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Connective Tissue
Connective tissue is derived from mesoderm , the middle germ layer of the embryonic tissue, except in certain areas of the head and neck, where mesenchyme develops from neural crest cells of the developing embryo and is known as ectomesenchyme . Mesenchyme and ectomesenchyme give rise to multipotential cells of the embryo, known as mesenchymal cells , which migrate throughout the body, giving rise to the connective tissues and their cells, including those of bone, cartilage, tendons, capsules, blood and hemopoietic cells, and lymphoid cells ( Fig. 6.1 ).
Schematic diagram of the origins of the cells of connective tissue. Top: Fixed cells; bottom: transient cells. Cells are not drawn to scale.
Mature connective tissue is classified as connective tissue proper , the major subject of this chapter, or specialized connective tissue (i.e., cartilage and bone, detailed in Chapter 7 ; and blood, detailed in Chapter 10 ).
Connective tissue is composed of cells and extracellular matrix (ECM), consisting of ground substance and fibers ( Figs. 6.2, 6.3, and 6.4 ).
Light micrograph of loose (areolar) connective tissue displaying collagen (C) and elastic (E) fibers and some of the cell types common to loose connective tissue (×132).
This is a higher magnification of an area of Fig. 6.2. Note that the fibroblast nuclei (Fn) are oval and that they are larger and paler than the macrophage nuclei (Mn). Mast cells (MC) are the largest cells; they are red because of their numerous, closely packed granules. The thin elastic fibers (EF) and the thicker collagen fibers (CF) are easily distinguishable from each other. (×270).
Schematic diagram illustrating the cell types and fiber types in loose connective tissue. Cells are not drawn to scale.
Some types of connective tissue are recognized because of the preponderance of their fibers, whereas other connective tissues are distinguished by the predominance of their cells. From a functional perspective, fibroblasts are the most important component of loose connective tissue because they manufacture and maintain the fibers and ground substance composing the ECM. In contrast, fibers are the most important component of tendons and ligaments because they function in attaching muscle to bone and bone to bone, respectively. In still other connective tissues, the ground substance is the most important component because it is where certain specialized connective tissue cells, such as extravasated white blood cells, carry out their functions.
Functions of Connective Tissue
The primary functions of connective tissue include structural support ; serving as a medium for exchange of nutrients and waste products, as well as signaling molecules; aiding in the defense , protection , and repair of the body; and acting as a site for storage of fat. Connective tissues also help protect the body by forming a physical barrier to invasion and dissemination of microorganisms. Repair is performed mostly by fibroblasts that manufacture fibrous connective tissue and by cells of bone that mend broken or fractured bones.
Extracellular Matrix
The ECM , a nonliving material, is composed of ground substance and fibers designed to resist compressive and stretching forces. The components of the ECM are ground substance and fibers , as described in Chapter 4 ; the reader is directed to that chapter to review their features.
Cellular Components
The cells in connective tissues are grouped into two categories: fixed cells and transient cells (see Fig. 6.1 ). Fixed cells remain mostly stationary within the connective tissue, where they were formed; it is there that they perform their functions. Transient cells (free or wandering cells) originate mainly in the bone marrow and circulate in the bloodstream, which they leave to enter the connective tissue spaces to perform their specific functions.
Fixed Connective Tissue Cells
The connective tissue cell types that are clearly fixed (fibroblasts, adipose cells, pericytes, mast cells, and macrophages, which exhibit both fixed and transient properties) are described in this section.
Fibroblasts
Fibroblasts, the most abundant cell type in the connective tissue, are responsible for the synthesis of almost the entire ECM.
Fibroblasts form the largest and most profusely distributed cell types of connective tissue proper. They are the least specialized cellular components of connective tissue. They may be active, fibroblasts that manufacture ECM ( Figs. 6.1, 6.3, 6.4, and 6.5 ), or inactive, fibroblasts that do not manufacture ECM.
Active fibroblasts (see Fig. 6.5 ) often reside in close association with type I collagen bundles, where they lie parallel to the long axis of the fibers ( Fig. 6.6 ). Such fibroblasts are elongated, fusiform cells possessing pale-staining cytoplasm, which is often difficult to distinguish from collagen when stained with hematoxylin and eosin. The most obvious portion of the cell is the darker-stained, large, granular, ovoid nucleus containing a well-defined nucleolus. Electron microscopy reveals a prominent Golgi apparatus and abundant rough endoplasmic reticulum (RER) in the fibroblast, especially when the cell is actively manufacturing matrix, as in wound healing.
Inactive fibroblasts (sometimes called fibrocytes) are smaller and more ovoid and possess an acidophilic cytoplasm. Their nuclei are smaller, elongated, and more deeply stained. Electron microscopy reveals sparse amounts of RER but an abundance of free ribosomes.
Clinical Correlations
Although considered to be fixed cells in the connective tissues, fibroblasts are capable of some movement. These cells seldom undergo cell division but may do so during wound healing and may differentiate into adipose cells, chondrocytes (during formation of fibrocartilage), and osteoblasts (under pathological conditions).
Myofibroblasts
Myofibroblasts are modified fibroblasts that demonstrate characteristics similar to those of both fibroblasts and smooth muscle cells.
Histologically, fibroblasts and myofibroblasts are not easily distinguished by routine light microscopy. Electron microscopy, however, reveals that myofibroblasts have bundles of actin filaments and myosin and dense bodies similar to those of smooth muscle cells. Additionally, the surface profile of the nucleus resembles that of a smooth muscle cell; however, myofibroblasts are not surrounded by an external lamina (basal lamina). Myofibroblasts, transitional modifications of fibroblasts, are abundant in areas undergoing wound healing, where they function in wound contraction.
Pericytes
Pericytes surround endothelial cells of capillaries and small venules and technically reside outside of the connective tissue compartment because they possess their own basal lamina.
Pericytes (also known as perivascular cells and adventitial cells ), derived from undifferentiated mesenchymal cells, partly surround the endothelial cells of capillaries and small venules (see Fig. 6.4 ). These cells are outside of the connective tissue compartment because they are surrounded by their own basal lamina, which is usually fused with that of the endothelial cells. Pericytes possess some characteristics of smooth muscle cells in that they contain actin, myosin, and tropomyosin, suggesting that they may function in contraction. They are multipotential cells that, under certain conditions, are able to differentiate into other cells, including vascular smooth muscle cells, endothelial cells, and fibroblasts. Pericytes are discussed more fully in Chapter 11 .
Adipose Cells
Adipose cells are fully differentiated cells that function in the synthesis, storage, and release of fat.
Fat cells , or adipocytes , are derived from undifferentiated fibroblast-like mesenchymal cells ( Fig. 6.7 ), although, under certain conditions, they may arise from fibroblasts.
Fat cells rarely undergo cell division. They manufacture, store, and release triglycerides, as well as synthesize and release hormones called adipokines (see white adipose tissue section in this chapter). There are two types of fat cells: (1) those with a single, large lipid droplet, called unilocular fat cells , which congregate to form white adipose tissue ; and (2) cells with multiple, small lipid droplets, called multilocular fat cells , which congregate to form brown adipose tissue . White fat is much more abundant than brown fat, is distributed differently, and its physiology is different. Here, we describe the histological characteristics of the adipocytes themselves.
Unilocular adipocytes are large spherical cells, up to 120 μm in diameter, which become polyhedral when crowded into adipose tissue ( Fig. 6.8 ). They store fat as a single droplet, which continues to increase in size so that the cytoplasm and nucleus are displaced peripherally against the plasma membrane; the cell resembles a “signet ring” when viewed by light microscopy. Electron micrographs reveal a small Golgi complex situated adjacent to the nucleus, only a few mitochondria, and sparse RER, but an abundance of free ribosomes. Additionally, adipocytes have their own basal lamina. That the fat droplet is not bound by a membrane is clear in electron micrographs but unclear in light micrographs. Their plasma membranes possess receptors for glucocorticoids, growth hormone, insulin, and norepinephrine, which regulate free fatty acid, glycerol, and triglyceride transport into and out of the cell. Minute pinocytotic vesicles of unknown function have been noted on the surface of the plasma membrane. During fasting, the cell surface becomes irregular, displaying pseudopod-like projections. Individual unilocular fat cells are located throughout the body in loose connective tissue and are concentrated along blood vessels. They may also accumulate into masses, forming white adipose tissue.
Multilocular adipocytes are smaller and more polygonal than white fat cells. They store lipids in several small droplets; therefore, their spherical nucleus is not squeezed up against the plasma membrane. Moreover, they house more mitochondria and smooth ER but fewer free ribosomes than unilocular fat cells ( Fig. 6.9 ). By uncoupling oxidation from phosphorylation, these cells generate heat.
Beige adipose cells ( brite adipose cells ), a form of multilocular fat cells, are present among unilocular adipocytes of the inguinal region; they function in heat generation and lipid storage.
Mast Cells
Mast cells arise from bone marrow stem cells and function in mediating the inflammatory process and immediate hypersensitivity reactions.
Mast cells , among the largest of the fixed cells of the connective tissue, are 20 to 30 μm in diameter. They are ovoid and possess a centrally placed, spherical nucleus ( Figs. 6.10 and 6.11 ). Unlike the three types of fixed cells discussed earlier, mast cells probably derive from precursors in the bone marrow (see Fig. 6.1 ).
Electron microscopic studies of mast cells demonstrate that they possess numerous granules of various sizes (0.3-0.8 μm in diameter) in their cytoplasm ( Fig. 6.12 ), as well as a few mitochondria, a sparse number of RER profiles, and a relatively small Golgi complex.
Mast cell granules contain various pharmacological agents, including heparin , histamine (or chondroitin sulfates ), neutral proteases (tryptase, chymase, and carboxypeptidases), aryl sulfatase (as well as other enzymes, such as β-glucuronidase, kininogenase, peroxidase, and superoxide dismutase), eosinophil chemotactic factor ( ECF ), and neutrophil chemotactic factor ( NCF ). Because they are present within the granules, they are referred to as the primary mediators ( preformed mediators ). Mast cells also synthesize a number of pharmacological agents as needed and these are known as secondary mediators (or newly synthesized mediators ). Some are manufactured from membrane arachidonic acid precursors and include leukotrienes ( C 4 , D 4 , and E 4 ), thromboxanes ( TXA 2 and TXB 2 ), and prostaglandins (PGD 2 ). Others are not derived from arachidonic acid precursors, such as platelet-activating factor ( PAF ), bradykinins , interleukins ( IL-4 , IL-5 , IL-6 ), and tumor necrosis factor-alpha ( TNF-α ). These pharmacological agents, whether primary or secondary, function in the immune system by the initiation of an inflammatory response (discussed later).
Mast Cell Development and Distribution
Basophils and mast cells share some characteristics, but they are different cells and have different precursors (see Fig. 6.1 ). Mast cells have a life span of less than a few months and, occasionally, undergo cell division. There are two types of mast cells: those concentrated along small blood vessels, which are known as connective tissue mast cells ; and those that are present in the subepithelial connective tissue of the respiratory and digestive systems, which are called mucosal mast cells . Mast cells in connective tissue contain the sulfated glycosaminoglycan (GAG) heparin in their granules, whereas those located in the alimentary tract mucosa house the GAG chondroitin sulfate. GAGs stain metachromatically with toluidine blue (i.e., toluidine blue stains the granules purple), a characteristic feature of mast cells.
Clinical Correlations
The central nervous system is devoid of mast cells, most probably to prevent swelling of the brain and spinal cord.
Mucosal mast cells release histamine to facilitate the activation of parietal cells of the stomach to produce hydrochloric acid.
Mast Cell Activation and Degranulation
Mast cells possess high-affinity cell-surface Fc receptors (FcεRI) for immunoglobulin E (IgE). These cells function in the immune system by initiating an inflammatory response known as the immediate hypersensitivity reaction (whose systemic form, known as an anaphylactic reaction , may have lethal consequences). This response commonly is induced by foreign molecules (antigens) such as bee venom, pollen, and certain drugs, as follows:
- 1.
The first exposure to any of these antigens elicits formation of IgE antibodies by plasma cells. The IgE binds to the Fc ε RI receptors of the plasmalemma of mast cells, thereby sensitizing these cells.
- 2.
On subsequent exposure to the same antigen, the antigen binds to the IgE on the mast cell surface, causing cross-linking of the bound IgE antibodies and clustering of the receptors ( Fig. 6.13 ).
- 3.
Cross-linking and clustering activate membrane-bound receptor coupling factors , which, in turn, initiate at least two independent processes, the release of primary mediators from the granules and synthesis and release of the secondary mediators ( Table 6.1 ).
TABLE 6.1Principal Primary and Secondary Mediators Released by Mast CellsSubstance Type of Mediator Source Action Histamine Primary Granule Increases vascular permeability; vasodilation; smooth muscle contraction of bronchi; increases mucus production Heparin Primary Granule (of CT mast cells) Anticoagulant; binds to and inactivates histamine Chondroitin sulfate Primary Granule (of mucosal mast cells) Binds to and inactivates histamine Aryl sulfatase Primary Granule Inactivates leukotriene C 4 , thus limiting the inflammatory response Neutral proteases Primary Granule Protein cleavage to activate complement (especially C3a); increases inflammatory response Eosinophil chemotactic factor Primary Granule Attracts eosinophils to site of inflammation Neutrophil chemotactic factor Primary Granule Attracts neutrophils to site of inflammation Leukotrienes C 4 , D 4 , and E 4 Secondary Membrane lipid Vasodilator; increases vascular permeability; bronchial smooth muscle contractant Prostaglandin D 2 Secondary Membrane lipid Causes contraction of bronchial smooth muscle; increases mucus secretion; vasoconstriction Thromboxane A 2 Secondary Membrane lipid Causes platelet aggregation; vasoconstriction Bradykinins Secondary Formed by activity of enzymes located in granules Causes vascular permeability and is responsible for pain sensation Platelet-activating factor Secondary Activated by phospholipase A 2 Attracts neutrophils and eosinophils; causes vascular permeability and contraction of bronchial smooth muscle - 4.
The primary and secondary mediators released by mast cells during immediate hypersensitivity reactions initiate the inflammatory response, activate the body’s defense system by attracting leukocytes to the site of inflammation, and modulate the degree of inflammation (see Fig. 6.13 ).
Sequence of Events in the Inflammatory Response
- 1.
Histamine dilates and increases the permeability of nearby blood vessels. It also causes bronchospasms and increases mucus production in the respiratory tract.
- 2.
Complement components that escaped blood vessels are cleaved by neutral proteases to form additional inflammatory agents.
- 3.
ECF attracts eosinophils to the site of inflammation. These cells phagocytose antigen–antibody complexes, destroy any parasites present, and limit the inflammatory response.
- 4.
NCF attracts neutrophils to the site of inflammation. These cells phagocytose and kill microorganisms, if present.
- 5.
Leukotrienes C 4 , D 4 , and E 4 increase vascular permeability and cause bronchospasms. They are several thousand times more potent than histamine in their vasoactive effects.
- 6.
Prostaglandin D 2 causes bronchospasms and increases secretion of mucus by the bronchial mucosa.
- 7.
PAF causes greater vascular permeability.
- 8.
Thromboxane A 2 is a vigorous platelet-aggregating mediator that also causes vasoconstriction. It is quickly transformed into thromboxane B 2 , its inactive form.
- 9.
Bradykinin is a powerful vascular dilator that causes vascular permeability. It is also responsible for pain.
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