Normal cell growth21
In order to function appropriately, cells and tissues need to maintain a steady state (homeostasis). Within defined limits, cells are capable of adapting to a variety of stimuli which may upset normality. Cellular adaptation is the state between a normal unstressed cell and the overstressed injured cell. By definition, an adaptive process is one which is potentially reversible. This chapter covers:
• normal cell growth and the cell cycle
• reversible adaptive responses.
3.1. Normal cell growth
Regeneration
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.)
Box 3
• Stable tissues. Although stable tissues also contain stem cells, the turnover is slow because the differentiated cells are long-lived. Therefore, a histological section of the tissue may not contain any mitoses. However, if the tissue is damaged and many cells are lost, the tissue can become highly active mitotically and regenerate itself. This can occur because the remaining stem cells are stimulated to divide, e.g. bone. Alternatively, in some tissues the differentiated cells can be stimulated to re-enter the cell cycle; an example is liver, in which it appears that liver cells can divide while retaining the characteristics of differentiated liver cells.
• Permanent tissues. These tissues only contain cells capable of division in fetal life. Therefore, cells lost after birth cannot be replaced. Examples of permanent cells are neurones and cardiac/skeletal muscle cells (although cardiac and skeletal muscle may be capable of limited proliferation under some circumstances).
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.
Repair
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 cell cycle
The four main stages of the cell cycle (Figure 6) are:
• M phase: mitosis when the cell divides (about 1 hour)
• G1 phase: gap 1, the preparation for S phase
• S phase: DNA synthesis
• G2 phase: gap 2, during which assembly of the apparatus for the distribution of chromosomes occurs.
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| Figure 6 |
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.
Control of the cell cycle
Growth factors
Growth factors are proteins of low molecular weight that have a similar mechanism of action to hormones. In general, the growth factor is produced by a cell, for example a macrophage, and acts either on the cell itself (autocrine action) or on a neighbouring cell (paracrine action) by linking to cell surface receptors. This interaction activates the receptor and triggers a series of cytoplasmic events usually involving phosphorylation-dephosphorylation of proteins. Ultimately, a signal reaches the nucleus where genes are switched on, new proteins produced and cell growth and division are initiated. Growth factors often have actions that go beyond effects on the cell cycle. They can also inhibit or promote apoptosis (programmed cell death, see Ch. 4), and can stimulate differentiation of cells.
Cyclins
The cyclins are a family of proteins which coordinate the journey of cells through the different phases of the cell cycle. They form complexes with a protein kinase (phosphorylating) enzyme. The cellular concentration and activity of different cyclins varies through the cell cycle.
3.2. Cellular adaptation
There are four main adaptive states (Figure 7):
• atrophy: shrinkage of an organ as a result of a decrease in cell size and/or number
• hypertrophy: enlargement of an organ as a result of increased cell size
• hyperplasia: enlargement of an organ through an increase in cell number
• metaplasia: change in tissue type as a result of replacement of one differentiated cell type by another.
These adaptations remain under the control of the complex web of genetic and environmental factors that control normal growth and development. In general, they are potentially reversible. Thus they differ from neoplasia, which is an irreversible process in which normal responses to control of growth and differentiation are lost.
Atrophy
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:
• denervation, e.g. wasting of muscle caused by a lack of nerve stimulation, for example in poliomyelitis
• reduced blood supply, e.g. shrinkage of brain caused by atherosclerosis of carotid arteries
• inadequate nutrition, e.g. wasting of muscles and major organs in starvation
• decreased workload (disuse), e.g. wasting of muscles and bone (osteoporosis) after immobilisation of a limb in a plaster cast
• pressure, e.g. due to an adjacent tumour or cyst
• loss of endocrine stimulation, e.g. infarction of the pituitary gland results in atrophy of the tissues dependent on pituitary hormones, including the thyroid gland and adrenal gland.
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