Cell-adhesion molecules (fibronectin, laminin, others).[Water (about 65% of tissue weight).]8Schematic view of ECMFigure by MIT OpenCourseWare. After Ricci.9The Extracellular Matrices. Part I. Collagens10Hierarchy of structural order in proteinsPrimary structure: the complete sequence of amino acids (AA) in the polypeptide chain. Scale: 1 nm. Secondary structure: the local chain configuration (sequence of 3 - 5 AA). Scale: 10 nm. Tertiary structure: the configuration of the entire macromolecule. Scale: 100 nm.11Hierarchy of structural order in proteins (cont.)Quaternary structure: The packing pattern of several identical molecules that characterizes a crystalline fiber. Scale: 1000 nm = 1 μm. Architecture: Pattern comprising several fibers of a protein that constitute a macroscopic tissue. Often contains fibers of two different proteins (collagen and elastin) and one or more proteoglycan molecules. Scale: 1-10 mm.12Collagens(most fibrous collagens)Primary structure: Glycine “hinge” every third AA makes polypeptide chains capable of rotation. Hydroxyproline (25% of total AA content) stiffens polypeptide chains. Varies with organ; several such “collagens” have been identified. Fibrous collagens to be discussed here only.Secondary structure: Combination of hinge-like glycine and stiff hydroxyproline units, leads to helical macromolecule with sharp pitch.13Tertiary structureCollagens (cont.)(most fibrous collagens): Three helical polypeptide units twist to form a triple-helical collagen molecule: a molecular “rope” which has some bending stiffness and does not undergo rotation. Quaternary structure: Several collagen molecules pack side-by-side in a highly specific register to give a crystalline fiber with a 64-nm periodicity (collagen banding pattern).The architecturalstructure of collagen is uniaxial orientation in tendon, biaxial orientation in the dermis, etc. It determines the mechanical behavior of the tissue.14COLLAGEN STRUCTUREPrimarySecondaryTertiaryQuaternary bandingDiagram removed due to copyright restrictions.15Collagen structureElectron microscopyImages removed due to copyright restrictions.16Cross-linking of collagen moleculesDiagram removed due to copyright restrictions.Formation of intramolecular and intermolecular cross-links in type I collagen.17Collagen structure-function relations• The primary structure of collagen is tissue-specific. Type I in tendon, type II in cartilage, etc.• The secondary and the tertiary structures are specific substrates for the metalloprotein enzyme collagenase that degrades collagen fibers. Remodeling of tissues during wound healing by collagenase. Melting of collagen to gelatin (loss of tertiary structure) spontaneously follows such degradation.• The banding (quaternary structure) of collagen fibers determines the blood clot-forming properties of collagen (primarily through induction of platelet aggregation).18Collagen structure-function relations (cont.)• The architectural structure of collagen determines the function of collagen fibers as mechanical reinforcements of connective tissues (tendon, skin, bone, arteries etc.). Tendonfibers are bundles of uniaxially aligned fibers that are crimped. Skin(dermis) is a random planar array of crimped collagen fibers. Bone is a ductile ceramic (hydroxyapatite) which is reinforced by collagen fibers. Large blood vessels(aorta, large arteries) are interpenetrating networks of elastin fibers and collagen fibers.19Exposed to collagenaseNo enzymeExposed longerEffect of exposure of collagen fibers to collagenaseThree photos removed due to copyright restrictions.20Degradation of collagen molecule by collagenase(Gross)spontaneous melting to gelatin following degradationcollagenDiagram removed due


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