Classification of cell death: How do cells die? | Cell Structure Function |

Cell death can be classified according to its morphological appearance (which may be apoptotic, necrotic, autophagic or associated with mitosis), enzymological criteria (with and without the involvement of nucleases or of distinct classes of proteases, such as caspases, calpains, cathepsins and transglutaminases), functional aspects (programmed or accidental, physiological or pathological) or immunological characteristics (immunogenic or non-immunogenic).


The Nomenclature Committee on Cell Death (NCCD) has formulated a first round of recommendations in 2005, in Cell Death and Differentiation. Since then, the field of cell death research has continued its expansion, significant progress has been made and new putative cell death modalities have been described. The NCCD provides a forum in which names describing distinct modalities of cell death are critically evaluated and recommendations on their definition and use are formulated, hoping that a non-rigid, yet uniform, nomenclature will facilitate the communication among scientists and ultimately accelerate the pace of discovery.


As it stands now, three distinct routes of cellular catabolism can be defined according to morphological criteria, namely apoptosis (which is a form of cell death), autophagy (which causes the destruction of a part of the cytoplasm, but mostly avoids cell death) and necrosis (which is another form of cell death). Although frequently employed in the past, the use of Roman numerals (i.e., type I, type II and type III cell death, respectively) to indicate these catabolic processes should be abandoned.


Moreover, several critiques can be formulated against the clear-cut distinction of different cell types in the triad of apoptosis, autophagic cell death and necrosis. First, although this vocabulary was originally introduced based on observations of developing animals, it has rapidly been adopted to describe the results of in vitro studies performed on immortalized cell lines, which reflect very poorly the physiology of cell death in vivo. In tissues, indeed, dying cells are usually engulfed well before signs of advanced apoptosis or necrosis become detectable. Thus, it may be acceptable - if the irreversibility of these phenomena is demonstrated - to assess caspase activation and/or DNA fragmentation to diagnose apoptotic cell death in vivo.


Second, there are numerous examples in which cell death displays mixed features, for instance with signs of both apoptosis and necrosis, a fact that lead to the introduction of terms like ‘necroapoptosis’ and ‘aponecrosis’ (whose use is discouraged by the NCCD to avoid further confusion). Similarly, in the involuting D. melanogaster salivary gland, autophagic vacuolization is synchronized with signs of apoptosis, and results from genetic studies indicate that caspases and autophagy act in an additive manner to ensure cell death in this setting.  Altogether, these data argue against a clear-cut and absolute distinction between different forms of cell death based on morphological criteria.


Third (and most important), it would be a desideratum to replace morphological aspects with biochemical/functional criteria to classify cell death modalities. Unfortunately, there is no clear equivalence between morphology and biochemistry, suggesting that the ancient morphological terms are doomed to disappear and to be replaced by truly biochemical definitions. In this context, ‘loss-of-function’ and ‘gain-of function’ genetic approaches (e.g., RNA interference, knockout models and plasmid-driven overexpression systems) represent invaluable tools to characterize cell death modes with more precision, but only if such interventions truly reduce/augment the rate of death, instead of changing its morphological appearance (as it is often the case). Present cell death classifications are reminiscent of the categorization of tumors that has been elaborated by pathologists over the last one and a half centuries. As old morphological categorizations of tumors are being more and more supported (and will presumably be replaced) by molecular diagnostics (which allows for a more sophisticated stratification of cancer subtypes based on molecular criteria), the current catalog of cell death types is destined to lose its value as compared with biochemical/functional tests. In the end, such efforts of classification are only justified when they have a prognostic and/or predictive impact, allowing the matching of each individual cancer with the appropriate therapy. Similarly, a cell death nomenclature will be considered useful only if it predicts the possibilities to pharmacologically/genetically modulate (induce or inhibit) cell death and/or if it predicts the consequences of cell death in vivo, with regard to inflammation and recognition by the immune system.



Via Dr. Stefan Gruenwald