Disorders of growth, differentiation and morphogenesis

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Chapter 5 Disorders of growth, differentiation and morphogenesis

Definitions 74
Commonly confused conditions and entities relating to growth, differentiation and morphogenesis98

Growth, differentiation and morphogenesis are the processes by which a single cell, the fertilised ovum, develops into a large complex multicellular organism, with co-ordinated organ systems containing a variety of cell types, each with individual specialised functions. Growth and differentiation continue throughout adult life, as many cells of the body undergo a constant cycle of death, replacement and growth in response to normal (physiological) or abnormal (pathological) stimuli.

There are many stages in human embryological development at which anomalies of growth and/or differentiation may occur, leading to major or minor abnormalities of form or function, or even death of the fetus. In post-natal and adult life, some alterations in growth or differentiation may be beneficial, as in the development of increased muscle mass in the limbs of workers engaged in heavy manual tasks. Other changes may be detrimental to health, as in cancer, where the outcome may be fatal.

This chapter explores the wide range of abnormalities of growth, differentiation and morphogenesis that may be encountered in clinical practice, relating them where possible to specific deviations from normal cellular functions or control mechanisms.



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:

Multiplicative, involving an increase in numbers of cells (or nuclei and associated cytoplasm in syncytia) by mitotic cell divisions. This type of growth is present in all tissues during embryogenesis.
Auxetic, resulting from increased size of individual cells, as seen in growing skeletal muscle.
Accretionary, an increase in intercellular tissue components, as in bone and cartilage.
Combined patterns of multiplicative, auxetic and accretionary growth as seen in embryological development, where there are differing directions and rates of growth at different sites of the developing embryo, in association with changing patterns of cellular differentiation.

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


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).


image Complex process of embryological development
image Responsible for formation of shape and organisation of body organs
image Involves cell growth and differentiation, and relative movement of cell groups
image 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.


Within an individual organ or tissue, increased or decreased growth takes place in a range of physiological and pathological circumstances as part of the adaptive response of cells to changing requirements for growth. In both fetal and adult life, tissue growth depends upon the balance between the increase in cell numbers, due to cell proliferation, and the decrease in cell numbers, due to cell death. Non-proliferative cells are termed ‘quiescent’; such cells differentiate and adopt specific phenotypes capable of carrying out their specific function (Fig. 5.2).


Fig. 5.2 Cell proliferation and death. Individual cells have three potential fates: proliferation, differentiation or apoptosis. After division, individual daughter cells may differentiate, and under some circumstances some differentiated cells may re-enter the cell cycle. The growth rate of a tissue is determined by the net balance between proliferation, differentiation and apoptosis.

In fetal life, growth is rapid and all cell types proliferate, but even in the fetus there is constant cell death, some of which is an essential (and genetically programmed) component of morphogenesis. In post-natal and adult life, however, the cells of many tissues lose their capacity for proliferation at the high rate of the fetus, and cellular replication rates are variably reduced. Some cells continue to divide rapidly and continuously, some divide only when stimulated by the need to replace cells lost by injury or disease, and others are unable to divide whatever the stimulus.


image Process of replacing injured or dead cells
image Cell types vary in regenerative ability
image Labile cells: very high regenerative ability and rate of turnover (e.g. intestinal epithelium)
image Stable cells: good regenerative ability but low rate of turnover (e.g. hepatocytes)
image 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:

haemopoietic cells of the bone marrow, and lymphoid cells
epithelial cells of the skin, mouth, pharynx, oesophagus, the gut, exocrine gland ducts, the cervix and vagina (squamous epithelium), endometrium, urinary tract (transitional epithelium), etc.

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.

Molecular events in the cell cycle

Cell division is a highly complex process and cells possess elaborate molecular machinery to ensure its successful completion. A number of internal ‘checkpoints’ exist to ensure that one phase is complete before the next commences (Fig. 5.3). This is vital to ensure, for example, that DNA replication has been performed accurately and that cells do not divide before DNA replication is complete. The various proteins and enzymes that carry out DNA replication, mitotic spindle formation, etc. are typically only present and active during the appropriate phases of the cycle. The timely production and activation of these proteins is regulated by the activity of a family of evolutionarily conserved proteins called cyclin dependent kinases (CDKs), which activate their target proteins by phosphorylation. The activity of CDKs is, in turn, regulated by a second family of proteins, the cyclins. Transitions from one phase of the cycle to the next are initiated by rises in the levels of specific cyclins. The transition from G0 to G1 at the initiation of the cell cycle, for example, is triggered by external signals such as growth factors leading to rises in the levels of cyclin D. Problems during cell division, such as faulty DNA replication, result in rises in the levels of a third family of proteins, the CDK inhibitors (CDKIs), which can prevent CDKs from triggering the next phase of cell division until the issue is resolved. In the face of major failures, cells will typically initiate apoptosis rather than permit the generation of improperly formed progeny. Damage to the genes that encode proteins involved in the regulation of cell-cycle progression is seen in many cancers (Ch. 11).

Duration of the cell cycle

In mammals, different cell types divide at very different rates, with observed cell cycle times (also called generation times) ranging from as little as 8 hours, in the case of gut epithelial cells, to 100 days or more, exemplified by hepatocytes in the normal adult liver. However, the duration of the individual phases of the cycle is remarkably constant and independent of the rate of cell division. The principal difference between rapidly dividing cells and those that divide slowly is the time spent temporarily in G0 between divisions; some cells remain in the G0 phase for days or even years between divisions, whilst others rapidly re-enter G1 after mitosis.

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.


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 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

image Hyperplasia and hypertrophy are common tissue responses
image May be physiological (e.g. breast enlargement in pregnancy) or pathological (e.g. prostatic enlargement in elderly men)
image Hypertrophy: increase in cell size without cell division
image 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:

increasing its size without cell replication (hypertrophy)
increasing its numbers by cell division (hyperplasia)
a combination of these.

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.

Physiological hypertrophy and hyperplasia

Examples of physiologically increased growth of tissues include:

Muscle hypertrophy in athletes, both in the skeletal muscle of the limbs (as a response to increased muscle activity) and in the left ventricle of the heart (as a response to sustained outflow resistance).
Hyperplasia of bone marrow cells producing red blood cells in individuals living at high altitude. This is stimulated by increased production of the growth factor erythropoietin.
Hyperplasia of breast tissue at puberty, and in pregnancy and lactation, under the influence of several hormones, including oestrogens, progesterone, prolactin, growth hormone and human placental lactogen.
Hypertrophy and hyperplasia of uterine smooth muscle at puberty and in pregnancy, stimulated by oestrogens.
Thyroid hyperplasia as a consequence of the increased metabolic demands of puberty and pregnancy.

In addition to such physiologically increased tissue growth, hypertrophy and hyperplasia are also seen in tissues in a wide range of pathological conditions.

Pathological hypertrophy and hyperplasia

Many pathological conditions are characterised by hypertrophy or hyperplasia of cells. In some instances, this is the principal feature of the condition from which the disease is named. The more common examples are summarised in Table 5.1. For more detail, consult the relevant chapters.

Table 5.1 Examples of non-regenerative hypertrophy and hyperplasia

Organ/tissue Condition Comment
Myocardium Right ventricular hypertrophy Response to pulmonary valve stenosis, pulmonary hypertension or ventricular septal defect (Ch. 13)
Left ventricular hypertrophy Response to aortic valve stenosis or systemic hypertension (Ch. 13)
Arterial smooth muscle Hypertrophy of arterial walls Occurs in hypertension (Ch. 13)
Capillary vessels Proliferative retinopathy Complication of diabetes mellitus (Ch. 26)
Bone marrow Erythrocyte precursor hyperplasia Response to increased erythropoietin production (e.g. due to hypoxia) (Ch. 23)
Cytotoxic T-lymphocytes Hyperplastic expansion of T-cell populations Involved in cell-mediated immune responses (Ch. 9)
Breast Juvenile hypertrophy (females) Exaggerated pubertal enlargement (Ch. 18)
Due to high oestrogen levels (e.g. in cirrhosis, iatrogenic, endocrine tumours) (Ch. 18)
Gynaecomastia (males)
Prostate Epithelial and connective tissue hyperplasia Relative excess of oestrogens stimulates oestrogen-sensitive central zone (Ch. 20)
Thyroid Follicular epithelial hyperplasia Most commonly due to a thyroid-stimulating antibody (Graves’ disease) (Ch. 17)
Adrenal cortex Cortical hyperplasia Response to increased ACTH production (e.g. from a pituitary tumour or, inappropriately, from a lung carcinoma) (Ch. 17)
Myointimal cells Myointimal cell hyperplasia in atheromatous plaques Myointimal cells in plaques proliferate in response to platelet-derived growth factor (Ch. 13)

Apparently autonomous hyperplasias

In some apparently hyperplastic conditions, cells appear autonomous, and continue to proliferate rapidly despite the lack of a demonstrable stimulus or control mechanism. The question then arises as to whether these should be considered to be hyperplasias at all, or whether they are autonomous and hence neoplastic. If the cells can be demonstrated to be monoclonal (derived as a single clone from one cell), then this suggests that the lesion may indeed be neoplastic, but clonality is often difficult to establish.

Three examples are:

psoriasis, characterised by marked epidermal hyperplasia (Ch. 24)
Paget’s disease of bone, in which there is hyperplasia of osteoblasts and osteoclasts resulting in thick but weak bone (Ch. 25)
fibromatoses, which are apparently autonomous proliferations of myofibroblasts, occasionally forming tumour-like masses, exemplified by palmar fibromatosis (Dupuytren’s contracture), desmoid tumour, retroperitoneal fibromatosis and Peyronie’s disease of the penis.

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.


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.


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.


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

image Atrophy: decrease in size of an organ or cell
image Organ atrophy may be due to reduction in cell size or number, or both
image May be mediated by apoptosis
image Atrophy may be physiological (e.g. post-menopausal atrophy of uterus)
image 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.

Physiological atrophy and involution

Physiological atrophy occurs at times from very early embryological life, as part of the process of morphogenesis. The process of atrophy (mediated by apoptosis of cells) contributes to the physiological involution of organs such as the thymus gland in early adult life, and late old age is accompanied by atrophy of various tissues (Table 5.2).

Table 5.2 Tissues involved in physiological atrophy and involution

Embryo and fetus Early adult
Branchial clefts Thymus
Thyroglossal duct Late adult and old age
Müllerian duct (males) Uterus, endometrium (females)
Wolffian duct (females) Testes (males)
Bone (particularly females)
Neonate Gums
Umbilical vessels Mandible (particularly edentulous)
Ductus arteriosus Cerebrum
Fetal layer adrenal cortex Lymphoid tissue
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