Connective Tissue: Types and Functions

Connective Tissue Overview

• Connective tissue, along with epithelium, muscle, and nerve tissue, constitutes one of the primary tissue types in the body.
• Connective tissue proper, cartilage, bone, blood, elastic tissue, compact and spongy tissue, loose connective tissue types of areolar, reticular and adipose, and dense tissue types of regular, elastic and irregular are all types of connective tissue.
• Connective tissues enclose and separate organs.
• Connective tissues connect different tissues (ligaments and tendons), support/move joints and cartilage and store adipose tissue and bones in the body.
• Cushioning and insulating is done by adipose tissue while transport and protection is done by blood tissue within the body,
• Protection of the cranium and sternum is another function of connective tissue.
• Unlike other tissue types, connective tissue is characterized by an abundance of extracellular matrix.
• Extracellular matrix contains protein fibers, such as collagen, and ground substance.

Structure of Connective Tissue

• Connective tissue consists of 3 classes of components: cells, fibers, and ground substance.
• Cells in connective tissue consist of fibroblasts, macrophages, mast cells, plasma cells, lymphocytes, leukocytes, and adipose cells.
• Fibers in connective tissue consist of reticular, elastic, and collagen fibers.
• Ground substance consists of macromolecules and multiadhesive glycoproteins

Connective Tissue Proper

• Connective tissue proper exists throughout the body.
• Connective tissue connects epithelia to underlying structures, links muscles to bones, and holds joints together.
• Connective tissue serves defense, repair, storage, and nutrition purposes; also provides medium for oxygen and nutrients to diffuse from capillaries to cells.
• Connective tissue also resists organ stretching and tearing

Connective Tissue Cells

• Connective tissue categorized into resident or wandering cells
• Resident cells are relatively stable and permanent
• Wandering cells migrate into tissues from the blood
• Resident cells include fibroblasts, myofibroblasts, macrophages, adipocytes, mast cells, and adult stem cells.
• Wandering cells encompass lymphocytes, plasma cells (differentiated B cells), neutrophils, eosinophils, basophils, and monocytes.

Fibroblasts and Myofibroblasts

• Fibroblasts constitute the main cell population of connective tissue proper.
• They are large, flat, elongated (spindle-shaped) cells with processes extending from the cell body.
• The cell nucleus is flat and oval
• Fibroblasts produce and maintain the extracellular components of tissues.
• In adults, fibroblasts rarely divide, and are stimulated by locally released growth factors.
• Fibroblasts synthesize and secrete collagen, elastin, GAGs, proteoglycans, and multiadhesive glycoproteins.
• ECM components undergo modification outside the cell before matrix assembly.
• Myofibroblasts are fibroblasts involved in wound healing that play a critical role
• Myofibroblasts feature a well-developed contractile function and are enriched with a form of actin found in smooth muscle cells

Fibroblast Activity

• Fibroblast activity can be observed histologically on two levels.
• Cells with synthetic activity are morphologically distinct from quiescent fibroblasts.
• These quiescent fibroblasts are scattered within the matrix that they have already synthesized.
• Some histologists term active and quiescent cells "fibroblasts" and "fibrocytes" respectively
• Active fibroblasts exhibit abundant, irregularly branched cytoplasm plus a large, ovoid, euchromatic nucleus.
• Active fibroblasts show rough endoplasmic reticulum is present.
• Quiescent cells are smaller and have fewer processes than active fibroblasts and contain a darker, heterochromatic nucleus

Adipocytes

• Adipocytes, or fat cells, reside in the connective tissue of many organs.
• These mesenchymally derived cells specialize in cytoplasmic lipid storage as neutral fats.
• Deposits of fat in adipose connective tissue cushion and insulate organs and skin.
• Adipocytes have major metabolic and medical significance.

Leukocytes

• Besides macrophages and plasma cells, connective tissue contains leukocytes derived from circulating cells of the blood.
• Leukocytes, or white blood cells, make up a population of wandering cells within connective tissue
• Leukocytes leave the blood by migrating between endothelial cells lining venules via diapedesis.
• Diapedesis intensifies greatly during inflammation, a defense response to injury or foreign substances

Macrophages

• Macrophages are derived from monocytes.
• The cells turn over protein fibers and remove dead cells, tissue debris, or other particulate material
• Macrophages are characterized by phagocytic abilities
• Macrophages have unique morphologic features depending on their state and the tissue they inhabit.
• A typical macrophage measures 10-30 µm in diameter and features a kidney-shaped nucleus.
• "Histiocytes" is another name pathologist use when referring to macrophages
• In TEM, macrophages have an irregular surface with pleats, protrusions, and indentations, indicative of active pinocytosis and phagocytosis.
• Macrophages generally have a well-developed golgi apparatus and many lysosomes.

Mononuclear Phagocyte System

• Macrophages are derived from bone marrow precursor cells and circulate in the blood as monocytes
• Bone marrow cells cross the epithelial wall of venules and penetrate connective tissue.
• Monocyte cells differentiate, mature, and acquire the morphologic features of phagocytic cells.
• Monocytes and macrophages are considered the same cell at different stages of maturation.
• Macrophage-like cells have different names across other organs, with Kupffer cells in the liver and microglial cells in the central nervous system.
• All macrophage-like cells are derived from monocytes.
• Macrophage-like cells are long-living and may survive months in tissue and remove debris
• In addition to removing debris they are highly important for uptake, processing and antigen presentation for lymphocyte activation
• They are a direct function of the immune system.

Mast Cells

• Mast cells are a type of white blood cell that can be oval or irregularly shaped (7-20 μm)
• Mast cells are connective tissue cells, which have cytoplasm with granules and a centrally situated the nucleus obstructed by granules
• The heterogeneous granules range from 0.3–2.0 μm
• Granules are difficult to identify, as they are poorly preserved by common fixatives.
• Mast cells are the "master regulators" of the immune system.
• Mast cells originate from bone marrow progenitor cells that circulate in the blood and differntiate as they penetrate connective tissues

Mast Cell Mediators

• Release of mediators stored in mast cells promotes allergic or immediate hypersensitivity reactions
• Allergic reactions occur within minutes of encountering an antigen after sensitization to the same antigen
• Mast cells function in the local release of bioactive substances for inflammatory responses, innate imm‎unity and tissue repair.
• Mast cell mediators include Heparin, Histamine, Serine proteases, Eosinophil and neutrophil chemotactic factors, Cytokines and Phospholipid precursors.
• Heparin is a sulfated GAG that acts locally as an anticoagulant
• Histamine increases vascular permeability and results in smooth muscle contraction
• Serine proteases activate inflammation mediators, while eosinophil and neutrophil chemotactic factors attract leukocytes
• Cytokines polypeptides are system of leukocytes and phospholipid precusors convert to various mediators for the inflammatory response.

Plasma Cells

• Plasma cells are B-lymphocyte-derived, and produce antibodies
• Plasma cells feature large, ovoid shape and basophilic cytoplasm due to abundant RER presence
• Beside the nucleus, the Golgi apparatus and centrioles occupy a routine-preparation pale region.
• The nucleus is round but eccentrically placed.
• Few plasma cells are in tissues and they have a short lifespan at 10-20 days

Fibers

• Fibers are elongated structures of connective tissue that form from polymerized proteins secreted by fibroblasts
• Collagen, reticular, and elastic fibers are the main types
• Collagen and reticular are both formed from proteins of the collagen family and elastic are primarily made of the protein elastin
• The fibers unequally distribute into the different types of connective tissue

Collagen

• Collagens possess the ability to form a variety of extracellular structures.
• The various fibers, sheets, and networks made of collagens are extremely strong and resistant.
• Collagen is the most abundant protein in the human body (at 30% dry weight)
• Fibroblasts are the major source of collagen, which is also secreted by other cell types
• Turnover and renewal of collagen in connective tissue is very slow
• There are 28 types of collagen in vertebrates, but three main categories: fibrillar, sheet-forming, and linking/anchoring.

Collagen Groupings

• Fibrillar collagens include collagen types I, II, and III, aggregate to form large fibrils visible in the electron or light microscope.
• Collagen type I is the most abundant and widely distributed, collagen type one forms large, eosinophilic bundles called collagen fibers.
• Fibrillar structures fill connective tissue, forming structures like tendons, organ capsules, and dermis.
• Sheet-forming collagens like type IV collagen have subunits produced by epithelial cells.
• Type IV collagen are structural proteins of external and basal laminae in epithelia.
• Linking/anchoring collagens are short; they link fibrillar collagens to one another and components of the ECM.
• Type VII collagen binds to type IV collagen and anchors the basal lamina to the reticular lamina

Collagen Synthesis

• Collagen synthesis takes place in several cell types mainly fibroblasts.
• The initial procollagen chains are made first.
• Three ER chains are selected, aligned, and stabilized by disulfide bonds before folding into a triple helix
• The triple helix undergoes exocytosis and is cleaved into a rodlike procollagen molecule.
• Procollagen molecule that basic subunit for the fibers and sheets which assembling
• Subunits can be homotrimeric with identical chains for the same collagen.
• Subunits can be heterotrimeric with different chains for the same collagen
• Procollagen has alpha chains in different combinations which produce types of collagen with distinct properties.

Collagen Clinical Disorders

• Because of so many steps, the collagen biosynthesis process can be interrupted or changed by defective enzymes or by disease
• Ehlers-Danlos syndrome involves faulty collagen synthesis leading to symptoms like aortic and/or intestinal rupture, and increased skin elasticity.
• Scurvy is due to a lack of Vitamin C so the Lack needed for proper Ulceration of gums will not occur
• Osteogenesis imperfecta involves is a change in a nucleotide in genes for type one collagen which results in Spontaneous fractures and cardiac insufficiency

Reticular Fibers

• Reticular fibers exist in the delicate connective tissue of organs.
• These consist of collagens III and glycosylated fibers and produce an extensive extremely thin network within the body
• Reticular fibers stain black due to impregnation with with silver salts
• Reticular fibers are periodic acid-Schiff (PAS) positive and contain 10% carbohydrate.
• These fibers, produced by fibroblasts, sit in the reticular lamina of basement membranes and surround adipocytes, muscle and nerve fibers
• They serve as the stroma for the parenchymal, secretory cells and microvasculature of the liver/endocrine glands
• They characterize stroma hemopoietic tissue and some lymphoid organs.

Elastic Fibers

• Elastic fibers are thinner than type I collagen fibers, they form networks in organs particularly where bending or stretching is needed.
• Elastic fibers allow tissues to be stretched or distended and return to their original shape.
• Elastin occurs as fenestrated sheets called elastic lamellae in large artery walls.
• Elastic fibers stain poorly with H&E, but stain more darkly than collagen with other stains, they are made of fibrillin and elastin.
• Fibroblasts, are the cells, vascular walls which produce elastic fibers step wise
• Microfibrils form from the protein fibrillin, elastin deposits elastin through each elastic fiber forming a random coil that contains elastic quality
• The elastin molecule is rich in glycine, proline, and lysine.
• Desmosine cross-links elastin subunits to permit movements and structural integrity

Ground Substance

• Ground substance provides a complex mixture of macromolecules and is rich in glycosaminoglycans (GAGs), proteoglycans and multiadhesive glycoproteins.
• Ground substance fills spaces between cells and acts as both a lubricant and protective fluid.
• Its viscous nature acts as a barrier to the penetration of invaders

Other Substances and Fibers

• A major function of ground substance is the provision of a medium for the exchange fluids, like nutrients and the metabolic wastes between cells and the blood supply.
• Glycoproteins help stabilize the ECM by binding to other matrix components and to integrins in cell membranes.
• GAGs consisting of repeating disaccharide units are a main source of mucopolysaccharides, with an example being hyaluronic acid.
• GAGs bind to large amounts of water, which causes the polyanions to swell and occupy a large space.
• All of them differ in tissue distributions, disaccharide units and GAGs contain major dermatan sulfate

More Ground Substances

• Proteoglycans consist of a core protein to which sulfated GAGs are covalently attached.
• They are synthesized on RER and matured in the Golgi.
• GAG side chains are added within the cell and secreted through exocytosis.
• While similar to glycoproteins components are cartilage and protein and may span a composition of long chains
• A region of ECM contain contain different composition from ECM and has proteins of various length
• A small proteoglycan, decorin, has few GAG side and binds fibrils of type I collagen.
• Cell surface proteoglycan molecules, such as syndecan, have transmembrane coreproteins and serve as additional cell connections into the ECM.

Ground Substance Components

• Components, such as aggrecan, in the best known proteoglycans core has chain of cartilage, Multiadhesive glycoproteins have multiple binding sites for surface of cell and are binding areas through matrix macromolecule.
• Adhesive glycoproteins feature branched chains as roles for adhesions between cell walls an the adhesive process of substrate processes
• A large glycoprotein, a laminin, has a adhesion process for epithelial other areas cell where are integrins, with Collagen IV proteglycans.
• Extracellular fluid is rich in laminin, and provides essential structures for assembling and maintenence of surface
• Fibronectin synthesized with fibroblasts it has collage-like region with certain GAGS that is insoluble fibrinonectin throughout tissue.
• Proteins serve to bind and give cell migration strength and cellular binding through its ECM

Interstitial Fluid and Basement Membrane

• There is also a small quantity of free interstitial fluid, with ion composition similar to that of blood plasma.
• This fluid contains plasma proteins and travels through capillaries and in the smallest area of blood vessels.
• The basement membrane consists of a basal lamina (protein filaments in amorphous matrix) produced by the cells from the epithelium.
• The reticular lamina holds reticular fibers in substance from ground.
• Some other tasks of support of the epithelial and of cells.

Basement Membrane Function

• Basement Membrane acts as a filter and separates the layers cells of tissues The macromolecules are basal poles at epithelial cells and are three-dimensional structure
• Large glycoproteins self-assemble into networks through adhesive glycoprotein which makes them self sufficient
• Monomers have formed cell-shaped assembly through collagen layers this includes, collagen ,anchoring and binding with base
• The meshwork of reticular consist type three cell with collagen