Be able to answer the following questions:

How have histologists classified the extracellular matrix?

What types of connective tissue fibers are found in the extracellular matrix? Which matrix is present as a sheet?

List the types of cells found in connective tissue and their functions.

If you were a leukocyte migrating through a capillary into a loose connective tissue, describe what extracellular matrix structures you would encounter and what adhesive glycoproteins you might attach to during your journey.

What are examples of connective tissue diseases?

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I.  INTRODUCTION - WHAT IS CONNECTIVE TISSUE

Early histologists classified tissues into four basic types: epithelia, nervous tissue, muscle, and connective tissue. Each of these is composed of cells embedded in extracellular matrix (ECM), which is the complex of proteins, polysaccharides, and tissue fluid surrounding cells. ECM composition determines the basic mechanical characteristics of tissue, such as strength, elasticity and resilience. Whereas epithelia and nervous tissue have virtually no ECM, the defining feature of connective tissue is its abundant ECM. Connective tissues are specialized for mechanical functions, supporting, protecting, connecting, dividing and shaping various organs. Connective tissue proper may be defined as a tissue of mesodermal origin composed of relatively few cells and a very large amount of extracellular material. It is generally quite vascular and contains the blood vessels-lymph vessels and nerves plus capillary networks responsible for transfer of nutrients to muscle, glandular and surface epithelial tissues. It forms fascial membranes which support and connect epithelial and muscle tissues--also separating muscles one from the other. It develops into tendons and ligaments for joining muscles to bone or skin and for joining bones to bones.

Connective tissues have been classified into a variety of general and specialized types. General types found throughout the body (e.g. loose, dense, adipose, mucous) are introduced below. Connective tissues specialized for particular structural roles (i.e. cartilage and bone) have more specialized cells and ECM, and these tissues are discussed separately in a later chapter. General connective tissues do serve a variety of functions beyond the basic structural roles provided by their abundant ECM. These tissues include cells responsible for a range of other important functions, including many defense mechanisms and storage of substances such as fat. Some connective tissue cells are permanent residents of the tissue, such as fibroblasts, and some are transient migrants, such as lymphocytes passing through the tissue space from blood to lymph.

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II. MAJOR CELL TYPES IN GENERAL CONNECTIVE TISSUE

The common cell types in general connective tissue are introduced here and are revisited in later chapters in regard to each organ system. The various cells in connective tissue all arise developmentally from mesenchyme and mesoderm. These include both long-term tissue residents, such as fibroblasts and adipose cells, and transient migratory residents, such as plasma cells and lymphocytes, which move back and forth between tissue space and blood or lymph.

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II.A. LONG-TERM RESIDENT CELLS:

1). FIBROBLASTS:

- are the most abundant connective tissue cell type and are the most active cell in synthesis, secretion, and turnover of ECM.

Fibroblasts are particularly active in embryonic or injured tissue and then have abundant RER, prominent Golgi, numerous secretory vesicles, a large pale nucleus with prominent nucleolus, and an irregularly branched - stellate - cell shape.

They are smaller and more quiescent in mature tissue - more spindle shaped - fusiform - with few processes and relatively stable with little mitosis.

However, proper stimulus can cause reversion to an active synthetic and mitotic state (e.g. during wound healing).

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2). ADIPOCYTES (Adipose Cells):

- are large spherical cells, distended by stored lipid.

They store, synthesize, and secrete lipid under hormonal and neuronal regulation.
Stored lipids are chiefly triglycerides derived from:
1) dietary fat transported in the blood in chylomicrons,
2) liver synthesized fat transported in VLDL,
3) and also fat synthesized endogenously in the adipocyte.

These cells are long-lived (boo!), but do not proliferate (yeah!).

Unilocular adipocytes have a single, central lipid droplet. They are common in well vascularized loose connective tissue. Their eccentric nucleus is flattened giving a "signet ring" appearance in section.

Multilocular adipocytes (not shown) each include many lipid droplets, a central nucleus, and numerous mitochondria (which give this type of adipose tissue the name "brown fat"). These cells function in heat generation, and are highly developed in hibernating animals. Humans have few, primarily in infants.

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3). TISSUE MACROPHAGES:

- are mononuclear phagocytes derived from blood monocytes.

They enlarge after entering connective tissue and can reside there for months.
They can also migrate in tissue in response to various inflammatory stimuli.

Macrophages play several critical roles in defense:
1) ingestion and degradation of foreign matter, e.g. microorganisms and damaged cells.
2) stimulation of the immune response by immune presentation (display digested foreign peptides on their surface), which triggers specific lymphocytes to produce antibodies.
3) efficient ingestion of antibody coated (opsonized) material which binds to the many antibody (Fc) receptors on the macrophage surface.
4) secretion of lytic enzymes, prostaglandins, cytokines, complement proteins, growth factors, etc in response to inflammatory stimuli.

These are large, irregularly shaped cells (10-30 microns in diameter).   They are most easily resolved histologically after phagocytizing substances such as ink particles or ferritin. They have abundant lysosomes, reflecting their active role in digesting scavenged material. When stimulated they can also be active in secretion and then have well developed RER and Golgi.

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4). MAST CELLS:

- are similar to blood basophils, but clearly distinct.  They, too, originate in bone marrow and circulate to connective tissue, but reside there for weeks to months.  Like basophils, mast cells include abundant, large, metachromatic granules, containing histamine, heparin, and other mediators of inflammation (e.g. chemotactic factors, proteases, and cytokines).  Granule metachromasia (purple/red color) is due to high polyanion (e.g. heparin) content.

When surface receptors for IgE antibodies bind cognate antigen, granule release is triggered, initiating immediate hypersensitivity reaction.
Histamine causes vasodilation and increased vascular permeability.
Mast cells are typically located near blood vessels, thus vessel response to released substances is rapid. Capillaries dilate, small venules release plasma, and smooth muscle contracts (for instance in bronchioles).

Mast cells are round to ovoid, 20-30 microns in diameter.

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II.B. TRANSIENT CELLS:

These include all blood leukocytes, some of which reside in connective tissue for their entire functional life span. For example B lymphocytes differentiate into tissue plasma cells, monocytes differentiate into tissue macrophages, and eosinophils remain with their characteristic appearance. Cells enter tissue from the blood by squeezing between endothelial cells of capillaries or venules by a process called "diapedesis".

1). LYMPHOCYTES:

- circulate from blood to tissue and back, and are quite common in loose connective tissue.

Lymphocytes are small cells (6-8 micron diameter) with little cytoplasm and a large basophilic nucleus with condensed chromatin.  T and B types are indistinguishable without special staining techniques.

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2). PLASMA CELLS:

As B lymphocytes migrate through tissue, encounter with specific antigen cause them to differentiate into plasma cells, which actively secrete antibody.

Plasma cells are seen in highest number beneath epithelial surfaces (e.g. G.I. tract, salivary glands), which are prone to penetration by foreign material (e.g. bacteria, foreign protein).

Plasma cells have a characteristic "clock face" appearance, due to an eccentric nucleus with characteristic dense chromatin clumps along its periphery.

These are large ovoid cells with basophilic cytoplasm.

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3). EOSINOPHILS:

- function in resisting parasitic invasion.

Specific granules are large acidophilic (eosinophilic) vesicles containing many enzymes (e.g. lysozyme, peroxidase, protease) and crystals of MBP (major basic protein), a parasite toxin which is rich in arginine and accounts for the cell's high degree of eosinophilia.

Eosinophils increase in tissue in response to both allergy and parasites.
Chemotactic factors released in inflammation attract more eosinophils.

These cells also help brake the inflammatory reaction. Secreted arylsulfatase and histaminase destroy leukotriene and histamine mediators of inflammatory reaction. Eosinophils can also phagocytose and digest antigen-antibody complexes.

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III. ORGANIZATION OF GENERAL CONNECTIVE TISSUE

1). LOOSE (AREOLAR):

- serves as a cushioning layer throughout the body and stores fat.

This connective tissue is flexible, well vascularized, and has little tensile strength.  It appears as a loose, irregular network of fibers and cells with abundant ground substance. The ground substance is not preserved in routine histological preparation, resulting in an empty appearance with scattered cells in section.  Examples: the hypodermis and the lamina propria of serosal linings of epithelia.

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2). DENSE:

- is less flexible, but has higher strength.

Dense connective tissue has relatively abundant collagen fibers, less ground substance, and even fewer cells, mostly fibroblasts.

Dense connective tissue can be sub-classified into regular and irregular types.

Dense regular - has a high degree of parallel ordering of large collagen fiber bundles, giving strong unidirectional stress resistance (e.g. in tendon, ligament).

Dense irregular  (below) - has a random network of large collagen fiber bundles giving stress resistance in many directions (e.g. in dermis, organ capsules).

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3). ADIPOSE:

Adipose tissue has an especially high content of fat cells in loose connective tissue.

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4). ELASTIC:

Elastic connective tissue is rich in parallel bundles of elastic fibers, and is found in specialized sites (e.g. yellow ligaments of vertebral column, vocal chords).

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5). RETICULAR:

Reticular connective tissue is marked by a branching network of thin reticular fibers, which provide a delicate structural framework for organ stroma (e.g. bone marrow, lymph nodes, spleen). Macrophages anchor to this framework.

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6). MUCOUS:

Mucous connective tissue is a particularly embryonic type of tissue (e.g. umbilical cord, Wharton's jelly). It is marked by very abundant ground substance, giving a jelly-like consistency. The loose structure provides a pathway for cells to migrate and proliferate during morphogenesis.

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7). HEMATOPOIETIC:

The chief function is to produce the cells of blood and lymph. Postnatally, there are two types of hematopoietic tissue, lymphatic and myeloid (bone marrow). This tissue is a complex mixture of different cell types and a rich lattice of reticular fibers.

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IV.  CLINCAL CORRELATION: Marfans Syndrome

A number of diseases of connective tissue have been identified. In many cases, the disease can be traced to a genetic defect in a specific extracellular matrix component. These include Ehlers-Danlos syndrome, osteogenesis imperfecta, and Marfan's syndrome. Marfan's syndrome is defined by characteristic changes in connective tissue systems: the skeleton, the eye, and cardiovascular system. Manifestations include dislocated lens, long thin face, long fingers and extremities. The aorta in such patients is subject dilation and can progress to eventual rupture. Abraham Lincoln is believed to have suffered from this disease. This is an inheritable disease and the "Marfan gene" has been mapped. The disease is believed to be due to a defect or deficiency in a elastin-associated protein called fibrillin. A point mutation in the fibrillin gene has been identified. However, the disease still goes undetected and therefore untreated. Currently, diagnostic tests are under development.

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V.  SUMMARY: MAJOR FUNCTIONS OF CONNECTIVE TISSUE

1). Connective tissue serves as a protective package and support for organs, a mechanical support and link for bearing weight and transmitting force (e.g. bones, tendons, ligaments), and an elastic bond allowing local mobility.   In addition to these basic structural or architectural roles, connective tissue participates in organ maintenance, defense, and repair.

2). Connective tissue presents a structural barrier to tissue infection or invasion and also hosts cells active in phagocytosis and immune response.

3). Connective tissue also serves as a major storage depot for a range of body resources, such as fat, minerals, water, electrolytes, protein, and metabolites.

4). The large amount of ground substance in connective tissue provides a pathway for connective tissue cell migration and passage of ions, proteins, metabolites, etc.

5). Finally, connective tissue is active in wound healing and fills lesions with the dense ECM of scar tissue, mainly laid down by fibroblasts.