Connective Tissue | Junqueira’s Basic Histology: Text and Atlas, 15e | AccessMedicine (2023)

Fibroblasts are the key cells in connective tissue proper (Figure 5–2 and Table 5–1). Fibroblasts originate locally from mesenchymal cells and are permanent residents of connective tissue. Other cells found here, such as macrophages, plasma cells, and mast cells, originate from hematopoietic stem cells in bone marrow, circulate in the blood, and then move into connective tissue where they function. These and other white blood cells (leukocytes) are transient cells of most connective tissues, where they perform various functions for a short period as needed and then die by apoptosis.


Cellular and extracellular components of connective tissue.

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Connective tissue is composed of fibroblasts and other cells and an ECM of various protein fibers, all of which are surrounded by watery ground substance. In all types of connective tissue the extracellular volume exceeds that of the cells. (Reproduced, with permission, from McKinley M, O'Loughlin VD. Human Anatomy. 2nd ed. New York, NY: McGraw-Hill; 2008; McKinley M, O'Loughlin VD. Human Anatomy. 3rd ed. New York, NY: McGraw-Hill; 2012; McKinley MP, O'Loughlin VD, Bidle TS. Anatomy & Physiology: An Integrative Approach. New York, NY: McGraw-Hill; 2013; McKinley MP, O'Loughlin VD, Bidle TS. Anatomy & Physiology: An Integrative Approach. 2nd ed. New York, NY: McGraw-Hill; 2016).

TABLE 5–1Functions of cells in connective tissue proper.

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TABLE 5–1 Functions of cells in connective tissue proper.

Cell Type Major Product or Activity
Fibroblasts (fibrocytes) Extracellular fibers and ground substance
Plasma cells Antibodies
Lymphocytes (several types) Various immune/defense functions
Eosinophilic leukocytes Modulate allergic/vasoactive reactions and defense against parasites
Neutrophilic leukocytes Phagocytosis of bacteria
Macrophages Phagocytosis of ECM components and debris; antigen processing and presentation to immune cells; secretion of growth factors, cytokines, and other agents
Mast cells and basophilic leukocytes Pharmacologically active molecules (eg, histamine)
Adipocytes Storage of neutral fats


Fibroblasts (Figure 5–3), the most common cells in connective tissue proper, produce and maintain most of the tissue’s extracellular components. Fibroblasts synthesize and secrete collagen (the most abundant protein of the body) and elastin, which both form large fibers, as well as the GAGs, proteoglycans, and multiadhesive glycoproteins that comprise the ground substance. As described later, most of the secreted ECM components undergo further modification outside the cell before assembling as a matrix.



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(a) Fibroblasts typically have large active nuclei and eosinophilic cytoplasm that tapers off in both directions along the axis of the nucleus, a morphology often referred to as “spindle-shaped.” Nuclei (arrows) are clearly seen, but the eosinophilic cytoplasmic processes resemble the collagen bundles (C) that fill the ECM and are difficult to distinguish in H&E-stained sections. (Reproduced, with permission, from Berman I. Color Atlas of Basic Histology. 3rd ed. New York, NY: McGraw-Hill; 2003).

(b) Both active and quiescent fibroblasts may sometimes be distinguished, as in this section of dermis. Active fibroblasts have large, euchromatic nuclei and basophilic cytoplasm, while inactive fibroblasts (or fibrocytes) are smaller with more heterochromatic nuclei (arrows). The round, very basophilic round cells are in leukocytes. (Both X400; H&E)

Distinct levels of fibroblast activity can be observed histologically (Figure 5–3b). Cells with intense synthetic activity are morphologically different 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 more abundant and irregularly branched cytoplasm, containing much rough endoplasmic reticulum (RER) and a well-developed Golgi apparatus, with a large, ovoid, euchromatic nucleus and a prominent nucleolus. The quiescent cell is smaller than the active fibroblast, is usually spindle-shaped with fewer processes, much less RER, and a darker, more heterochromatic nucleus.

Fibroblasts are targets of many families of proteins called growth factors that influence cell growth and differentiation. In adults, connective tissue fibroblasts rarely undergo division. However, stimulated by locally released growth factors, cell cycling and mitotic activity resume when the tissue requires additional fibroblasts, for example, to repair a damaged organ. Fibroblasts involved in wound healing, sometimes called myofibroblasts, have a well-developed contractile function and are enriched with a form of actin also found in smooth muscle cells.


The regenerative capacity of connective tissue is clearly observed in organs damaged by ischemia, inflammation, or traumatic injury. Spaces left after such injuries, especially in tissues whose cells divide poorly or not at all (eg, cardiac muscle), are filled by connective tissue, forming dense irregular scar tissue. The healing of surgical incisions and other wounds depends on the reparative capacity of connective tissue, particularly on activity and growth of fibroblasts.

In some rapidly closing wounds, a cell called the myofibroblast, with features of both fibroblasts and smooth muscle cells, is also observed. These cells have most of the morphologic characteristics of fibroblasts but contain increased amounts of actin microfilaments and myosin and behave much like smooth muscle cells. Their activity is important for the phase of tissue repair called wound contraction.


Adipocytes (L. adeps, fat + Gr. kytos, cell), or fat cells, are found in the connective tissue of many organs. These large, mesenchymally derived cells are specialized for cytoplasmic storage of lipid as neutral fats, or less commonly for the production of heat. Tissue with a large population of adipocytes, called adipose connective tissue, serves to cushion and insulate the skin and other organs. Adipocytes have major metabolic significance with considerable medical importance and are described and discussed separately in Chapter 6.

Macrophages & the Mononuclear Phagocyte System

Macrophages have highly developed phagocytic ability and specialize in turnover of protein fibers and removal of apoptotic cells, tissue debris, or other particulate material, being especially abundant at sites of inflammation. Size and shape vary considerably, corresponding to their state of functional activity. A typical macrophage measures between 10 and 30 μm in diameter and has an eccentrically located, oval or kidney-shaped nucleus. Macrophages are present in the connective tissue of most organs and are sometimes referred to by pathologists as “histiocytes.”


Besides their function in turnover of ECM fibers, macrophages are key components of an organism’s innate immune defense system, removing cell debris, neoplastic cells, bacteria, and other invaders. Macrophages are also important antigen-presenting cells required for the activation and specification of lymphocytes.

When macrophages are stimulated (by injection of foreign substances or by infection), they change their morphologic characteristics and properties, becoming activated macrophages. In addition to showing an increase in their capacity for phagocytosis and intracellular digestion, activated macrophages exhibit enhanced metabolic and lysosomal enzyme activity. Macrophages are also secretory cells producing an array of substances, including various enzymes for ECM breakdown and various growth factors or cytokines that help regulate immune cells and reparative functions.

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When adequately stimulated, macrophages may increase in size and fuse to form multinuclear giant cells, usually found only in pathologic conditions.

In the TEM, macrophages are shown to have a characteristic irregular surface with pleats, protrusions, and indentations, features related to their active pinocytotic and phagocytic activities (Figure 5–4). They generally have well-developed Golgi complexes and many lysosomes.


Macrophage ultrastructure.

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Characteristic features of macrophages seen in this TEM of one such cell are the prominent nucleus (N) and the nucleolus (Nu) and the numerous secondary lysosomes (L). The arrows indicate phagocytic vacuoles near the protrusions and indentations of the cell surface. (X10,000)

Macrophages derive from precursor cells called monocytes circulating in the blood (see Chapter 12). Monocytes cross the epithelial wall of small venules to enter connective tissue, where they differentiate, mature, and acquire the morphologic features of macrophages. Monocytes formed in the yolk sac during early embryonic development circulate and become resident in developing organs throughout the body, comprising a group of related cells called the mononuclear phagocyte system. Many of these macrophage-like cells with prominent functions in various organs have specialized names (Table 5–2). All are long-living cells, surviving with relative inactivity in tissues for months or years. During inflammation and tissue repair which follow organ damage, macrophages become activated and play a very important role. Under such conditions these cells increase in number, mainly in the connective tissue stroma, both by proliferation and by recruiting additional monocytes formed in the bone marrow (see Chapter 13). The transformation from monocytes to macrophages in connective tissue involves increases in cell size, increased protein synthesis, and increases in the number of Golgi complexes and lysosomes. In addition to debris removal, macrophages secrete growth factors important for tissue repair and also function in the uptake, processing, and presentation of antigens for lymphocyte activation, a role discussed later with the immune system.

TABLE 5–2Distribution and main functions of the cells of the mononuclear phagocyte system.

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TABLE 5–2 Distribution and main functions of the cells of the mononuclear phagocyte system.

Cell Type Major Location Main Function
Monocyte Blood Precursor of macrophages
Macrophage Connective tissue, lymphoid organs, lungs, bone marrow, pleural and peritoneal cavities Production of cytokines, chemotactic factors, and several other molecules that participate in inflammation (defense), antigen processing, and presentation
Kupffer cell Liver (perisinusoidal) Same as macrophages
Microglial cell Central nervous system Same as macrophages
Langerhans cell Epidermis of skin Antigen processing and presentation
Dendritic cell Lymph nodes, spleen Antigen processing and presentation
Osteoclast (from fusion of several macrophages) Bone Localized digestion of bone matrix
Multinuclear giant cell (several fused macrophages) In connective tissue under various pathological conditions Segregation and digestion of foreign bodies

Mast Cells

Mast cells are oval or irregularly shaped cells of connective tissue, between 7 and 20 μm in diameter, filled with basophilic secretory granules that often obscure the central nucleus (Figure 5–5). These granules are electron dense and of variable size, ranging from 0.3 to 2.0 μm in diameter. Because of the high content of acidic radicals in their sulfated GAGs, mast cell granules display metachromasia, which means that they can change the color of some basic dyes (eg, toluidine blue) from blue to purple or red. The granules are poorly preserved by common fixatives, so mast cells may be difficult to identify in routinely prepared slides.


Mast cells.

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Mast cells are components of loose connective tissues, often located near small blood vessels (BV).

  • (a) They are typically oval shaped, with cytoplasm filled with strongly basophilic granules. (X400; PT)

  • (b) Ultrastructurally mast cells show little else around the nucleus (N) besides these cytoplasmic granules (G), except for occasional mitochondria (M). The granule staining in the TEM is heterogeneous and variable in mast cells from different tissues; at higher magnifications some granules may show a characteristic scroll-like substructure (inset) that contains preformed mediators such as histamine and proteoglycans. The ECM near this mast cell includes elastic fibers (E) and bundles of collagen fibers (C).

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Mast cells function in the localized release of many bioactive substances important in the local inflammatory response, innate immunity, and tissue repair. A partial list of molecules released from these cells’ secretory granules includes the following:

  • Heparin, a sulfated GAG that acts locally as an anticoagulant

  • Histamine, which promotes increased vascular permeability and smooth muscle contraction

  • Serine proteases, which activate various mediators of inflammation

  • Eosinophil and neutrophil chemotactic factors, which attract those leukocytes

  • Cytokines, polypeptides directing activities of leukocytes and other cells of the immune system

  • Phospholipid precursors, which are converted to prostaglandins, leukotrienes, and other important lipid mediators of the inflammatory response.

Occurring in connective tissue of many organs, mast cells are especially numerous near small blood vessels in skin and mesenteries (perivascular mast cells) and in the tissue that lines digestive and respiratory tracts (mucosal mast cells); the granule content of the two populations differs somewhat. These major locations suggest that mast cells place themselves strategically to function as sentinels detecting invasion by microorganisms.

Release of certain chemical mediators stored in mast cells promotes the allergic reactions known as immediate hypersensitivity reactions because they occur within a few minutes after the appearance of an antigen in an individual previously sensitized to that antigen. There are many examples of immediate hypersensitivity reaction; a dramatic one is anaphylactic shock, a potentially fatal condition. Anaphylaxis consists of the following sequential events (Figure 5–6). The first exposure to an antigen (allergen), such as bee venom, causes antibody-producing cells to produce an immunoglobulin of the IgE class that binds avidly to receptors on the surface of mast cells. Upon a second exposure to the antigen, it reacts with the IgE on the mast cells, triggering rapid release of histamine, leukotrienes, chemokines, and heparin from the mast cell granules that can produce the sudden onset of the allergic reaction. Degranulation of mast cells also occurs as a result of the action of the complement molecules that participate in the immunologic reactions described in Chapter 14.


Mast cell secretion.

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Mast cell secretion is triggered by reexposure to certain antigens and allergens. Molecules of IgE antibody produced in an initial response to an allergen such as pollen or bee venom are bound to surface receptors for IgE (1), of which 300,000 are present per mast cell.

When a second exposure to the allergen occurs, IgE molecules bind this antigen and a few IgE receptors very rapidly become cross-linked (2). This activates adenylate cyclase, leading to phosphorylation of specific proteins (3), entry of Ca2+ and rapid exocytosis of some granules (4). In addition, phospholipases act on specific membrane phospholipids, leading to production and release of leukotrienes (5).

The components released from granules, as well as the leukotrienes, are immediately active in the local microenvironment and promote a variety of controlled local reactions that together normally comprise part of the inflammatory process called the immediate hypersensitivity reaction. “ECF-A” is the eosinophil chemotactic factor of anaphylaxis.

Like macrophages, mast cells originate from progenitor cells in the bone marrow, which circulate in the blood, cross the wall of small vessels called venules, and enter connective tissues, where they differentiate. Although mast cells are in many respects similar to basophilic leukocytes, they appear to have a different lineage at least in humans.

Plasma Cells

Plasma cells are lymphocyte-derived, antibody-producing cells. These relatively large, ovoid cells have basophilic cytoplasm rich in RER and a large Golgi apparatus near the nucleus that may appear pale in routine histologic preparations (Figure 5–7).


Plasma cells.

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Antibody-secreting plasma cells are present in variable numbers in the connective tissue of many organs.

(a) Plasma cells are large, ovoid cells, with basophilic cytoplasm. The round nuclei frequently show peripheral clumps of heterochromatin, giving the structure a “clock-face” appearance. (X640; H&E)

(b) Plasma are often more abundant in infected tissues, as in the inflamed lamina propria shown here. A large pale Golgi apparatus (arrows) at a juxtanuclear site in each cell is actively involved in the terminal glycosylation of the antibodies (glycoproteins). Plasma cells leave their sites of origin in lymphoid tissues, move to connective tissue, and produce antibodies that mediate immunity. (X400 PT)

The nucleus of the plasma cell is generally spherical but eccentrically placed. Many of these nuclei contain compact, peripheral regions of heterochromatin alternating with lighter areas of euchromatin. At least a few plasma cells are present in most connective tissues. Their average life span is only 10-20 days.


Plasma cells are derived from B lymphocytes and are responsible for the synthesis of immunoglobulin antibodies. Each antibody is specific for the one antigen that stimulated the clone of B cells and reacts only with that antigen or molecules resembling it (see Chapter 14). The results of the antibody-antigen reaction are variable, but they usually neutralize harmful effects caused by antigens. An antigen that is a toxin (eg, tetanus, diphtheria) may lose its capacity to do harm when it is bound by a specific antibody. Bound antigen-antibody complexes are quickly removed from tissues by phagocytosis.


Other white blood cells, or leukocytes, besides macrophages and plasma cells normally comprise a population of wandering cells in connective tissue. Derived from circulating blood cells, they leave blood by migrating between the endothelial cells of venules to enter connective tissue. This process increases greatly during inflammation, which is a vascular and cellular defensive response to injury or foreign substances, including pathogenic bacteria or irritating chemical substances.

Inflammation begins with the local release of chemical mediators from various cells, the ECM and blood plasma proteins. These substances act on local blood vessels, mast cells, macrophages, and other cells to induce events characteristic of inflammation, for example, increased blood flow and vascular permeability, entry and migration of leukocytes, and activation of macrophages for phagocytosis.

Most leukocytes function in connective tissue only for a few hours or days and then undergo apoptosis. However, as discussed with the immune system, some lymphocytes and phagocytic antigen-presenting cells normally leave the interstitial fluid of connective tissue, enter blood or lymph, and move to selected lymphoid organs.

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Increased vascular permeability is caused by the action of vasoactive substances such as histamine released from mast cells during inflammation. Classically, the major signs of inflamed tissues include “redness and swelling with heat and pain” (rubor et tumor cum calore et dolore). Increased blood flow and vascular permeability produce local tissue swelling (edema), with increased redness and warmth. Pain is due mainly to the action of the chemical mediators on local sensory nerve endings. All these activities help protect and repair the inflamed tissue. Chemotaxis (Gr. chemeia, alchemy + taxis, orderly arrangement), the phenomenon by which specific cell types are attracted by specific molecules, draws much larger numbers of leukocytes into inflamed tissues.


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