Connective tissue is derived from the third germ layer, the mesoderm, which is the same source of origin of muscle tissue. The different types of connective tissue include adipose, fibrous, and elastic tissues as well as blood, bone, and cartilage. All connective tissues are characterized by the presence of a matrix in addition to cells. Matrix is a structural network of non-living intercellular materials. Each connective tissue consists of its own specific matrix. The matrix of blood, for example, contains blood plasma, which is mostly water. The bone matrix is made primarily of calcium salts, which are hard and strong.
Connective tissues provide support to the body, including:
- Physical support (e.g., bone and cartilage)
- Pathways for nerves and blood vessels
- Compartment for exchange between capillaries and active cells
- Immune activity
Connective tissue consists of autochthonous fibrocytes. They form network-like structures over desmosomes and actin filaments. Fibrocytes are recognizable by their long and slim shape in addition to their spindle-shaped nucleus. They synthesize proteins for the extracellular matrix.
These proteins primarily include collagens and proteoglycans. Proteoglycans consist of proteins, the so-called ‘core proteins’ together with long, repeating disaccharide units known as glycosaminoglycans, which are attached to the core proteins. Therefore, proteoglycans are macromolecules containing multiple hydrophilic elements, which facilitate binding with increased quantities of water resulting in a gelatinous texture of the extracellular matrix.
The extracellular matrix is a combination of:
- Non-collagenous glycoproteins
- Proteoglycan aggregates
Collagen is a protein arranged outside the cells in collagen fascicles. The amino acid sequence of Glycine – Proline – Hydroxyproline is vital for the collagen structure. This sequence is constantly repeated, sometimes with variations. The triple helix structure of procollagen is formed by post-translational modifications such as glycosylation and hydroxylation. Tropocollagen is obtained from procollagen via limited proteolysis and loss of fibrocytes. Tropocollagen units aggregate to form a primary filament. Similarly, primary filaments aggregate to form collagen fibrils (also referred to as single fibers). The final step in the process involves the formation of collagen fiber bundle, consisting of multiple fibers.
The most important types of collagen include type I, II, III and IV. Collagen type I is distributed widely in the human body, including the skin, tendons, bones and tooth dentin. Type II collagen, however, is thinner and is primarily found in intervertebral discs, cartilage and in the vitreous humor of the eye. Type III collagen is the finest type and principally lies in smooth muscles, lymphatic tissue, and bone marrow. By contrast, type IV collagen is not fibrillar and is found in the basement membrane and lamina externa of the lens capsule.
Connective tissue also contains mobile cells from the blood and bone marrow, which represent the cellular defense system.
Supportive tissue consists of bone and cartilage tissues. Chondrocytes are found in the cartilage. They are round to oval, containing abundant glycogen stores and occasional fat droplets. Chondrocytes evolve and regenerate until the age of adolescence. Adult chondrocytes lose the ability to proliferate and therefore are usually seen in isogenous groups. Such tightly packed chondrocytes are called ‘chondrons’. Chondrocytes are responsible for matrix formation. The dark chondron color, which is known as the territorial matrix or basophilic ring consists of a newly formed matrix and stains darker due to its basophilic properties.
When viewed under a light microscope, chondrocytes are already dead, since the specimen staining is a very slow procedure. As a consequence, cellular nuclei are often atrophied and deformed. Additional artifacts may include the so-called lacunae, which are formed by leaked cytoplasm.
The cartilage matrix primarily consists of proteoglycans such as aggrecan and hyaluronan, which bind with water in abundance. Compared with connective tissue, the collagen fibrils of cartilage are not arranged in parallel but appear ‘arcade-like’ (mainly type II) to prevent the gel disintegration and redirect the pressure exerted on the bone without crushing the chondrocytes.
Under a light microscope, the cartilage fibrils are often masked and therefore invisible due to their homogenous distribution between the aggrecans. The unique refractive properties cease to exist. However, in aged cartilage, these fibrils may be unmasked, which is a sign of degeneration known as ‘asbestos fibers’.
The cartilage tissue circulation is often poor. Nerves are also hard to find since the mechanical pressure exerted on the cartilage destroys all pathways. Therefore, cartilage survives under minimal nutrition and is a bradytroph. The nutrient supply for cartilage is provided by the synovial fluid, which is synthesized by the synovial cells of the joint cavity.
Cartilage is also surrounded by connective tissue known as the perichondrium. It consists of an outer fibrous layer and an inner chondrogenic layer. The inner layer generates new cartilage cells externally during appositional growth.
In humans, 4 important types of cartilage exist.
First, the embryonic or fetal cartilage contains evenly distributed chondrocytes with round nuclei. It contains the undifferentiated cartilage precursor cells.
Second, the hyaline cartilage is the most common type and typically includes chondrons containing 4–6 chondrocytes. It contains masked collagen II fibers and is found, for e.g., in joint cavities, the trachea, nose, larynx, and the primordial skeleton.
The third type, elastic cartilage (or yellow cartilage) contains more chondrons, which, however, contain only one to two chondrocytes. Its matrix is primarily composed of elastic fibers and few type II collagen fibrils. It is found in the auricle and in small bronchioles.
The fourth type, fibrocartilage is a mixture of connective and cartilage tissue, containing both fibrocytes and chondrons with one to two chondrocytes. Its matrix contains collagen type I. Fibrocartilage is found in the intervertebral discs or cartilaginous joints.
By contrast, despite similar structure, bone tissue is not malleable. The bone tissue contains calcium apatite precipitating along the collagen fibers, which makes the majority of the tissue inorganic. The bone tissue is discussed further in the article on bones.
Adipose tissue is a special type of connective tissue containing differentiated cells known as adipocytes, which are designed for fat storage. The fibers typical of the connective tissue move into the background. The two categories of adipose tissue include white and brown types.
Brown adipose tissue is also known as plurivacuolar adipose tissue, which contains small and round cells with centrally located nuclei. The cells are very well vascularized and generate heat. Brown adipose tissue is mainly found in newborns and young children, and rarely in adults.
White adipose tissue (monovacuolar adipose tissue) contains adipocytes with a broad diameter for fat storage. The nucleus in an adipocyte is located peripherally. White adipose tissue is hardly vascularized. It is a sub-category of loose connective tissue and thus contains collagen type III fibers. White adipose tissue is responsible for storing energy and acts as a heat regulator, stuffing material and as a cushion.
Recent studies suggest that adipose tissue also has an endocrine function, because it secretes hormones such as leptin, adiponectin, and resistin. Leptin is an appetite-suppressing hormone secreted by adipocytes. It signals the hypothalamus in the brain when fat storage is adequate. A diminished secretion of leptin signals an appetite increase.
Adipocytes secrete adiponectin and resistin to regulate the insulin levels in glucose and fat metabolism. Low levels of adiponectin and elevated resistin levels are strongly associated with increased risk of insulin resistance, type 2 diabetes (T2DM), metabolic syndrome (MS) and cardiovascular disease. Adipose tissue is also involved in inflammation, the body’s first response to injury, by producing cytokines that activate white blood cells.
Cellular mobility is based on motor proteins displaying ATPase activity. In muscle tissue, this mobility must be directed and coordinated to generate effective contraction. The actin-myosin complex plays a vital role in this process, which is unique to muscle cells. The three types of muscle include: skeletal muscle, smooth muscle and cardiac muscle.
Skeletal muscle is also known as striated or voluntary muscle. The skeletal muscle cells are cylindrical and carry several nuclei each. The cells appear striated or striped as a result of the precise arrangement of the contracting proteins within the cells. The skeletal muscle cells are distinguished by their long nucleus and striation, which are observed only in longitudinal sections and preferably at higher magnification. Single skeletal muscle cells build a syncytium in the muscles to fuse and form a big cell, which is up to 20 cm long. The syncytia are organized in parallel arrays, forming muscle fibers. In contrast to smooth muscles, they are not connected with gap junctions.
The sarcomere is the functional unit of a striated skeletal muscle. It contains all the components essential for the muscle contraction. A sarcomere extends from one Z-line to the next. The barbed ends (plus-ends) of actin filaments are fastened by actinin on each Z-line. The myosin filaments exist in between the actin filaments and are bound to the actin filaments by their heads. The myosin filaments reverse their polarity in the middle of their path. This location within the sarcomere is called the M-Line. Further, the myosin filaments are elastically attached to the Z-lines by titin, which is the largest known protein in humans.
When viewed under a microscope, the muscle displays different types of bands causing the striations in the first place. The A-band refers to the anisotropic part of the sarcomere, which appears mostly dark and contains the entire length of myosin filaments. The H-band lies in the middle of the A-band as a lighter portion containing only myosin filaments and overlaps with actin filaments. The isotropic part of the sarcomere is called the I-band, which contains the Z-lines and actin filaments, appearing light in color microscopically.
During contraction, the Z-lines slide past each other, until the actin filaments ‘bump into each other’. The H-band also disappears. This motion is rendered possible via the cross-bridge cycle. The contraction is limited by the length of the actin filaments, which occurs in active insufficiency.
In case of a more powerful stretch, the Z-lines are pulled so far from each other that only the last myosin head remains attached to the actin filaments. However, in case of an unduly powerful stretch, a filament rupture can occur. This type of limited stretching ability is called a passive insufficiency.
An optimal contraction requires the coordinated action of all the syncytia. Therefore, Z-lines from different cells are bound together by desmin. Further, Z-lines are fastened on the cell membrane by plectin. In striated muscles, this is referred to as sarcolemma, which displays multiple invaginations or T-tubules (transversal tubules) extending deep into the cytoplasm. The T-tubules facilitate the rapid transfer of cell membrane depolarization to the inside of the cell.
The endoplasmic reticulum of muscles is called the sarcoplasmic reticulum, which forms the longitudinal tubule system (L-tubule) responsible for Ca2+ storage.
Striated muscle communicates with the surrounding connective tissue. The individual myocyte is ensheathed by endomysium, which consists of collagen types III and IV. Connections between the extracellular matrix and muscle cells are facilitated by focal adhesions via dystrophin and integrin. Further, satellite cells that exist between the basement membrane and the muscle cells act as stem cells. Their ‘daughter cells’ fuse with muscle fibers and produce additional cell organelles or increase the biosynthesis and the average number of fibers.
Nearly 20 muscle fibers are surrounded by internal perimysium, and most of them are demarcated by the external perimysium. The epimysium extends around the entire muscle and towards the tendon. The perimysium and epimysium contain mainly collagen type I.
The muscular connective tissue is vital to the stabilization, power transfer and individualization of muscles in the fiber groups. Additionally, it facilitates the integration of blood vessels and nerves into the muscle.
In case of severe muscle traumatization, the connective tissue also forms a bridge, resulting in scar formation and limited muscle mobility, since the muscle is no longer able to actively contract.
Striated muscle fibers function according to the all-or-none principle, i.e. they can either completely contract or rest. Our ability to exert different levels of muscular power during activity is guaranteed via innervation. Thus, in circumstances requiring less force exertion, fewer fibers are activated when compared with conditions requiring great strain.
Smooth muscle is also called involuntary or visceral muscle. The cells of smooth muscle carry tapered ends, a single nucleus, and lack striations. Smooth muscles are present in the walls of hollow organs. They contract slowly, but more powerfully than striated muscles. Further, the varying tension of smooth muscle results in maintenance of a real tone. Similar to a striated muscle, the sliding of actin filaments facilitates the contraction of smooth muscles. However, the contractile apparatus is arranged like a snake fence and is therefore distinguished from the strictly parallel skeletal muscles. The actin filaments are bound together via the so-called ‘dense bodies’ (equivalent to the Z-lines), and the connection with the cell membrane is facilitated via adhesion plaques. The non-longitudinal structure facilitates the contraction of smooth muscle cells in multiple directions.
The cellular network of the contractile apparatus draws the organelles in the vicinity of the centrally located nucleus, and are therefore considered perinuclear cell organelles.
Smooth muscles also require a coordinated work of individual cells to generate contraction. Therefore, most of them are connected via gap junctions. This phenomenon is referred to as a functional linkage and is distinct from the syncytium of the striated muscles.
The functions of smooth muscle are dictated by the other internal organ systems. In the stomach and intestines, smooth muscle contracts in peristaltic waves to propel food through the digestive tract. In the walls of arteries and veins, smooth muscle constricts or dilates the vessels to maintain normal blood pressure. The iris of the eye contains two sets of smooth muscle fibers to constrict or dilate the pupil, which regulates the amount of light that strikes the retina.
Typical histology of smooth muscle reveals alternating longitudinal and transverse sections of cells. Except for tongue specimens, no such histology is found in striated muscles.
Since smooth muscle displays no striation, it is often confused by medical students with connective tissue. In order to avoid this misconception, one should examine the network-like structure of the connective tissue, which is rich in the extracellular matrix, and distinguish it from the smooth muscle tissue with poor matrix displaying a parallel array only approximately.
Cardiac muscle is often deemed an intermediate form between smooth and striated muscle. In reality, it encompasses structures from both tissue types. Similar to smooth muscle, cardiac muscle consists of individual cells that form a functional syncytium aided by cell-to-cell adhesions and gap junctions. The intercellular adhesions facilitate mechanical linkage for the transfer of tractive forces, whereas the gap junctions are responsible for the exchange of ions, second messengers, and tiny metabolites between adjacent cells.
The cardiac muscle is striated like skeletal muscle, but in very well-preserved specimen it displays the so-called intercalated discs. These always occur at the crossover between single cardiac cells and run orthogonal to the direction of the fibers. Most often, they are dark in color or even black. The intercalated discs are typical of cardiac muscle as a result of adhesion and communicating junctions between individual cells.
This intricate organization enables precise waves of contraction from the upper to the lower chambers in a heart. Cardiac muscle is also known as the myocardium and forms the walls of the four chambers of the heart. Its function, therefore, is to pump blood. The myocardial contractions generate blood pressure and ensure blood circulation and function throughout the body.
Cardiac muscle cells can contract autonomously. Thus, the heart maintains its own beat. The role of nerve impulses is to increase or decrease the heart rate, depending upon the specific needs in any situation.
Epithelial tissue covers surface areas of the body and contains no extracellular matrix. Because they have no capillaries of their own, the epithelial tissues receive oxygen and nutrients from the blood supply of the underlying connective tissue. Several epithelial tissues are capable of secretion and may be known as the glandular epithelium, or more simply, as glands. Due to the existence of multiple types of epithelium in humans, a complete article is devoted to the Histology of epithelium.
Nervous tissue consists of nerve cells, surrounded by a 10-fold higher number of glial cells. Both cell types are derived from the ectoderm. Similar to fibrocytes, nerve cells also exhibit a network-like structure. Nerve tissue includes the brain, spinal cord, and peripheral nerves. The nervous system is divided into the central nervous system (CNS) and the peripheral nervous system (PNS).
Brain and spinal cord are the organs of the CNS. They are composed of neurons and specialized cells known as neuroglia.
The PNS consists of all the nerves that emerge from the CNS and supply the rest of the body. These nerves are made of neurons and specialized cells called Schwann cells.
Nerve cells are also called neurons and are responsible for processing the signals transmitted between chemical synapses. Their dendrites, varying in number and measuring up to 1 m in length, receive the neuronal signal and transmit it to the 1-m-long axon.
The cytosol of the neurons is referred to as the perikaryon or soma. Neurons contain the usual cell organelles, but display an abundance of the rough endoplasmic reticulum (RER), which is responsible for the constant cellular repair. This repair mechanism is particularly important for the neurons, as they exhibit limited regenerative ability over a lifetime. The components of RER are basophilic and have a typical blue stain. They are observed in the soma but decrease at the point where the axon hillock begins.
The substances produced in the soma are transported over the whole length of the axon during the axoplasmic flow. The kinesin system is responsible for the anterograde (from the soma to the axon) transportation of the neurotransmitters, which are essential for the synapses. The retrograde flow from the axon to the soma is facilitated by the dynein system and is responsible for the axonal feedback. In the case of pressure exertion, this flow is hindered, which leads to a sensation of limbs ‘falling asleep’. Persistence of this pressure for several days can result in an irreversible disorder, e.g., due to a plaster cast on the lower leg without proper fibular head padding.
The different types of neurons are categorized by the number of dendrites protruding from their soma. Unipolar neurons contain no dendrites, but only a long axon, and are not very common. Bipolar neurons carry a dendrite, which is split distally, and an axon. They are typically found in sensory organs such as the eyes and the ears. Pseudounipolar nerve cells are bipolar neurons with merged axon and dendrite, and a laterally translocated soma. Since only a single extension is observed, they are called pseudounipolar neurons. They are mostly found in sensory nerves. Their cellular bodies constitute the sensory ganglia, e.g., the dorsal roots of spinal nerves. Multipolar nerve cells act as higher control centers and process information related to interconnected multiple nerve cells. They are the type of neurons most commonly found in the central nervous system and contain mainly short dendrites and a single longer axon.
Glial Cells (Neuroglia)
There are many different types of glial cells, with distinct function and locations. Ependymal cells are found only in the central nervous system and in small subarachnoid spaces, with an epithelial-like function. Astrocytes are also exclusively located in the central nervous system and supply the neurons with nutrients, thanks to their star-shaped connections with blood vessels. Further, they induce the formation of endothelial tight junctions and are responsible for the specific density of these blood vessels, playing an important role in the blood-brain-barrier (BBB). They also fill the extracellular space of the central nervous system. Satellite cells line the soma in the neurons of the peripheral nervous system.
Oligodendrocytes and Schwann cells produce myelin around the neural extensions. They form the myelin sheath around an axon to generate a spiral structure, consisting of cellular membrane and neural extensions, which actually constitute an insulation sheath. Since the protein-streaked membrane cannot exist completely without cytoplasm, the so-called Schmidt-Lanterman incisures are left in the spiral. A Schwann cell is responsible for the myelination of a single extension, whereas oligodendrocytes wrap themselves around additional extensions. However, an unmyelinated axon is merely embedded in the cytoplasm of the Schwann cell surrounding multiple extensions.
Signal transmission between unmyelinated fibers is considerably slower than the saltatory conduction of myelinated axons, which significantly increases the velocity of action potentials. Under such conditions, the action potential is propagated from one node of Ranvier to another, namely from the locations between two Schwann cells or oligodendrocytes, due to a myelin sheath gap.
The internode is part of the extension that is insulated by a glial cell. An internode is, therefore, always found between the two nodes of Ranvier. The longer the internode, the quicker the signal transmission. The length of the internode depends on the size of the glial cell and is increased as the thickness of the extension increases. The conduction velocity of a nerve ranges from 1–100 m/s.
Microglia are an exception to the rest of the glial cells since they are derived from the bone marrow and have developed from the mesoderm. They are categorized under macrophages and play a role in the defense of the nervous system.