Cells that are lost through death or injury need to be replaced. Furthermore, normal growth of tissues depends on a balance between the number of cells actively dividing and the number of cells dying. Therefore, tissues contain a population of cells capable of repeated mitotic division, called stem cells. Sometimes, differentiated cells can return to the cell cycle and divide to produce daughter cells. However, unless they take on the characteristics of stem cells, they cannot do so indefinitely. The reason is that the terminal ends of chromosomes called telomeres become slightly shorter with each cell division. Eventually, when the telomeres become too short, further mitotic division is not possible. In a sense, the telomeres act like a clock counting down the number of mitoses a cell is allowed. However, stem cells possess the enzyme telomerase, which reconstitutes the telomeres at each mitosis, allowing an infinite number of cell divisions. Most neoplastic cells (see Ch. 11) also possess telomerase, which explains why they too can divide indefinitely.

When a stem cell divides, it produces two daughter cells. One of these retains the characteristics of a stem cell so that it can divide again, but the other can differentiate and become a specialised cell of the tissue, such as an epithelial or connective tissue cell.

Traditionally, tissues have been divided into three types according to the nature of cell turnover they exhibit, namely: labile, stable and permanent. Labile tissues have a high cell turnover and show continuous mitotic activity, stable tissues contain cells with a longer lifespan and mitoses are rare or absent, and permanent tissues are incapable of any cell division. These concepts are useful when thinking about the way in which tissues respond to injury, and are defined in Box 3. (The term injury is used in a broad sense by pathologists to include any pathological alteration in the environment or integrity of a cell.)

In labile and stable tissues, stem cells can quickly replace dead cells within their population by cell division and replace them with cells of exactly the same type. This process is called regeneration (Figure 5). For example, removal of part of the liver triggers hepatocytes close to the area removed to enter the cell cycle, divide and replace the lost tissue. Successful regeneration of cell populations depends on an intact connective tissue matrix around the cells. If this matrix is destroyed, repair by fibrosis and scar formation is likely.

Permanent cells by definition cannot divide and replace lost cells by the same cell type. Instead, repair by fibrosis occurs (Figure 5). In this process, dead tissue is removed and scar tissue (collagen-rich fibrous tissue) fills the defect. The scar provides continuity and strength to the tissue but there is loss of the original specialised cell function. Repair, rather than regeneration, is also likely when labile or stable tissues show extensive injury that disrupts the normal architecture of the tissue or damages the connective tissue matrix. The mechanism of fibrosis is described in Chapter 10.

The four main stages of the cell cycle (Figure 6) are:

In addition, a G0 phase of the cell cycle is recognised. This phase is non-proliferative and is known as growth arrest. Cells in G0 may re-enter the cell cycle at G1, thereby regaining the proliferative state. Locally active small-molecular-weight proteins called growth factors are important in stimulating this re-entry.

Stem cells are capable of going round the cell cycle indefinitely. In contrast, cells which undergo terminal differentiation cannot re-enter the cell cycle (Figure 6). In a permanent cell population, all the cells are terminally differentiated.

Atrophy is a reduction in the mass of cells leading to a reduction in size of the tissue or organ. Two mechanisms can be involved: a reduction in the number of cells through apoptosis, and a reduction in the size of the cells.

Atrophy occurs in physiological circumstances, i.e. during normal growth and development, generally due to loss of endocrine stimulation. For example, the fall in circulating oestrogen after the menopause causes shrinkage of the endometrium, breast tissue, mucosal lining of the vagina, etc.

There are many ways in which atrophy occurs pathologically, i.e. as a result of a disease process:

Cell structural components are reduced in atrophy. There are:

The metabolic rate is reduced in atrophy. There is:

In atrophy, there is an increase in the number of autophagic vacuoles (intracellular dustbins) which contain fragments of intracellular debris such as organelles awaiting destruction. Lysosomes fuse with these vacuoles and discharge their digestive enzymes, which digest the material in the vacuole. Proteins destined for degradation are conjugated with the protein ubiquitin, which marks the protein for destruction in a specialised proteolytic organelle, called a proteasome.

Lipofuscin granules are yellow/brown in colour and represent non-digestible fragments of lipids and phospholipids combined with protein within autophagic vacuoles. They are commonly seen in ageing cells, particularly in the liver and myocardium.

An organ or tissue can enlarge due to an increase in the number of constituent cells or to an increase in the size of the cells. The term hypertrophy is used to describe an increase in mass due to an increase in cell size, whereas hyperplasia is an increase in mass due to an increase in cell number. In practice, hypertrophy and hyperplasia commonly occur together. However, hyperplasia requires that the cells be capable of division. Therefore, it can only occur in labile and stable cell populations. Permanent cell populations can only enlarge by hypertrophy. Both hypertrophy and hyperplasia are reversible processes. If the cause is removed, the tissue can return towards normal.

In general, hypertrophy and hyperplasia are due to increased mechanical demand or to stimulation by hormones and/or growth factors. In the case of muscle cells, both types of signal promote hypertrophy, i.e. mechanical stress on the tissue, such as increased stretch, and the release of growth factors due to increased blood flow. As a result, the expression of genes is altered, causing protein synthesis to increase and protein degradation to decrease. Some of the changes shown by hypertrophic muscle cells include increased synthesis of membrane components and myofilaments, increased ATP synthesis and increased enzyme activity. In the skeletal muscles, athletic training will have these effects. In the heart, increased workload due to increased cardiac output or increased resistance to outflow causes hypertrophy. However, there is a limit beyond which the muscle cannot enlarge any further; the limiting factors for maximum muscle size are poorly understood but seem to involve the nutrient and blood supply available for oxidative phosphorylation.

The term compensatory hypertrophy or compensatory hyperplasia is used when tissue is lost through disease or surgical resection and the remaining tissue enlarges. An example is seen in the heart if part of the muscle is lost through myocardial infarction. The undamaged muscle cells become hypertrophic to compensate, at least partially, for the loss of muscle in the infarcted area. The term compensatory hyperplasia is analogous; it refers to hyperplasia in the remaining tissue after some of the tissue is lost. It is seen when the liver regenerates after partial hepatectomy.

Hypertrophy and hyperplasia can be physiological (normal) or pathological (abnormal).

Metaplasia is the term used when one differentiated tissue is replaced by another. It is a potentially reversible change, in that if the cause of the metaplasia is removed the tissue may revert to normal. It is generally seen in epithelia, usually as a response to chronic physical or chemical irritation.

Metaplasia is a response to a change in the environment of the tissue, and is typically an adaptive response that produces a tissue more able to withstand an adverse environment. A common type of metaplasia is the replacement of glandular or transitional epithelium by stratified squamous epithelium, which is often better able to withstand mechanical or chemical irritation. For example:

Sometimes stratified squamous epithelium changes into glandular epithelium. This occurs in the lower oesophagus in patients with gastro-oesophageal reflux. The reflux of the acidic gastric contents into the oesophagus injures the oesophageal squamous epithelium, which changes into a mucus-secreting glandular epithelium; the mucus protects the oesophageal lining from the acidic gastric juice.