Growth

Growth is the process of increase in size resulting from the synthesis of specific tissue components. The term may be applied to populations, individuals, organs, cells, or even subcellular organelles such as mitochondria.

Types of growth in a tissue (Fig. 5.1A) are:

Fig. 5.1 Growth and differentiation. Types of growth in a tissue. Differentiation of undifferentiated cells into ciliated cells in bronchus.

Differentiation

Differentiation is the process whereby a cell develops an overt specialised function or morphology that distinguishes it from its parent cell. There are many different cell types in the human body, but all somatic cells in an individual have identical genomes. Differentiation is the process by which genes are expressed selectively and gene products act to produce a cell with a specialised function (Fig. 5.1B). After fertilisation of the human ovum, and up to the eight-cell stage of development, all of the embryonic cells are apparently identical. Thereafter, cells undergo several stages of differentiation in their passage to fully differentiated cells, such as, for example, the ciliated epithelial cells lining the respiratory passages of the nose and trachea. Although the changes at each stage of differentiation may be minor, differentiation can be said to have occurred only if there has been overt change in cell morphology (e.g. development of a skin epithelial cell from an ectodermal cell), or an alteration in the specialised function of a cell (e.g. the synthesis of a hormone).

Morphogenesis

Complex process of embryological development

Responsible for formation of shape and organisation of body organs

Involves cell growth and differentiation, and relative movement of cell groups

Programmed cell death (apoptosis) removes unwanted features

Morphogenesis is the highly complex process of development of structural shape and form of organs, limbs, facial features, etc. from primitive cell masses during embryogenesis. For morphogenesis to occur, primitive cell masses must undergo co-ordinated growth and differentiation, with movement of some cell groups relative to others, and focal programmed cell death (apoptosis) to remove unwanted features.

Regeneration

Process of replacing injured or dead cells

Cell types vary in regenerative ability

Labile cells: very high regenerative ability and rate of turnover (e.g. intestinal epithelium)

Stable cells: good regenerative ability but low rate of turnover (e.g. hepatocytes)

Permanent cells: no regenerative ability (e.g. neurones)

Regeneration enables cells or tissues destroyed by injury or disease to be replaced by functionally identical cells. These replaced ‘daughter’ cells are usually derived from a tissue reservoir of ‘parent’ stem cells (discussed below, p. 92). The presence of tissue stem cells, with their ability to proliferate, governs the regenerative potential of a specific cell type. Mammalian tissues fall into three classes according to their regenerative ability:

Labile cells proliferate continuously in post-natal life; they have a short life-span and a rapid ‘turnover’ time. Their high regenerative potential means that lost cells are rapidly replaced by division of stem cells. However, the high cell turnover renders these cells highly susceptible to the toxic effects of radiation or drugs (such as anti-cancer drugs) that interfere with cell division. Examples of labile cells include:

The high regenerative potential of the skin is exploited in the treatment of patients with skin loss due to severe burns. The surgeon removes a layer of skin which includes the dividing basal cells from an unburned donor site, and fixes it firmly to the burned graft site where the epithelium has been lost (Ch. 6). Dividing basal cells in the graft and the donor site ensure regeneration of squamous epithelium at both sites, enabling rapid healing in a large burned area where regeneration of new epithelium from the edge of the burn would otherwise be prolonged.

Stable cells (sometimes called ‘conditional renewal cells’) divide very infrequently under normal conditions, but their stem cells are stimulated to divide rapidly when such cells are lost. This group includes cells of the liver, endocrine glands, bone, fibrous tissue and the renal tubules.

Permanent cells normally divide only during fetal life, but their active stem cells do not persist long into post-natal life, and they cannot be replaced when lost. Cells in this category include neurones, retinal photoreceptors and neurones in the eye, cardiac muscle cells and skeletal muscle (although skeletal muscle cells do have a very limited capacity for regeneration).

The cell cycle

Successive phases of progression of a cell through its cycle of replication are defined with reference to DNA synthesis and cellular division. Unlike the synthesis of most cellular constituents, which occurs throughout the interphase period between cell divisions, DNA synthesis occurs only during a limited period of the interphase; this is the S phase of the cell cycle. A further distinct phase of the cycle is the cell-division stage or M phase (Fig. 5.3) comprising nuclear division (mitosis) and cytoplasmic division (cytokinesis). Following the M phase, the cell enters the first gap (G₁) phase and, via the S phase, the second gap (G₂) phase before entering the M phase again. Although initially regarded as periods of inactivity, it is now recognised that these ‘gap’ phases represent periods when critical processes occur, preparing the cells for DNA synthesis and mitosis.

Fig. 5.3 The four stages of the cell cycle. G1 represents preparation for DNA synthesis (S phase), and G2 represents preparation for mitosis (M phase). After mitosis individual daughter cells may each re-enter the cycle at G1 if appropriate stimuli are present. Alternatively, they may permanently or temporarily enter G0 and differentiate. Progress around the cell cycle is one-way. ‘Checkpoints’ ensure one phase does not commence until the previous phase is completed. Failure of a phase to complete satisfactorily results in cell cycle arrest, or—if the problem is irretrievable—apoptosis.

After cell division (mitosis), individual daughter cells may re-enter G1 to undergo further division if appropriate stimuli are present. Alternatively, they may leave the cycle and become quiescent or ‘resting’ cells—a state often labelled as G₀. Entry to G₀ may be associated with a process of terminal differentiation, with loss of potential for further division and death at the end of the lifetime of the cell; this occurs in permanent cells, such as neurones. Other quiescent cells retain some ability to proliferate by re-entering G1 if appropriate stimuli are present.

Therapeutic interruption of the cell cycle

Many of the drugs used in the treatment of cancer affect particular stages within the cell cycle (Fig. 5.4). These drugs inhibit the rapid division of cancer cells, although there is often inhibition of other rapidly dividing cells, such as the cells of the bone marrow and lymphoid tissues. Thus, anaemia, a bleeding tendency and suppression of immunity may be clinically important side-effects of cancer chemotherapy.

Fig. 5.4 Pharmacological interruption of the cell cycle. The sites of action in the cell cycle of drugs that may be used in the treatment of cancer.

Cell death in growth and morphogenesis

It seems illogical to think of cell death as a component of normal growth and morphogenesis, although we recognise that the loss of a tadpole’s tail, which is mediated by the genetically programmed death of specific cells, is part of the metamorphosis of a frog. It is now clear that such cell death has an important role in human development and in the regulation of tissue size throughout life. Alterations in the rate at which cell death occurs are important in situations such as hormonal growth regulation, immunity and neoplasia.

Apoptosis

The term apoptosis is used to denote a physiological cellular process in which a defined and programmed sequence of intracellular events leads to the death of a cell without the release of products harmful to surrounding cells. It is a biochemically specific mode of cell death characterised by activation of non-lysosomal endogenous endonuclease which digests nuclear DNA into smaller DNA fragments. Morphologically, apoptosis is recognised as death of scattered single cells which form rounded, membrane-bound bodies; these are eventually phagocytosed (ingested) and broken down by adjacent unaffected cells.

The co-existence of apoptosis alongside mitosis within a cell population ensures a continuous renewal of cells, rendering a tissue more adaptable to environmental demands than one in which the cell population is static.

Apoptosis can be triggered by factors outside the cell or it can be an autonomous event (‘programmed cell death’). In embryological development, there are three categories of autonomous apoptosis:

• morphogenetic

• histogenic

• phylogenetic.

Morphogenetic apoptosis is involved in alteration of tissue form. Examples include:

• interdigital cell death responsible for separating the fingers (Fig. 5.5)

• cell death leading to the removal of redundant epithelium following fusion of the palatine processes during development of the roof of the mouth

• cell death in the dorsal part of the neural tube during closure, required to achieve continuity of the epithelium, the two sides of the neural tube and the associated mesoderm

• cell death in the involuting urachus, required to remove redundant tissue between the bladder and umbilicus.

Fig. 5.5 Morphogenesis by apoptosis. Genetically programmed apoptosis (individual cell death) causing separation of the fingers during embryogenesis.

Failure of morphogenetic apoptosis in these four sites is a factor in the development of syndactyly (webbed fingers), cleft palate, spina bifida, and bladder diverticulum (pouch) or fistula (open connection) from the bladder to the umbilical skin, respectively.

Histogenic apoptosis occurs in the differentiation of tissues and organs, as seen, for example, in the hormonally controlled differentiation of the accessory reproductive structures from the Müllerian and Wolffian ducts. In the male, for instance, anti-Müllerian hormone produced by the Sertoli cells of the fetal testis causes regression of the Müllerian ducts (which in females form the fallopian tubes, uterus and upper vagina) by the process of apoptosis.

Phylogenetic apoptosis is involved in removing vestigial structures from the embryo; structures such as the pronephros, a remnant from a much lower evolutionary level, are removed by the process of apoptosis.

Regulation of apoptosis

Apoptosis may be triggered by external signals, such as detachment from the extracellular matrix, the withdrawal of growth factors, or specific signals from other cells. This mode of activation of apoptosis is called the extrinsic pathway. By contrast, the intrinsic pathway is activated by intracellular signals, such as DNA damage or failure to conduct cell division correctly. Although apoptosis can be induced by diverse signals in a variety of cell types, a few genes appear to regulate a final common pathway. The most important of these are the members of the bcl-2 family (bcl-2 was originally identified at the t(14;18) chromosomal breakpoint in follicular B-cell lymphoma, and it can inhibit many factors that induce apoptosis). The bax protein (also in the bcl-2 family) forms bax–bax dimers which enhance apoptotic stimuli. The ratio of bcl-2 to bax determines the cell’s susceptibility to apoptotic stimuli, and constitutes a ‘molecular switch’ which determines whether a cell will survive, leading to tissue expansion, or undergo apoptosis.

The study of factors regulating apoptosis is of considerable importance in finding therapeutic agents to enhance cell death in malignant neoplasms.

Increased growth: hypertrophy and hyperplasia

Hyperplasia and hypertrophy are common tissue responses

May be physiological (e.g. breast enlargement in pregnancy) or pathological (e.g. prostatic enlargement in elderly men)

Hypertrophy: increase in cell size without cell division

Hyperplasia: increase in cell number by mitosis

The response of an individual cell to increased functional demand is to increase tissue or organ size (Fig. 5.6) by:

Fig. 5.6 Hyperplasia and hypertrophy. In hypertrophy, cell size is increased. In hyperplasia, cell number is increased. Hypertrophy and hyperplasia may co-exist.

The stimuli for hypertrophy and hyperplasia are very similar, and in many cases identical; indeed, hypertrophy and hyperplasia commonly co-exist. In permanent cells hypertrophy is the only adaptive option available under stimulatory conditions. In some circumstances, however, permanent cells may increase their DNA content (ploidy) in hypertrophy, although the cells arrest in the G₂ phase of the cell cycle without undergoing mitosis; such a circumstance is present in severely hypertrophied hearts, where a large proportion of cells may be polyploid.

An important component of hyperplasia, which is often overlooked, is a decrease in cell loss by apoptosis; the mechanisms of control of this decreased apoptosis are unclear, although they are related to the factors causing increased cell production (Fig. 5.7).

Fig. 5.7 Control of tissue growth by induction or inhibition of apoptosis. Quiescent (mitotically inactive) cells in G0 are recruited into a high turnover (mitotically active) state by growth factors. Their subsequent fate depends on the presence or absence of apoptosis inducers or inhibitors. The inducers and inhibitors are mediated by the bax and bcl-2 proteins respectively, among others.

Hyperplasia in tissue repair

The proliferation of vascular (capillary) endothelial cells and myofibroblasts in scar tissue, and the regeneration of specialised cells within a tissue, are the important components of the response to tissue damage.

Angiogenesis is the process whereby new blood vessels grow into damaged, ischaemic or necrotic tissues in order to supply oxygen and nutrients for cells involved in regeneration and repair (the term ‘vasculogenesis’ should be reserved specifically for the blood vessel proliferation that occurs in the developing embryo and fetus). In response to local tissue damage, vascular endothelial cells within pre-existing capillaries are activated by angiogenic growth factors such as vascular endothelial growth factor (VEGF), released by hypoxic cells or macrophages. These activated endothelial cells then migrate towards the angiogenic stimulus to form a ‘sprout’. Cell migration is facilitated by the secretion of enzymes including the matrix metalloproteinases, which selectively degrade extracellular matrix proteins. Adjacent sprouts connect to form vascular loops, which canalise and establish a blood flow. Later, mesenchymal cells—including pericytes and smooth muscle cells—are recruited to stabilise the vascular architecture, and the extracellular matrix is remodelled.

Two other initiating mechanisms exist in addition to the above ‘sprouting’ form of angiogenesis: existing vascular channels may be bisected by an extracellular matrix ‘pillar’ (intussusception), with the two channels subsequently being extended towards the angiogenic stimulus. The final mechanism involves circulating primordial stem cells which are recruited at sites of hypoxia and differentiate into activated vascular endothelial cells. Note that a similar process of angiogenesis occurs in response to tumour cells, as an essential component of the development of the blood supply of enlarging neoplasms. Such angiogenesis is a potential therapeutic target in the treatment of malignant neoplasms, although theoretically such drugs might impair angiogenesis and therefore delay healing of wounds.

Myofibroblasts often follow new blood vessels into damaged tissues, where they proliferate and produce matrix proteins such as fibronectin and collagen to strengthen the scar. Myofibroblasts eventually contract and differentiate into fibroblasts. The resulting contraction of the scar may cause important complications, such as:

• deformity and reduced movements of limbs affected by extensive scarring following skin burns around joints

• bowel stenosis and obstruction caused by annular scarring

• detachment of the retina due to traction caused by contraction of fibrovascular adhesions between the retina and the ciliary body following intra-ocular inflammation.

Thus vascular endothelial cell and myofibroblast hyperplasia are important components of repair and regeneration at various sites in the body, as described below.

Skin

The healing of a skin wound is a complex process involving the removal of necrotic debris from the wound and repair of the defect by hyperplasia of capillaries, myofibroblasts and epithelial cells. Figure 5.8 illustrates some of the key events, most of which are mediated by growth factors.

Fig. 5.8 Factors mediating wound healing. A wound is shown penetrating the skin and entering a blood vessel. (1) Blood coagulation and platelet degranulation, releasing growth factors (GF). (2) These are chemotactic for macrophages, which migrate into the wound to phagocytose bacteria and necrotic debris (3). Epidermal basal epithelial cells are activated by released growth factors from the platelets (4) and dermal myofibroblasts (5); from epidermal cells by paracrine (6) and autocrine (7) mechanisms; and from saliva (8) (if the wound is licked). Nutrients and oxygen (9) and circulating hormones and growth factors diffusing from blood vessels all contribute to epidermal growth. Growth factors from the platelets stimulate cell division in myofibroblasts (10), which produce collagen and fibronectin. Fibronectin stimulates migration of dermal myofibroblasts (11) and epidermal epithelial cells (12) into and over the wound. Angiogenic growth factors (not shown) stimulate the proliferation and migration of new blood vessels into the area of the wound (13).

When tissue injury occurs there is haemorrhage into the defect from damaged blood vessels; this is controlled by normal haemostatic mechanisms, during which platelets aggregate and thrombus forms to plug the defect in the vessel wall. Because of interactions between the coagulation and complement systems, inflammatory cells are attracted to the site of injury by chemotactic complement fractions. In addition, platelets release two potent growth factors, platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta), which are powerfully chemotactic for inflammatory cells, including macrophages; these migrate into the wound to remove necrotic tissue and fibrin.

In the epidermis, PDGF acts synergistically with epidermal growth factor (EGF), derived from epidermal cells, and the somatomedins, insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2), to promote proliferation of basal epithelial cells. EGF is also present in high concentrations in saliva and may reach wounds when they are licked. In the dermis, myofibroblasts proliferate in response to PDGF (and TGF-beta); collagen and fibronectin secretion is stimulated by TGF-beta, and fibronectin then aids migration of epithelial and dermal cells. Capillary budding and proliferation are stimulated by angiogenic factors such as VEGF. The capillaries ease the access of inflammatory cells and fibroblasts, particularly into large areas of necrotic tissue.

Hormones (e.g. insulin and thyroid hormones) and nutrients (e.g. glucose and amino acids) are also required. Lack of nutrients or vitamins, the presence of inhibitory factors such as corticosteroids or infection, or a locally poor circulation with low tissue oxygen concentrations, may all materially delay wound healing; these factors are very important in clinical practice.

Liver

In severe chronic hepatitis (Ch. 16) extensive hepatocyte loss is followed by scarring, as is the case in the skin or other damaged tissues. Like epidermal cells in the skin, hepatocytes have massive regenerative potential and surviving hepatocytes may proliferate to form nodules. Hyperplasia of hepatocytes and fibroblasts is presumably mediated by a combination of hormones and growth factors, although the mechanisms are far from clear. Regenerative nodules of hepatocytes and scar tissue are the components of cirrhosis of the liver.

Heart

Myocardial cells are permanent cells (i.e. they remain permanently in G0 and cannot enter G1), and so cannot divide in a regenerative response to tissue injury. In myocardial infarction, a segment of muscle dies and, if the patient survives, it is replaced by scar tissue. As the remainder of the myocardium must work harder for a given cardiac output, it undergoes compensatory hypertrophy (without cell division) (Fig. 5.9). Occasionally, there may be right ventricular hypertrophy as a result of left ventricular failure and consequent pulmonary hypertension.

Fig. 5.9 Cardiac hypertrophy. A horizontal slice through the myocardium of the left (L) and right (R) ventricles. (1) Normal. (2) Area of anteroseptal left ventricular infarct. (3) Compensatory hypertrophy of the surviving left ventricle. (4) Right ventricular hypertrophy secondary to left ventricular failure and pulmonary hypertension.

Decreased growth: atrophy

Atrophy: decrease in size of an organ or cell

Organ atrophy may be due to reduction in cell size or number, or both

May be mediated by apoptosis

Atrophy may be physiological (e.g. post-menopausal atrophy of uterus)

Pathological atrophy may be due to decreased function (e.g. an immobilised limb), loss of innervation, reduced blood or oxygen supply, nutritional impairment or hormonal insufficiency

Atrophy is the decrease in size of an organ or cell by reduction in cell size and/or reduction in cell numbers, often by a mechanism involving apoptosis. Tissues or cells affected by atrophy are said to be atrophic or atrophied. Atrophy is an important adaptive response to a decreased requirement of the body for the function of a particular cell or organ. It is important to appreciate that for atrophy to occur there must be not only a cessation of growth but also an active reduction in cell size and/or a decrease in cell numbers, mediated by apoptosis.

Atrophy occurs in both physiological and pathological conditions.

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