Background Science

Cell death

Cell death is common, both in our bodies and in the laboratory. In each of these locations, cells die by two major mechanisms:

1. On purpose – via the activation of a ‘suicidal’ cell-death programme, which is controlled by the cell itself. The best-known form of programmed cell death is apoptosis.
2. By accident - following exposure to noxious agents or physical trauma. This type of cell death is commonly known as necrosis.

Apoptosis – purposeful cell death

In all our tissues, the size of individual cell populations is governed, on the one hand, by cell birth brought about by division of cells – mitosis – and, on the other hand, by a controlled cell deletion process known as apoptosis. The name apoptosis is derived from the ancient Greek meaning ‘the falling of leaves from trees or petals from flowers’.

During embryonic development, we are fashioned not only through mitosis, cell differentiation and cell migration, but also through the ‘useful cell death’ that is apoptosis. Many of the tissues in our adult bodies are maintained by a fine balance between mitosis and apoptosis. For example, immune responses to infection are boosted by cell division and finely tuned and curtailed by apoptosis; cells of the gut and skin are renewed through cycles of mitosis and apoptosis; the lactating breast regresses post-lactation by apoptosis.

It is likely that all cells of all our tissues possess the ability to undergo apoptosis. The machinery that drives the process is genetically controlled and is known as the apoptosis programme. Often apoptosis is called ‘programmed cell death’. The apoptosis programme can be activated by a wide diversity of triggers ranging from normal, physiological micro-environmental 'cues' to toxic stimuli, such as radiation-induced genomic damage. In many cases apoptosis occurs by default – that is apoptosis is activated when critical survival factors are lacking from the cell’s environment. This indicates that the apoptosis programme is ‘pre-formed’ within cells in a dormant mode that awaits triggering. Amongst the dormant molecules that are key players in the apoptosis programme are the protein-cleaving enzymes, the caspases that reside in the cell in an inactive state, awaiting activation which allows them to cause the destruction of critical elements within the cell including the cytoskeleton and DNA. In other normal circumstances, apoptosis can be triggered by death receptors that engage with natural ligands known as death factors. In a given apoptosis pathway, activation of caspases may be initiated by death-receptor/death-factor interaction, or by the movement of molecules out of mitochondria, or both.   

When apoptosis is triggered, cells undergo a series of stereotypical changes including shrinkage, loss of contact with their neighbours, changes in nuclear structure, controlled protein and DNA cleavage and alterations in molecules at the cell surface. Their altered surface architecture allows apoptotic cells to be recognised and engulfed (phagocytosed) by neighbouring cells. Apoptotic cells also release factors that allow professional scavenger cells of the immune system, the macrophages (from the Greek meaning “big eaters”) , to sense the dying cells from a distance, seeking them out through directed locomotion called chemotaxis.  The engulfment process is critical - it prevents dead cells from causing inflammation and tissue damage.

Necrosis – accidental and catastrophic cell death

Apoptotic cell death contrasts markedly with the accidental form of cell death, necrosis. Necrosis is abnormal, thermodynamically downhill cell death that is catastrophic. Necrotic cells rapidly lose plasma-membrane integrity and fall apart, causing direct or indirect (inflammatory) damage to their neighbours. Necrosis is not genetically regulated and serves no useful purpose.

Clearance of apoptotic cells

The natural habitat of the apoptotic cell is within a macrophage or neighbouring cell, since a variety of different cell types can engulf their apoptotic neighbours. The value of apoptosis lies in the capacity of the apoptotic cell to ‘flag’ itself for phagocytosis and in the capacity of the phagocyte to receive the apoptotic cell or its membrane-bound fragments (apoptotic bodies). Without phagocytosis, the apoptotic cell takes on the guise of a necrotic cell with its catastrophic tissue-damaging, pro-inflammatory properties. The key to the biological value of apoptosis is successful phagocytic clearance that is (1) rapid and (2) non-inflammatory. Apoptotic cells display on their surfaces “eat me” signals for rapid engulfment by phagocytes. The phagocytes display a variety of receptors that engage the “eat me” signals and mediate anti-inflammatory engulfment.

Thus, efficient clearance of dying cells in situ keeps tissues healthy. When cells are cultured in vitro, these clearance mechanisms are absent. This causes cell cultures to be sub-optimal, with dead cells exerting inhibitory effects on their viable neighbours.