The connective tissue, composed of cells and extracellular matrix, forms a framework designated as stroma, which connects and supports all other tissues of the body. However, it is not only an inert scaffolding to stabilize other tissues and organs, but is dynamic and the site of multiple regulatory processes involved in tissue organization, development, wound healing, immune response, and organ repair. The extracellular matrix is constantly renewed and molecules of the extracellular matrix modulate the functional activities of cells. They also play key roles in disease processes, including inflammatory and degenerative diseases and cancer. The matrix is involved in tumor invasion, metastasis, and tumor angiogenesis.

The extracellular matrix is produced by fibroblasts, and mainly consists of fibrils and fibers of collagen and elastin embedded in a ground substance of non-collagenous glycoproteins and proteoglycans. Fibrils, fibers, and components of the ground substance differ between the different types of connective tissue. Contents and architectures of the diverse collagen and elastic fibers determine the tissue’s properties, such as consistency and elasticity. This in turn forms the basis for the classification in loose connective tissue shown in this figure, in dense irregular and dense regular connective tissues (cf. Fig. 160), and in reticular and elastic tissues. Collagen is constituent of thick collagen fibers (type I collagen, cf. Fig. 158) and of fine reticular fibers (mainly type III collagen) present in the fibrillar layers of basement membranes (cf. Fig. 106) and in the reticular connective tissue of the bone marrow and lymphatic organs.

Loose connective tissue is shown in this survey micrograph. It is found in multiple organs, surrounding blood vessels, lymphatics, nerves, and muscles. The figure shows a section of the wall of the rat small intestine. A group of smooth muscle cells of the muscle layer is on display in the left lower corner. The main part of the micrograph presents the submucosal loose connective tissue with sections of cell bodies of a fibroblast and a macrophage. The fibroblast cytoplasm is stuffed with rough endoplasmic reticulum. The prominent Golgi region (G) is in perinuclear position. It is clearly visible that the main architecture of the tissue is made up of two types of networks, the one consisting of fine fibroblast processes (F), the other built by collagen fibrils and fibers (C). Longitudinal and cross sections of collagen fibers are apparent side by side, indicating the reticular arrangement. Collagen fibrils also accompany multiple unmyelinated nerve fibers of the vegetative nerve system (asterisks).

In panels a and b, respectively, an active fibroblast and its inactive counterpart, referred to as fibrocyte, are shown. Fibroblasts constitute the main resident cells of the connective tissue. They synthesize and secrete both the components of the connective tissue ground substance and the precursor molecules of various types of collagen and elastic fibers. The secretory program of the fibroblasts determines the composition of the extracellular matrix and, as a consequence, provides the basis for the construction of a certain type of connective tissue. Fibroblasts are spindle-shaped and show all the characteristics of cells active in protein synthesis. In the karyoplasm, nucleoli are prominent. The long cytoplasmic extensions with multiple surface folds contain densely packed rough endoplasmic reticulum (ergastoplasm). In the Golgi apparatus, the secretory proteins are modified and, after completion, packaged into small vesicles or other post-Golgi carriers to be subsequently transported to the cell surfaces and exported via exocytosis. All components of the ground substance, as well as procollagens and components of elastic fibers, are secreted constitutively. Unlike the events during regulated secretion, cell products are continuously packaged at the Golgi apparatus and subsequently exported; they are not accumulated in the cells. Both transport of nascent secretory molecules across the Golgi stacks and their pathways from the Golgi apparatus to the cell surface were subjects of extensive studies. In contrast to soluble secretory proteins such as albumin, procollagen molecules traverse the Golgi apparatus without leaving the cisternal lumen (cf. Fig. 46). The extremely fine end pieces of the fibroblasts’ processes (arrows) are in contact with each other and build up a network, which, together with bundles of collagen fibrils (C), make up the basic architecture of the connective tissue.

In the inactive fibrocytes (panel b), the cytoplasm is less voluminous compared with the active fibroblasts. Fibrocytes lack ergastoplasm. Their cell processes like wings surround collagen fibers (C), leading to a compartmentalized organization of the tissue. In tendons, the respective fibroblasts are called “wing cells.”

In panel c, a higher magnification of the macrophage shown in Fig. 156 is on display. The surface is jagged and shows deep invaginations of the plasma membrane and multiple endocytosis profiles. Macrophages are mobile cells deriving from monocytes in the blood (cf. Fig. 193). They are equipped with extensive phagocytic properties and contain abundant lysosomes and phagosomes. As in other tissues and organs, macrophages fulfill important tasks during unspecific and specific immune reactions. In the connective tissue, macrophages also are involved in the turnover of extracellular matrix materials and senescent fibers. Elastic fibers (E) and collagen fibrils (C) are apparent close to the surface of macrophages and are present in the spaces that are formed and surrounded by deep plasma membrane invaginations.

Both the precursors of collagen and elastic fibers are synthesized and secreted by fibroblasts and assemble extracellularly to form fibrils and fibers. Panel a shows collagen (C) and elastic fibers (E) in the loose connective tissue of the small intestinal wall. It is the type I collagen that forms particularly thick fibers measuring up to 20 μm in diameter. Collagen fibers are composed of collagen fibrils (C in panel b), which show a characteristic striated pattern effected by differentiated staining caused by the staggered array of the individual tropocollagen molecules (diagram). Arrows in panel a indicate unmyelinated nerve fibers.

Formation of collagen fibers is summarized in the diagram:

The diagram is drawn with modifications according to Kierszenbaum (2002).

Elastic fibers (E in panels a, c and d) have unique properties. Like a rubber, they recoil passively after tissues have been stretched. They are made up of elastin and microfibrils (arrows in panel d), composed of fibrillins 1 and 2 and associated glycoproteins. Microfibrils initiate formation of elastic fibers and form a scaffolding for elastin. Panel d shows that elastin and microfibrils are closely associated. Microfibrils are present in the fibers’ interior and form an enclosing layer outside (arrows). The elastic fiber in panel d is surrounded by fine branching processes of fibroblasts (F).

Precursors of elastic fibers are produced by fibroblasts and also by chondroblasts in the elastic cartilage and by smooth muscle cells in the walls of blood vessels. All three components of elastic fibers – tropoelastin, fibrillins 1 and 2, and microfibril-associated glycoproteins – are synthesized on the rough endoplasmic reticulum and, after glycosylation in the Golgi apparatus, packaged into secretory vesicles and exported via exocytosis. Extracellularly, tropoelastin assembly is initiated by bundles of microfibrils. Cross-linking of tropoelastin is catalyzed by lysyl oxidase. Oxydized lysins condensate into a desmosin ring that covalently cross-links tropoelastin molecules to each other. Fibrillins 1 and 2 provide a force-bearing support and regulate further tropoelastin assembly. Immature elastic fibers formed initially aggregate to build up mature elastic fibers. The two amino acids desmosin and isodesmosin are characteristic for elastin; they are necessary for cross-linking mature elastic fibers and are responsible for their “elastic” properties, allowing stretching and recoil.