Connective Tissue: IntroductionThe different types of connective tissues are responsible for providing and maintaining form in the body. Functioning mechanically, they provide a matrix that connects and binds the cells and organs and ultimately gives support to the body.Structurally, connective tissue is formed by three classes of components: cells, fibers, and ground substance. Unlike the other tissues (epithelium, muscle, and nerve), which are formed mainly by cells, the major constituent of connective tissue is the extracellular matrix. Extracellular matrices consist of different combinations of protein fibers (collagen, reticular, and elastic) and ground substance.Fibers, predominantly composed of collagen, constitute tendons, aponeuroses, capsules of organs, and membranes that envelop the central nervous system (meninges). They also make up the trabeculae and walls inside several organs, forming the most resistant component of the stroma, or supporting tissue of organs.Ground substance is a highly hydrophilic, viscous complex of anionic macromolecules (glycosaminoglycans and proteoglycans) and multiadhesive glycoproteins (laminin, fibronectin, and others) that imparts strength and rigidity to the matrix by binding to receptor proteins (integrins) on the surface of cells and to the other matrix components. In addition to its conspicuous structural function, the molecules of connective tissue serve other important biological functions, such as serving as a reservoir for hormones controlling cell growth and differentiation.The connective tissue matrix is also the medium through which nutrients and metabolic wastes are exchanged between cells and their blood supply.The wide variety of connective tissue types in the body reflects variations in the composition and amount of the three components (cells, fibers, and ground substance) that are responsible for the remarkable structural, functional, and pathological diversity of connective tissue. The connective tissues originate from the mesenchyme, an embryonic tissue formed by elongated cells, the mesenchymal cells. These cells are characterized by an oval nucleus with prominent nucleoli and fine chromatin. They possess many thin cytoplasmic processes and are immersed in an abundant and viscous extracellular substance containing few fibers. The mesenchyme develops mainly from the middle layer of the embryo, the mesoderm. Mesodermal cells migrate from their site of origin, surrounding and penetrating developing organs. In addition to being the point of origin of all types of connective tissue cells, mesenchyme develops into other types of structures, such as blood cells, endothelial cells, and muscle cells. |

Cells of the Connective TissueA variety of cells with different origins and functions are present in connective tissue (Figure 5–1 and Table 5–1). Fibroblasts originate locally from undifferentiated mesenchymal cells and spend all their life in this tissue; other cells such as mast cells, macrophages, and plasma cells originate from hematopoietic stem cells in the bone marrow, circulate in the blood, and move to connective tissue, where they remain and execute their functions. Blood leukocytes, which are transient cells of connective tissue, also originate in bone marrow. They usually migrate to connective tissue where they reside for a few days and die. |

Fibroblasts
Fibroblasts synthesize collagen, elastin, glycosaminoglycans, proteoglycans, and multiadhesive glycoproteins. Fibroblasts are the most common cells in connective tissue (Figure 5–2) and are responsible for the synthesis of extracellular matrix components. Two stages of activity—active and quiescent—are observed in these cells. Cells with intense synthetic activity are morphologically distinct from the quiescent fibroblasts that are scattered within the matrix they have already synthesized. Some histologists reserve the term fibroblast to denote the active cell and fibrocyte to denote the quiescent cell.
The active fibroblast has an abundant and irregularly branched cytoplasm. Its nucleus is ovoid, large, and pale staining, with fine chromatin and a prominent nucleolus. The cytoplasm is rich in rough endoplasmic reticulum, and the Golgi complex is well developed

The quiescent fibroblast, or fibrocyte, is smaller than the active fibroblast and tends to be spindle shaped. It has fewer processes; a smaller, darker, elongated nucleus; an acidophilic cytoplasm; and a small amount of rough endoplasmic reticulum.
Fibroblasts synthesize proteins, such as collagen and elastin, that form collagen, reticular, and elastic fibers, and the glycosaminoglycans, proteoglycans, and glycoproteins of the extracellular matrix. Fibroblasts are also involved in the production of growth factors that influence cell growth and differentiation. In adults, fibroblasts in connective tissue rarely undergo division; however, mitoses are observed when the organism requires additional fibroblasts.
MEDICAL APPLICATION
The regenerative capacity of the connective tissue is clearly observed when tissues are destroyed by inflammation or traumatic injury. In these cases, the spaces left after injury to tissues whose cells do not divide (eg, cardiac muscle) are filled by connective tissue, which forms a scar. The healing of surgical incisions depends on the reparative capacity of connective tissue. The main cell type involved in repair is the fibroblast.
When it is adequately stimulated, such as during wound healing, the fibrocyte reverts to the fibroblast state, and its synthetic activities are reactivated. In such instances the cell reassumes the form and appearance of a fibroblast. The myofibroblast, a cell with features of both fibroblasts and smooth muscle, is also observed during wound healing. These cells have most of the morphological characteristics of fibroblasts but contain increased amounts of actin microfilaments and myosin and behave like smooth muscle cells. Their activity is responsible for wound closure after tissue injury, a process called wound contraction.
Macrophages & the Mononuclear Phagocyte System
Macrophages were discovered and initially characterized by their phagocytic ability. Macrophages have a wide spectrum of morphological features that corresponds to their state of functional activity and to the tissue they inhabit.When a vital dye such as trypan blue or India ink is injected into an animal, macrophages engulf and accumulate the dye in their cytoplasm in the form of granules or vacuoles visible in the light microscope. In the electron microscope, they are characterized by an irregular surface with pleats, protrusions, and indentations, a morphological expression of their active pinocytotic and phagocytic activities. They generally have a well-developed Golgi complex, many lysosomes, and a prominent rough endoplasmic reticulum.
Macrophages derive from bone marrow precursor cells that divide, producing monocytes that circulate in the blood. In a second step, these cells cross the wall of venules and capillaries to penetrate the connective tissue, where they mature and acquire morphological features of macrophages. Therefore, monocytes and macrophages are the same cell in different stages of maturation. Tissue macrophages can proliferate locally, producing more cells.
Macrophages, which are distributed throughout the body, are present in most organs and constitute the mononuclear phagocyte system (Table 5–2). They are long-living cells and may survive for months in the tissues. In certain regions, macrophages have special names, eg, Kupffer cells in the liver, microglial cells in the central nervous system, Langerhans cells of the skin, and osteoclasts in bone tissue. The process of monocyte-to-macrophage transformation results in an increase in protein synthesis and cell size. Increases in the Golgi complex and in the number of lysosomes, microtubules, and microfilaments are also apparent. Macrophages measure between 10 and 30 m and usually have an oval or kidney-shaped nucleus located eccentrically.
MEDICAL APPLICATION
When adequately stimulated, macrophages may increase in size and are arranged in clusters forming epithelioid cells (named for their vague resemblance to epithelial cells), or several may fuse to form multinuclear giant cells. Both cell types are usually found only in pathological conditions (Figure 5–9).
Macrophages act as defense elements. They phagocytose cell debris, abnormal extracellular matrix elements, neoplastic cells, bacteria, and inert elements that penetrate the organism.
Macrophages are also antigen-presenting cells that participate in the processes of partial digestion and presentation of antigen to other cells (see Chapter 14: Lymphoid Organs). A typical example of an antigen-processing cell is the macrophage present in the skin epidermis, called the Langerhans cell (see Chapter 18: Skin). Although macrophages are the main antigen-presenting cells, under certain circumstances many other cell types, such as fibroblasts, endothelial cells, astrocytes, and thyroid epithelial cells, are also able to perform this function. Macrophages also participate in cell-mediated resistance to infection by bacteria, viruses, protozoans, fungi, and metazoans (eg, parasitic worms); in cell-mediated resistance to tumors; and in extrahepatic bile production, iron and fat metabolism, and the destruction of aged erythrocytes.
When macrophages are stimulated (by injection of foreign substances or by infection), they change their morphological characteristics and metabolism. They are then called activated macrophages and acquire characteristics not present in their nonactivated state. These activated macrophages, in addition to showing an increase in their capacity for phagocytosis and intracellular digestion, exhibit enhanced metabolic and lysosomal enzyme activity.
Macrophages also have an important role in removing cell debris and damaged extracellular components formed during the physiological involution process. For example, during pregnancy the uterus increases in size. Immediately after parturition, the uterus suffers an involution during which some of its tissues are destroyed by the action of macrophages. Macrophages are also secretory cells that produce an impressive array of substances, including enzymes (eg, collagenase) and cytokines that participate in defensive and reparative functions, and they exhibit increased tumor cell–killing capacity.
Mast Cells
Mast cells are oval to round connective tissue cells, 10–13 micros in diameter, whose cytoplasm is filled with basophilic secretory granules. The rather small, spherical nucleus is centrally situated; it is frequently obscured by the cytoplasmic granules. The secretory granules are 0.3–2.0 microns in diameter. Their interior is heterogeneous in appearance, with a prominent scroll-like substructure (Figure 5–11) that contains preformed mediators such as histamine and heparin, a highly acidic, sulfated glycosaminoglycan. The principal function of mast cells is the storage of chemical mediators of the inflammatory response.
Mast cell granules are metachromatic because of the high content of acidic radicals in the heparin glycosaminoglycan. Metachromasia is a property of certain molecules that changes the color of some basic aniline dyes (eg, toluidine blue). The structure containing the metachromatic molecules takes on a color (purple-red) different from that of the applied dye (blue). Other constituents of mast cell granules are histamine, which promotes an increase in vascular permeability that is important in inflammation, neutral proteases, and eosinophil chemotactic factor of anaphylaxis (ECF-A). Mast cells also release leukotrienes (C4, D4, E4) or slow-reacting substance of anaphylaxis (SRS-A), but these substances are not stored in the cell. Rather, they are synthesized from membrane phospholipids and immediately released to the extracellular microenvironment upon appropriate stimulation, such as interaction with fibroblasts. The molecules produced by mast cells act locally in paracrine secretion.
Although they have similar morphology, there are at least two populations of mast cells in connective tissues. One type, called the connective tissue mast cell, is found in the skin and peritoneal cavity; these cells measure 10–12 microns in diameter and their granules contain the anticoagulant heparin. The second type, the so-called mucosal mast cell, is present in the connective tissue of the intestinal mucosa and in the lungs. These cells are smaller (only 5–10 microns) than the connective tissue mast cells and their granules contain chondroitin sulfate instead of heparin.
Mast cells originate from progenitor cells in the bone marrow. These progenitor cells circulate in the blood, cross the wall of venules and capillaries, and penetrate the tissues, where they proliferate and differentiate. Although they are, in many respects, similar to basophilic leukocytes, they have a separate stem cell.
The surface of mast cells contains specific receptors for immunoglobulin E (IgE), a type of immunoglobulin produced by plasma cells. Most IgE molecules are bound to the surface of mast cells and blood basophils; very few remain in the plasma.
MEDICAL APPLICATION
Release of the chemical mediators stored in mast cells promotes the allergic reactions known as immediate hypersensitivity reactions, because they occur within a few minutes after penetration by an antigen of an individual previously sensitized to the same or a very similar antigen. There are many examples of immediate hypersensitivity reaction; a dramatic one is anaphylactic shock, a potentially fatal condition. The process of anaphylaxis consists of the following sequential events: The first exposure to an antigen (allergen), such as bee venom, results in production of the IgE class of immunoglobulins (antibodies) by plasma cells. IgE is avidly bound to the surface of mast cells. A second exposure to the antigen results in binding of the antigen to IgE on the mast cells. This event triggers release of the mast cell granules, liberating histamine, leukotrienes, ECF-A, and heparin (Figure 5–12). Degranulation of mast cells also occurs as a result of the action of the complement molecules that participate in the immunological reaction cited in Chapter 14: Lymphoid Organs.
Histamine causes contraction of smooth muscle (mainly of the bronchioles) and dilates and increases permeability (mainly in postcapillary venules). Any liberated histamine is inactivated immediately after release. Leukotrienes produce slow contractions in smooth muscle, and ECF-A attracts blood eosinophils. Heparin is a blood anticoagulant, but blood clotting remains normal in humans during anaphylactic shock. Mast cells are widespread in the human body but are particularly abundant in the dermis and in the digestive and respiratory tracts.
Plasma Cells
Plasma cells are large, ovoid cells that have a basophilic cytoplasm due to their richness in rough endoplasmic reticulum (Figures 5–13, 5–14, and 5–15). The juxtanuclear Golgi complex and the centrioles occupy a region that appears pale in regular histological preparations.