Connective Tissue 3b5u2d

CONNECTIVE TISSUE

Functions of Connective Tissue   

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Structural (capsules, bone, cartilage) Nutrition Defense (non-specific and immune) Cell growth and differentiation Cell migration Insulation

Connective Tissues: Special Characteristics 

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Common embryological origin (from mesoderm) Innervated and Vascular (direct blood supply) 

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Cartilage is the one exception with no capillary beds

Extracellular Matrix ground substance (gelatinous glycoproteins)  structural fibers (fibrous proteins, e.g., collagen, elastin, reticulin) 

Types of Connective Tissues 

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Connective Tissue Proper  areolar (loose fibrous) connective tissue  adipose tissue  reticular connective tissue  dense (fibrous) regular connective tissue  dense (fibrous) irregular connective tissue Cartilage  hyaline cartilage  elastic cartilage  fibrocartilage Bone Blood

Types of Connective Tissue

gelatinous

mineralized

liquid

Classified by the characteristics of the matrix

Connective Tissue Elements 

Ground substance  

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s cells, binds them together may be solid, fluid or gel Componets: 

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Interstitial Fluid –

Cell Adhesion ProteinsFibronectin, laminin and others  Serve as connective tissue glue 

Connective Tissue Elements  

Proteoglycans - large polysaccharide molecules bound to a protein core (like a bottle brush) Glycosaminoglycans (GAGs) are attached to proteoglycans 

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They trap water. As GAGs increase, so does viscosity hyaluronic acid – gelatinous, separates cells, traps extracellular fluid; lubricates ts; gives shape to eyeballs; fills body spaces chondroitin sulfate – capable of being mineralized; cartilage, bones, skin, blood vessels dermatin sulfate – harder; skin, tendons, blood vessels, heart valves keratin sulfate - still harder; bone, cartilage, cornea of the eyes

Connective Tissue Elements

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Fibers   

Proteins that are embedded in the ground substance Provide structural , adhesion, connect cells Collagen     

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tough; provides high tensile strength Also called white fibers highly polymerized, gigantic molecules tough, moderate flexibility bone, cartilage, tendons, ligaments

elastic fibers = elastin    

branched; smaller, thinner fibers than collagen very flexible and elastic but also strong can be stretched to 150% of its original length Also called yellow fibers

Connective Tissue Elements 

reticular fibers  

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branched collagenous fibers that form delicate networks thin, less polymerized collagen fibers

elastic & reticular fibers require special stains to be seen in the light microscope

Connective Tissue Elements 

Cells – fewer, rarely touching, surrounded by a matrix 

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immature forms (-blasts) secrete the matrix and can still divide once the matrix is secreted, the cells mature into cytes which have decreased cell divisions and secrete less matrix material chondro- cartilage, osteo- bone, fibro – connective, etc. Fibroblasts – connective tissue proper Chondroblasts – cartilage Osteoblasts – bone Hematopoietic stem cells – blood White blood cells, plasma cells, macrophages, and mast cells

Connective Tissue Structure

Connective tissue Fibers

Fibers 

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Long, rope-like protein extracellular polymers Present in variable proportions in the different types of connective tissues Three types: collagen, reticular and elastic fibers. Collagen and reticular fibers are composed of various types of collagen, elastic fibers are composed mainly of elastin

Collagen fibers

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Collagens are the most abundant proteins in the body. There are many types of collagen that differ in their origin, chemical composition, functions, distribution and pathology

Collagen biosynthesis

Collagen biosynthesis

Collagen biosynthesis

Collagen fibrils TRIPLE HELIX 2 x alpha1 + 1x alpha2

1,5 nm

Collagen fibrils

Collagen fibrils, TEM

Collagen types 

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Fibril-forming collagen: types I, II, III, V and XI Fibril-associated collagen: types IX and XII Network-forming collagen: type IV Anchoring collagen: type VII

Collagen types

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Collagen I  

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Collagen II  

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2 x a1 + a2 or 3 x a1 Forms fibrils, the most resistant to mechanical tension In: skin, bone, tendons, connective tissue capsules 3 x a(II)1 Forms fibrils In hyaline and elastic cartilage

Collagen IV  

3 x a(IV)1 or 3 x a(IV)2 Forms a network in the basal laminae

Elastic fibers 

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Isolated, thin fibers or arranged in networks Localised in lung, urinary bladder, skin, aorta and elastic cartilage Special staining : orcein

Elastic fibers 

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Elastin molecules are ed by covalent bonds to generate an extensive crosslinked network. Because each elastin molecule in the network can expand and contract like a random coil, the entire network can stretch and recoil like a rubber band. )

Elastic fibers

RETICULAR FIBERS  

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Thin fibers, forming networks Distribution : liver, spleen, lymph nodes, haematopoietic organs Special staining : silver impregnation

Connective tissue Elements:   

Ground substance Fibers Cells

Extracellular matrix

Ground substance

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Composed of glycoproteins and proteoglycans Participates to binding cells to fibers Colorless and transparent in usual stains Viscous

Ground substance 

Fibronectin (homodimer) binds cells, collagen and GAG

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Laminin (heterotrimer) mediates attachment

of epithelial cells to basal laminae Cells have membrane receptors, integrins, that bind collagen, fibrinectin, laminin and other extracellular structural components Integrins are also attached to the cytoskeleton (actin fibers)

Ground substance 

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Proteoglycans (PG) = proteic core + glycosaminoglycans (GAG) GAG are linear polysaccharides composed of repetitive disaccharide units Disaccharide units = uronic acid + hexosamine –Glucuronic ac. –Glucosamine –Iduronic ac. –Galactosamine

Ground Substance: Proteoglycan Structure

Ground substance   

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Except hyaluronic acid, GAG are part of PG PG are intensly hydrophilic polyanions They bind cations (Na+) thus attracting water – they regulate consistency of connective tissue GAG examples: dermatan sulfate, chondroitin sulfate, keratan sulfate, heparan sulfate

Ground substance 

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Structural glycoproteins (GP) are glycosilated proteins – branched oligosaccharide moieties GP mediate adhesion of cells to extracellular matrix components

Ground substance 

Fibronectin (homodimer) binds cells, collagen and GAG

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Laminin (heterotrimer) mediates attachment

of epithelial cells to basal laminae Cells have membrane receptors, integrins, that bind collagen, fibrinectin, laminin and other extracellular structural components Integrins are also attached to the cytoskeleton (actin fibers)

The molecular structure of proteoglycans and glycoproteins. 

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A: Proteoglycans contain a core of protein (vertical rod in drawing) to which molecules of glycosaminoglycans (GAGs) are covalently bound. A GAG is an unbranched polysaccharide made up of repeating disaccharides; one component is an amino sugar, and the other is uronic acid. Proteoglycans contain a greater amount of carbohydrate than do glycoproteins. B: Glycoproteins are globular protein molecules to which branched chains of monosaccharides are covalently attached.

Schematic diagram of cell-surface synedcan proteoglycan. The core protein spans the plasma membrane through the cytoplasmic domain. The syndecan proteoglycans possess 3 heparan sulfate chains and sometimes chondroitin sulfate.

A: The structure of fibronectin. Fibronectin is a dimer bound by S–S groups, formed by serially disposed coiled sites, that bind to type I collagen, heparan sulfate, other proteoglycans, and cell membrane receptors. B: The structure of laminin, which is formed by 3 intertwined polypeptides in the shape of a cross. The figure shows sites on the molecule with a high affinity for cell membrane receptors and type IV collagen and heparan sulfate, which are components of basal laminae. Laminin thus promotes adhesion of cells to basal laminae.

Integrin cell-surface matrix receptor. By binding to a matrix protein and to the actin cytoskeleton (via alpha-actinin) inside the cell, the integrin serves as a transmembrane link. The molecule is a heterodimer, with alpha and beta chains. The head portion may protrude some 20 nm from the surface of the cell membrane into the extracellular matrix.

Connective Tissue Cells

Connective tissue cells – classification 

Proper to CT (fixed cells) - fibroblast - fibrocyte (condro-, osteo-) - adipocyte (uni-, multilocular) - reticular cells

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Migrated (mobile cells) -

granulocytes B and T lymphocytes macrophages mastocyte melanocyte

Connective tissue cells – classification 

Cells that produce/degrade the extracellular matrix 

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Metabolic cells 

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fibroblasts, osteoblasts, condroblasts, macrophages

adipocytes

Defense (specific/non-specific) 

Lymphocytes, macrophages, neutrophils

Fibroblast 

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The most frequent cell Fibers (collagen, reticulin & elastic) and ECM components synthesis Elongated cells, 20 mm, branched processes, basophilic cytoplasm, oval , euchromatic nucleus, 1 or 2 nucleoli

Fibroblasts, fibrocytes

Fibroblast Produces:  Elements of the extracellular matrix: procollagen, proelastin, fibrillin, GAG, PG and GP;  Enzymes: matrix metalloproteinases collagenase (degrades collagen at neutral pH), elastase;  Growth factors

Fibroblast Properties:  Ability to switch its fenotype fibroblast ↔ fibrocyte  Can change shape  Mobile  Induces differentiation of surrounding cells

Fibrocyte 

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Less active than fibroblasts: smaller, lesser cytoplasm, a few short unbranched processes Eosinophilic cytoplasm Elongated and heterochromatic nucleus

Unilocular (white) adipocyte 

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Round (when isolated) or polygonal in groups One large lipid droplet (inclusion) A thin rim of cytoplasm at the periphery that contains a flattened, heterochromatic nucleus (“signet ring”)

Multilocular (brown) adipocyte  

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Smaller cells Many smaller lipid droplets in the cytoplasm – foamy look Round, central nucleus Mostly found before birth and in neonates Role in thermogenesis

Reticular cells 

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Variable functions but similar morpholgy; some contribute to forming the stroma of lymphoid and hematopoietic organs Star-shaped cells with long and thin processes that establish anchoring junctions with neighboring cells; round, central, pale nucleus, larger than nuclei surrounding it

Cytoreticule Cytoreticule = Reticular cells + Reticular fibers

Melanocytes 

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Cell of ectodermal origin Consequently migrates to dermis, epidermis, iris, hair root Snowflake-shaped cell, with many branched processes; 30 mm Melanin granules in the cytoplasm, darkbrown; Round, central, small nucleus

Melanocytes 

Melanosomes – visible in EM: 

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Primary melanosomes are Golgi vesicles that accumulate thyrosin (the melanin precursor) and thyrosinase, located at the base of cell processes Secondary melanosomes are heterogenous vesicles (EM) that accumulate melanin Tretiary melanosomes are found at the tips of the cell processes; they are released from melanocytes and engulfed by surrounding cells (keratinocytes)

Macrophages 

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Derived from peripheral blood monocytes, Involved in phagocytosis and inflamatory response A family of cells with various shapes, localisations and names:     

Histiocytes: connective tissue Kupfer cells: liver Alveolary macrophages: lung Osteoclasts: bone Microglia: central nervous system

Macrophages 

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Grouped as the “mononuclear phagocytic system” Macrophages of the connective tissue: about 30 mm, “ruffled” membrane, acidophilic lysosomes in the cytoplasm, can have various heterogenous “inclusions” – ingested material Round, oval or kidney-shaped nucleus, excentrical, can have nucleoli

Macrophage  

Main function: phagocytosis Triggered by a specific interaction between membrane receptors and ligands. Consequences:    

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Cell movement towards target particle Pseudopodae formation – engulfment Respiratory burst Secretion: cytokines, interferons, complement & coagulation factors Production of matrix metalloproteinases

Macrophage, TEM

Mast cells 

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Localized in most of the loose connective tissue areas, along blood vessels Oval cell, 20-30 mm Cytoplasm has numerous basophilic, metachromatic granules, 0,1-1 mm. Pseudopodae in EM. Round, small and central nucleus

Mast cells 

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Granules contain heparin or chondroitin sulfate, histamin, Eosinophil Chemotactic Factor, etc. The content can be released out of the cell “degranulation”. The process is triggered by chemical, physical stimuli, or through binding of antigen-IgE complexes by specialized receeptors Degranulation is mediated by cAMP and leads also to leukotriene synthesis

Mast cell degranulation

Mast cells, Toluidin blue stain

Mast cell, TEM

Plasma cells 

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Found in lymphoid organs (lymph nodes, spleen, bine marrow) and connective tissues associated to the respiratory and digestive mucosae Originate in B lymphocytes, that are terminaly differentiated as a response to antigen challenge Secrete immunoglobulins (antibodies): IgM, IgG, IgA, IgE

Plasma cells

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Oval cell, 20 mm Basophilic cytoplasm (due to abundant RER), with a perinuclear pale area (Golgi apparatus); can contain acidophilic Russel bodies (secretory granules) Excentric nucleus, with hetero- and euchromatin in a characteristic pattern: “spokes and barrel”, “clockface”. Visible nucleolus

Plasma cell

Plasma cell, TEM

Plasma cells, TB stain

Lymphocytes  

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T and B subpopulations Central role in the immune response, migrated from the blood stream Small round cells (10 mm), with a round and dark-staining nucleus and a few basophilic cytoplasm

Neutrophils 

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Migrated from the blood stream, role in phagocytosis (microphage) Eosinophilic cytoplasm with small granules Characteristic nucleus: heterochromatic, 2-5 lobes