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Integrating Cells Into Tissues

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Integrating Cells Into Tissues CMB 621 EXTRACELLULAR MATRIX Integrating Cells into Tissues Olivier Le Saux 692 1504 [email protected] Integrating Cells into Tissues Cells that constitute tissues and organs are organized by molecular interactions at the cell level. 1 - Cell can adhere to each other through membrane proteins called cell-adhesion molecules (CAMs). There are hundreds of known CAMS. 2 - Cells are bound through cell-matrix adhesion (adhesion receptors) that bind extracellular matrix (ECM). Cell adhesion molecules on the surface of cells bind one cell to another or bind cells to the extracelluar matrix (ECM) These cell-cell or cell- ECM interactions can be tight, long-lasting, weak, or of short duration Homophilic interactions are between two identical Heterophilic interactions are between two different molecules molecules Homotypic interactions are between cells of the Heterotypic interactions are between cells of same type different types Cell adhesion molecules (CAMs) are often linked to adaptor molecules inside the cell. The adaptors are often linked to the cytoskeleton (actin or intermediate filaments). The adaptors might also serve as signaling molecules to regulate protein function or gene expression Through these interactions, cells might get information about their environment and respond appropriately. These interactions can also influence the shape of the cell and the structure of the tissue or organ. Epithelial Tissue Epithelial tissue is usually on surfaces that are directly or indirectly exposed to the outside. Skin, linings of the gastrointestinal tract, linings of the lungs, ducts and glands. These surfaces can be protective, adsorptive, secretory. Generally epithelia have apical, lateral and basal surfaces (basolateral). The basal surface is usually connected to a underlying extracellular matrix called the basal lamina. The apical surface generally does not contact other cells or ECM but is exposed to the lumen of the organ (lumen of the gut, secretory ducts, lungs) Stomach, gut, cervical Urinary bladder tract Blood vessels mouth, esophagus, (endothelium), lungs, vagina, skin (keratinized) glomeruli Luminal/ abluminal Resists abrasion There are three types of junctions in animal cells: - Anchoring junctions (epithelial and non-epithelial cells) - Tight junctions (epithelial cells) - Gap junctions (epithelial and non-epithelial cells) * * * *3 types of anchoring junctions Types of junctions Epidermolysis bullosa Adherens junctions use cadherins to give cells rigidity and to link adjacent cells together. Most cadherins are transmembrane proteins. There are 100+ kinds of cadherins, each with unique properties. Cadherins participate in tissue differentiation. The adhesive property of cadherins is dependent of the presence of Ca++ (cadherin from Ca-dependent adherens) Homophilic interactions of the E- cadherins bind the two cells together A prototypical adherens junction MDCKII cells Desmosomes (one of the anchoring junctions) form spot adhesions between cells The cadherins are linked to a Desmoglein and desmocollin are cytoplasmic plaque which is cadherins that are heterophillic. linked to intermediate filaments of the cytoskeleton Mouse skin Desmosomes Cadherins Hemidesmosomes are usually on the basal surface of an Cytoplasmic plaque Intermediate filaments epithelial cell and anchor it to the ECM or the basal lamina Hemidesmosomes form adhesions between cells and basement membrane Tight junctions form a band around cells that do not allow fluids or particles to pass between the apical surface of a epithelial sheet and the basolateral surfaces Tight junctions (in cross section) The separation of the apical and basal surfaces of the cell is crucial for the specific uptake or secretion of compounds (e.g., in stomach, intestine, kidneys, urinary tract, salivary glands…..) often by transcellular pathways. Tight junctions form an impermeable band around adjacent cells Rows of transmembrane proteins* in the membranes of adjacent cells binding the cell together. *The proteins that constitute tight junctions are from occludin, claudin and JAM family of proteins (Junction adhesion molecule) Tight junctions form an impermeable band around adjacent cells: Experimental proof Apical Basal Lanthanum hydroxide Electron-dense Tight junctions also prevent membrane lipids and membrane proteins from moving between the apical surface to the basolateral surface. Thus, these membranes can be quite different (why would that be important?) Gap junctions allow small molecules (<1200-2000 Da) to diffuse between the cytoplasms of adjacent cells Nutrients or intermediary metabolites can be transferred from one cell to the next. Contraction waves can be propagated via gap junctions (e.g., intestine) Ions and many second signals (e.g., cAMP, Ca++) can pass from one cell to the next. Also, rapid transmission of ionic signals in heart and nerves. In vertebrates most gap junctions are made from a pair of hemichannels (a pair of connexons). Each hemichannel is Connexins are in a made from 6 family of more than 20 transmembrane proteins different proteins. Which connexin protein spanning the membrane of constitute a particular one cells. gap junction will affect what can pass through The hemichannel in one the channel membrane associate the hemichannel in the other membrane. Thus, the gap junction channel is made of a total of 12 connexin molecules Integrating Cells into Tissues Cells that constitute tissues and organs are organized by molecular interactions at the cell level. 1 - Cell can adhere to each other through membrane proteins called cell-adhesion molecules (CAMs). There are hundreds of known CAMS. 2 - Cells are bound through cell-matrix adhesion (adhesion receptors) that bind extracellular matrix (ECM). THE MATRIXOME metalloproteinases The sub-set of the proteome that are ECM tolloid proteinases, ADAMTS 1-20, molecules that constitutes the customized MMP 1-26 microenvironment of individual cell types cysteine proteinases cathepsins B, D, K, L, S ~300 genes serine proteinases neutrophil elastase, plasmin/tPA/uPA collagens adhesion glycoproteins cross-linking enzymes types I - XXVIII lysyl oxidases, transglutaminases fibronectin, vitronectin, “collagens” chondroadherin, osteomodulin, enhancers, inhibitors C1q, emilins, adiponectin, tenascins, dermatopontin PCPEs, TIMPs, elafin, testican, inter-a- hibernation specific proteins, inner trypsin inhibitors, PAIs ear structural protein, platelet associated acetylcholinesterase tail subunit, glycoproteins collectins, ficolins von Willebrand factor, fibrinogen matricryptins matrix glycoproteins “large” proteoglycans endostatin, restin, tumstatin fibulins, thrombospondins, matrilins, aggrecan, brevican, versican, neurocan hemicentins, polydom, cochlin, vitrin hyaluronan binding elastic fibre associated basement membrane proteins glycoproteins link protein, TSG-6 proteins laminins, nidogen, agrin fibrillins, elastin, MAGPs, MFAPs, cell surface associated mineralisation- proteoglycans associated proteins agrin, perlecan, bamacan, glypicans growth factors, bone sialoprotein, dentin sialoprotein, dentin matrix proteins, matrix gla leucine rich repeat signaling and protein, osteocalcin, osteonectin, proteoglycans associated proteins osteopontin, phosphophoryn, decorin, biglycan, lumican, TGFs, BMPs, CTGF, VEGF, Wnts, amelogenin, ameloblastin, enamelin fibromodulin, keratocan, opticin, LTBPs, osteoprotegerin, netrins osteoglycin, PRELP, asporin, epiphycan Extracellular Matrix (ECM) Multicellularity cell populations aggregate into tissues cells in contact with other cells - environment communicate with same and different cells Cells in tissues of multicellular organisms are embedded in an ECM made of secreted proteins and polysaccharides. ECM fill the space between cells and bind tissues component together Different cells in tissues build different matrix-environment Extracellular Matrix (ECM) Complex network of cell-secreted proteins and glycoaminoglycans Function ? Organize cells in tissues : - determining overall tissue morphogenesis and architecture - growth and development, - tissue remodeling, wound healing, inflammation degradation/synthesis - Metalloproteinases (MMP) + TIMP Co-ordinate cell function Regulates cell motility/migration --> immunity and tumor growth and invasion Extracellular Matrix (ECM) Other functions of the ECM Reservoir for cytokines, hormones, growth factor binding to low affinity receptor. –- hold, protect growth factors from degradation –- store at sites of action –- present to high affinity receptors Extracellular Matrix (ECM) The ECM form the frame of the vertebrate body, vary greatly in amount and composition Different tissues have different ECM – skin -- flexibility – joints -- mobility, friction – Tendons -- tensile strength – eye -- transparent matrix – Bone/teeth -- strength – kidney -- filtration – Brain (small amount) -- cell migration -- guidance -- in adult brain -- inhibition of migration Extracellular Matrix (ECM) Loose connective tissue Dense connective tissue Cartilage, bone, tendon Basement membrane Extracellular Matrix (ECM) Loose connective tissue Widely distributed, gel-like, many cells present - subcutaneous layer of skin, underlying mucous membranes - supporting framework of liver, spleen, lymph node, adipose Collagen VI (human liver) Spleen Extracellular Matrix (ECM) Embryonic chick skin Fibroblasts in rat cornea Extracellular Matrix (ECM) Loose connective tissue Dense connective tissue Basement membrane Extracellular Matrix (ECM) Dense connective tissue High density fibrous material
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