Intercellular Substances

INTERCELLULAR SUBSTANCES, a collective designation for various materials differing in morphological, chemical, and biological relationships, located in tissues between cells. Inter cellular substances include various liquid and semi-liquid substances found between cells, as well as the so-called cementing substance (German: Kittsubstanz), which binds tissue elements, and also various products of tissue differentiation, formerly designated as paraplasmic substances (Kupffer, 1896), which are formed either outside cells (fibers of connective tissue, cartilage ground substance, bone) or within cells but exit beyond their limits (neurofibrils, gliofibrils). In the earliest stages of embryonic development, cells are very densely adjacent to each other, and the entire embryo consists of cells resembling epithelium. With further development, cells move apart (with the exception of ectoderm and partially endoderm cells), becoming star-shaped, and intercellular spaces appear between them. Intercellular spaces reach their greatest development in mesenchyme. As they form, intercellular spaces are filled with liquid content—"intercellular substance" or "intermediate substance." Later, when processes of formation of specific structures begin from initially homogeneous cellular rudiments, very important changes for tissue specificity and differentiation occur in the intercellular substances. Intercellular substances of epithelial tissues. Epithelial cells connect with each other in two ways—either by means of small processes, "bridges," or they are directly adjacent to each other. In the first case, these processes, bridges, form due to the appearance between cells of a series of small vacuoles filled with liquid content. The fluid filling these vacuoles apparently differs in chemical composition in different epithelia. Thus, between intestinal cells in vacuoles separating them, fat may be encountered, especially with a fatty diet, whereas in intercellular vacuoles of covering epithelium fat is never encountered. The exact chemical composition of epithelial intercellular substance has not yet been established, but there are many reasons to believe that the intercellular fluid of epithelium is similar in composition to lymph. In the second type of connection, cells apparently come into direct contact with their surfaces, and no cementing intercellular substance, as was previously thought, exists; in any case, its presence is denied by most authors who have studied epithelium. The actual intercellular substance, as is currently believed, apparently develops only in single-layered epithelia. Here this substance forms the so-called terminal plates, which represent a continuous dense mesh-like skeleton, like a mesh frame covering the epithelium. The substances forming these terminal plates are well preserved in almost all fixatives and are stained by nuclear dyes. The intercellular substance is sometimes also considered to include the structureless membrane on which the epithelium is attached and which usually separates the epithelium from underlying tissues (the so-called membrana basilaris, or membrana terminalis). Intercellular substances of connective tissue. Intercellular substances reach their greatest development in connective tissue. They appear between cells very early in the form of a transparent fluid filling all spaces resulting from the divergence of mesenchymal cells. Later, mesenchyme begins to differentiate. Through the formation of tubes from mesenchymal cells, blood and lymphatic vessels develop, in which the intercellular substance, under the influence of substances secreted by cells, gradually transforms into blood plasma and lymph. Simultaneously, on certain areas, connective tissue proper begins to develop, then cartilaginous masses of the skeleton and bones are laid down. In all these rudiments, as they develop, the intercellular substance undergoes a series of deep chemical, physico-chemical, and morphological transformations leading to the formation of tissue ground substance between cells. Connective tissue proper. The main ground substance of connective tissue is completely homogeneous and has a viscous consistency. In the embryo, the ground substance is completely uniform, gelatinous, mucous, and in many ways resembles blood plasma. Later, in this initially uniform substance, areas of more diluted and more dense material appear. In the diluted areas, tissue lymph accumulates. In fixed preparations, due to the presence of these denser areas, the ground substance appears to be constructed of perforated plates. The chemical composition of the ground substance has not yet been sufficiently studied. It can be considered established that it consists of albumins completely insoluble in body fluids, which distinguishes it from lymph and blood. In addition to albumins (protein complex), it also contains substances very close to mucins. The ground substance swells very easily in water, which is of great importance in the formation of edemas. At certain stages of development, processes leading to the formation of fibers occur in the ground and intermediate substances. According to their staining and physico-chemical properties, they distinguish: 1) argyrophilic fibers (thin small fibers that blacken with silver and appear in very early stages of connective tissue development); 2) reticular fibers (fibers stained by aniline dyes); 3) collagen fibers; 4) elastic fibers. At present, after the work of Maximov and his students, it can be considered proven that all these fibers arise not in cells (the hypothesis of Flemming, Mewes, Lagues), but develop directly in the intercellular substance. Since all fibrous structures exhibit positive uniaxial double refraction (are anisotropic) and since it is now established that this double refraction depends, on one hand, on the crystalline nature of the smallest particles forming the fibers (see Micelles), and on the other hand, on their correctly periodic arrangement, then their appearance in the intercellular substance can be regarded as special crystallization processes. Intercellular substances of cartilage. Cartilage, like connective tissue, is characterized by the powerful development of intercellular substances. This intercellular substance is either completely homogeneous or fibrously striated. Regardless of its structure, collagen fibers and the main cartilaginous substance, consisting of chondromucoid and albuminoid and occupying all spaces between fibers, can always be found in it. Collagen fibers are always present, but due to their identical light refraction with the ground substance, they cannot always be detected by the microscope. Despite the fact that these fibers do not differ in their staining and optical properties from collagen of connective tissue, their chemical composition is however somewhat different: it contains only 16.4% of total nitrogen, which does not correspond to the amount of nitrogen in collagen of connective tissue. Intercellular substances of bone. The intercellular spaces of bone are filled with a dense and hard substance, the same in all vertebrates. In addition to water, the main intercellular substance of bone consists of organic substance—ossein—and inorganic salts. Ossein is a substance completely identical with collagen of connective tissue. The main components of ossein are osseomucoid and albuminoid. Bone albuminoid differs slightly from albuminoid of connective tissue in that it does not dissolve in 2% HCl and in 5% Na₃CO₃, but is readily soluble in 10% KOH. The inorganic salts impregnating the ground substance of bone are quite diverse (for details see Bone). In general, it can be said that intercellular substances play an essential role in the organism as a whole. Appearing very early in embryonic stages, they undergo various transformations depending on the rudiments, fibers form in them, various structures arise. In later stages of development, intercellular substances, having acquired specific qualities, can increase, regenerate, grow; this forces us to look at them not as lifeless structures secreted by cells, but as structures of a vital order which, while not being alive themselves, at the same time represent a necessary system of a lower order, forming together with cells a single living system of the organism. This does not exclude the dependence of various differentiations of the intermediate substance on cells, without which these differentiations cannot be carried out. The nature of this dependence for cartilage and bone has still not been studied in nearly as much detail as for connective tissue. The chemical dynamics of intercellular substances is still very little known, but physico-chemically they can be characterized for all tissues of connective tissue origin as systems with predominance of crystallization processes.

A. Rumyancev. The pathology of intercellular substances has been studied poorly and mainly only in a gross morphological way, despite the fact that a number of pathological processes probably have various physicochemical changes in intercellular substances as their basis; however, the latter are difficult to study. In addition to fluctuations in the amount of water in intercellular substances (see Edema), one can point to the loosening of various elements that make up intercellular substances, as well as their separation, for example, in edema, hemorrhages, inflammatory infiltration, tumor growth, etc. With various changes in tissue associated with its stretching, tears of intercellular substance elements are observed, for example, of collagen and elastic fibrils. Intercellular substances also exhibit manifestations of atrophy - either accompanying atrophic changes in the entire given tissue or as if independent (for example, atrophy of elastic tissue in the lungs in idiopathic emphysema). Specific processes of softening and liquefaction observed in the intercellular substances of connective tissue, in reticular tissue, in the cementing substance, and which are mostly due to enzymatic histolytic processes, lead to the dissociation of tissue elements. In the bone substance, softening can also be observed, associated with the disappearance of lime salts (see Calcinosis). In connective and cartilaginous tissues, there is sometimes a transformation of intercellular substances into mucin, which gives rise to the so-called mucoid degeneration (see) of connective tissue and cartilage. A change in intercellular substances of connective tissue similar to mucoid degeneration is the so-called mucoid edema (see Subcutaneous tissue). Hardening of intercellular substances is observed in hyaline degeneration (see) and in amyloid degeneration (see), which represent pathological changes in intercellular substances. Processes of impregnation, incrustation (see) of various elements of intercellular substances with various materials are very common; these include: deposition of lipoids in intercellular substances, which, manifesting in particular in the inner coat of arteries, results in the development of atherosclerosis (see Arteriosclerosis); incrustation of collagen fibrils and elastic fibers with iron, lime salts; deposition of lime in the cartilage substance. The processes of deposition lead to further changes in intercellular substances; thus, deposition of lipoids results in the breakdown of intercellular substances, incrustation of fibers with iron, lime makes them brittle, which is expressed in fractures, in fragmentation of these fibers (see also Bone, Connective tissue).