Connective Tissue

CONNECTIVE TISSUE

I. Introduction   

Consists of: Abundant extracellular matrix Various types of connective tissue cells

Functions: 

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Provides structural support for organs and cells Serves as a medium for exchange of nutrients and wastes between the blood and tissues Aids in protection against microorganisms Helps in repair of damaged tissues Provides a site for storage of fat

II. Extracellular Matrix   

Ground substance Fibers Tissue fluid

Ground Substance 

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Gel-like material that fills the space between the cells and fibers of connective tissues. Is a complex mixture of glycosaminoglycans, proteoglycans and adhesive glycoproteins Along with water and other small molecules (ex. nutrients ions) constitutes the extracellular environment Acts as a lubricant and helps prevent the penetration of tissues by foreign particles

GLYCOSAMINOGLYCANS (GAGs) The sulfated GAGs include:  Keratan sulfate  Heparan sulfate  Heparin  Chondroitin-4-sulfate  Chondroitin-6-sulfate  Dermatan sulfate  The only non-sulfated glycosaminoglycan is hyaluronic acid

PROTEOGLYCANS 

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When sulfated GAGs form covalent bonds with a protein core, they form a family of macromolecules known as proteoglycans Aggrecan-a macromolecular proteoglycan found in cartilage and connective tissue proper attached to hyaluronic acid This is responsible for the gel state of the extracellular matrix and acts as a barrier to fast diffusion of aqueous deposits

ADHESIVE GLYCOPROTEINS        

Fibronectin Fibronectin receptor Laminin Entactin Tenascin Chondronectin Osteonectin The ability of cells to adhere to components of the intercellular matrix is mediated by adhesive glycoprotein

Fibronectin       

Types and location Matrix fibronectin An adhesive glycoprotein that forms fibrils in the extracellular matrix Cell-surface fibronectin A protein that transiently attaches to the surface of cells Plasma fibronectin Is a circulating plasma protein that function in blood clotting, wound healing and phagocytosis.

Functions 

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Is a multifunctional molecule possessing domains for binding collagen, heparin, various cellsurface receptors, and cell-adhesion molecules Mediates cell adhesion to the extracellular matrix by binding to fibronectin receptors on the cell surface

Fibronectin receptor 

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Is a transmembrane protein, consisting of 2 polypeptide chains Belongs to the integrin family of receptors, and is known as a cell-adhesion molecule (CAM), since it enables cells to adhere to the extracellular matrix Function: To link fibronectin outside the cell with cytoskeletal components (ex. actin) inside the cell

Laminin 

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Is located in the basal (external) lamina and is synthesized by adjacent cells Possess binding sites for cell-surface receptors (integrins), heparan sulfate, type IV collagen and entactin Functions to mediate interaction between epithelial cells and the extracellular matrix by anchoring the cell surface to the basal lamina.

Entactin 

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Is a component of all basal (external) laminae Is a sulfated adhesive glycoprotein that binds laminin Functions to link laminin with Type IV collagen

Tenascin 

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Is an adhesive glycoprotein, most abundant in embryonic tissues Is secreted by glial cells in the developing nervous system Function: Promotes cell-matrix adhesion in cell migration

Chondronectin 

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Is a glycoprotein in cartilage that attaches chondrocytes to type II collagen Is a multifunctional molecule with binding sites for collagen, proteoglycans and cell-surface receptors Functions in the development and maintenance of cartilage by influencing the composition of its

Osteonectin  

Is an extracellular matrix in bone Functions to link minerals to Type I collagen and to influence calcification by inhibiting crystals growth

Fibers   

Collagen fibers Reticular fibers Elastic fibers

Collagen Fibers  

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Is very abundant constituting about 20% of all the proteins in the body Forms of a flexible fiber whose tensile strength is greater than that of stainless steel of comparable diameter Referred to as white fibers Stained with H & E, they appear as long, wavy pink fiber bundles Have the characteristics cross-banding at regular intervals of 67nm There are 15 different types of collagen known depending on the amino acid sequence of their chains

Important types of collagen      

Type I Type II Type III Type IV Type V Type VI

Elastic Fibers  

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Are usually slender, long and branching in loose connective tissue May form coarser bundles in ligaments and fenestrated sheets (found in ligamentum flava of the vertebral column, and concentric sheets in the walls of larger blood vessels) Are manufactured by fibroblasts of connective tissue as well as by smooth muscle cells of blood vessels Composed of elastin, a protein rich in glycine and proline and also contain the unusual amino acids desmosine and isodesmosine

Elastic Fibers 

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Form considerable cross-linking of the elastin molecules, imparting a high degree of elasticity to elastic fibers May be stretched to about 150% of their resting lengths prior to breakage Return to resting length after being stretched Core of elastic fibers is composed of elastin and is surrounded by a sheath of microfibrils, composed of the glycoprotein fibrillin. During the formation of elastic fibers, the microfibrils are elaborated first, and the elastin is deposited into the space surrounded by the microfibrils

Tissue Fluid 

Plasma from capillaries and venules enters the connective tissue spaces as tissue fluid which percolates through the ground substance. Tissue fluid re-enters the venule as well as lymphatic capillaries.

Connective Tissue Cells  

Fixed cells Transient cells

Fixed cells 

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Are resident population of cells that have developed and remain in place within the connective tissue, where they perform their functions Are a stable and long-lived population Include: Fibroblasts Adipose cells Mast cells Pericytes Macrophages like Kupffer cells of the liver can be considered fixed connective tissue cells

Transient cells  

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Free or wandering cells Originate mostly in the bone marrow and circulate in the bloodstream Upon receiving the proper stimulus or signal these cells leave the bloodstream and migrate into the connective tissue to perform their specific functions. Because most of these motile cells are usually short-lived, they must be replaced continuously from a large population of stem cells

Transient cells include:       

Plasma cells Lymphocytes Neutrophils Eosinophils Basophils Monocytes Some macrophages

FIBROBLASTS Most widely distributed and abundant  Arise from undifferentiated mesenchymal cells  Normally have an oval nucleus and often have 2 nucleoli

Active fibroblasts  

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Are spindle-shaped with long tapering ends (fusiform) Contain well-developed rough endoplasime reticulum (RER) and Golgi complex Are synthetically active, producing procollagen and other precursors of the extracellular matrix components Often reside in close association with collagen bundles, where they lie parallel to the long axis of the fiber With H & E pale-staining cytoplasm with darker stained, large granular ovoid nucleus containing a well-defined

Inactive fibroblast        

Smaller and more ovoid, with acidophilic cytoplasm Nucleus is smaller, elongated and more deeply stained EM reveals sparse amounts of RER but an abundance of free ribosomes Seldom undergo cell division, but may do so during wound healing May differentiate into: Adipose cells Chondrocytes (during formation of fibrocartilage) Osteoblasts (under pathological conditions)

Myofibroblasts  

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Are modified fibroblasts Have characteristics similar both fibroblasts and smooth muscle cells EM shows bundles of actin filaments and dense bodies similar to those of smooth muscle cells External lamina (basal lamina) is absent Abundant in areas undergoing wound healing Found in the periodontal ligament where they probably assist in tooth eruption

PERICYTES 

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Derived from undifferentiated mesenchymal cells Partly surround the endothelial cells of capillaries and small venules Possess characteristics of smooth muscle cells and endothelial cells, suggesting that under certain conditions, they may differentiate into other cells Technically pericytes are outside the connective tissue compartment because they are surrounded by their own basal lamina which maybe fused with that of the endothelial cell.

ADIPOSE CELLS 

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Derived from undifferentiated mesenchymal cells Fibroblasts may also give rise to adipose cells Are fully differentiated and do not undergo cell division Function: Synthesis and storage of triglycerides

2 types of fat cells 

Unilocular fat cells form white adipose tissue  cells with a simple large lipid droplet 

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Multilocular fat cells Form brown adipose tissue  Cells with multiple, small lipid droplets 

Unilocular Adipocytes 

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Are large cells, polyhedral in adipose tissue Continually store fat in the form of a single droplet, which enlarges so much displacing the cytoplasm and nucleus peripherally against the plasma membrane, giving these cells the “Signet ring” profile on light microscopy EM reveals only few mitochondria, sparse RER, abundant free ribosomes

Multilocular Adipocytes 

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Are smaller and more polygonal than unilocular fat cells Nucleus is spherical & not squeezed against the cell membrane because fat is stored in small droplets EM reveal many mitochondria, fewer free ribosomes, lacks RER, smooth ER is present

MAST CELLS 

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Arise from myeloid stem cells during hematopoiesis Nucleus: small, ovoid, pale-staining Cytoplasm: filled with coarse, deeply stained metachromatic granular Metachromasia is due to its content of heparin,a sulfated GAG

Granules contain:     

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Heparin Histamine Neutral proteases Aryl sulfatase Most cells also synthesize LEUKOTRIENES from membrane arachidonic acid precursors Mast cells is connective tissue contain mostly heparin in their granules, whereas those located in the alimentary tract mucosa contain chondroitin sulfate (mucosal mast cells)

MACROPHAGES 

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Some behave as fixed cells and some are transient cells Function in removing cellular debris and in protecting the body against foreign invaders

MONONUCLEAR PHAGOCYTE SYSTEM         

All members of the system: Arise from a common stem cell in the bone marrow Possess lysosomes Capable of phagocytosis Display Fc receptors and receptors for complement Macrophage development Monocyte develop in the bone marrow and circulate in the blood At the proper signal, they leave the bloodstream by migrating through the endothelium of capillaries or venules In connective tissue compartment they mature into macrophages, which normally have a lifespan of about 2 months

Distribution in the body       

Kupffer cells – liver Dust cells – lung Langerhans cells – skin Monocytes – blood Macrophages – connective tissue Osteoclasts – bone Microglia – brain

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Under chronic inflammatory conditions, macrophages congregate, greatly enlarge and become polygonal-shaped epithelioid cells. When the particulate matter to be disposed is excessively large, several to many macrophages may fuse to form foreign-body giant cell. ( a giant multinucleated macrophage) Resident macrophages Residing in the connective tissues Elicited macrophages Those that developed as a result of an exogenous stimulus and migrated to a particular site.

Macrophages       

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Size: 10-30 nm in diameter Irregularly shaped Cell surface presents short, blunt projections or finger-like filopodia Cytoplasm: Basophilic with many small vacuoles and small dense granules Nucleus: Ovoid indented on one side, eccentric in location, small more darkly stained, usually does not display nucleoli EM demonstrate Well developed Golgi apparatus Prominent RER Abundance of lysosomes, appearing as small, dense granules in LM

Functions of Macrophages 

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Phagocytose senescent, damaged and dead cells and cellular debris and digest the ingested material by action of hydrolytic enzymes in their lysosomes Assist in defense of the body by phagocytosing and destroying microorganisms During the immune response, factors released by lymhocytes activate macrophages, increasing their phagocytic activity

PLASMA CELLS 

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Found in greatest numbers in areas of chronic inflammation and where foreign substances or microorganisms have entered the sinuses Are derived from B lymphocytes Secrete antibodies upon encountering an antigen Plasma cells are large, ovoid cells, 20 nm in diamter Nucleus eccentric in location, with heterochromatin clumps at the periphery giving it the characteristic “clock-faced” appearance Cytoplasm: Intensely basophilic as a result of a welldeveloped RER with closely spaced cisternae EM show a large juxtanuclear Golgi complex and a pair of centrioles LM show a juxtanuclear negative Golgi image

LEUKOCYTES  

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Are white blood cells that circulate in the bloodstream Frequently migrate through the capillary walls to enter the connective tissues especially during inflammation, when they carry out various functions Neutrophils Eosinophils Lymphocytes

CLASSIFICATION OF CONNECTIVE TISSUE   

Embryonic Connective Tissue Connective Tissue Proper Specialized Connective Tissue

Embryonic Connective Tissue  

Mesenchymal Tissue Mucuous Tissue

Mesenchymal Tissue  

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Connective tissue present in embryos Consists of mesenchymal cells in a gel-like amorphous ground substance containing scattered reticular fibers Mesenchymal cells: Are pleuripotential cells Give rise to most of the cells of loose connective tissue Nucleus: oval, exhibiting fine chromatin network and prominent nucleoli Cytoplasm: sparse, pale-staining, extending small processes in several directions

Mucuos Tissue 

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Loose, amorphous connective tissue exhibiting a jelly-like matrix primarily composed of hyaluronic acid and sparsely populated with Type I and Type III collagen fibers and fibrobalsts Also known as Wharton’s jelly Found in the umbilical cord

Connective Tissue Proper   

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Loose Connective Tissue Dense Connective Tissue Dense Regular Collagenous Connective Tissue Dense Regular Elastic Connective Tissue Dense Irregular Connective Tissue

Loose Connective Tissue  

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Also called areolar tisse Posseses relatively fewer fibers but more cells than dense connective tissue Is well vascularized, flexible, and not resistant to sress Abundant ground substance and tissue fluid Cells are: fibroblasts, adipose cells, macrophages and mast cells & some undifferentiated cells Scattered are loosely woven collagen, reticular, and elastic fibers The loose connective tissue of mucous membrane is called the lamina propria Contains many transient cells responsible for

Dense Connective Tissue 

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Contains more fibers but fewer cells than loose connective tissue Classified according to orientation of fiber bundles

Dense Regular Collagenous Connective Tissue 

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Composed of coarse collagen bundles densley packed and oriented into parallel cylinders or sheets that resist tensile forces Thin sheet-like fibroblasts are located between bundles of collagen with their long axis parallel to the bundles Examples are tendons, ligaments and aponeuroses

Dense Regular Elastic Connective Tissue 

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Possesses coarse branching elastic fiber with only a few collagen fibers forming networks Elastic fibers are arranged parallel to each other and form either, thin sheets (ex. ligamentum flava, suspensory ligament of penis) or fenestrated membranes. (Ex. tunica media of aorta)

Dense Irregular Connective Tissue 

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Contains mostly coarse collagen fibers interwoven into a meshwork that resists stress from all directions Fine networks of elastic fibers are often scattered about the collagen bundles Fibroblasts are the most abundant cells in this tissue Found in the dermis of the skin, sheaths of nerves, capsules of spleen, testes, ovary, kidney and lymph node

Specialized Connective Tissue   

Reticular Tissue Adipose Tissue Pigment Connective Tissue

Reticular Tissue 

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Type III collagen is the major fiber component of reticular tissue Fibers form mesh-like networks with fibroblasts and macrophages Forms the framework of liver sinusoids adipose tissue, bone marrow, lymph nodes Reticular fibers readily stain with silverargyrophilic fibers

Adipose Tissue 

White adipose tissue 

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Composed of unilocular adipose cells

Brown adipose tissue 

Composed of multilocular adipose cells, containing numerous large mitochondria

Pigment Connective Tissue 

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Contains pigmented connective tissue cells - Melanophages Ex. dermo-epidermal junction