StemCell Therapy

Programmed cell-death (or PCD) is death of a cell in any form, mediated by an intracellular program.[1][2] PCD is carried out in a regulated process, which usually confers advantage during an organism's life-cycle. For example, the differentiation of fingers and toes in a developing human embryo occurs because cells between the fingers apoptose; the result is that the digits are separate. PCD serves fundamental functions during both plant and metazoa (multicellular animals) tissue development. Apoptosis and autophagy are both forms of programmed cell death, but necrosis is a non-physiological process that occurs as a result of infection or injury.[3]

Necrosis is the death of a cell caused by external factors such as trauma or infection and occurs in several different forms. Recently a form of programmed necrosis, called necroptosis, has been recognized as an alternate form of programmed cell death. It is hypothesized that necroptosis can serve as a cell-death backup to apoptosis when the apoptosis signaling is blocked by endogenous or exogenous factors such as viruses or mutations.

The concept of "programmed cell-death" was used by Lockshin & Williams[4] in 1964 in relation to insect tissue development, around eight years before "apoptosis" was coined. Since then, PCD has become the more general of these two terms.

The first insight into the mechanism came from studying BCL2, the product of a putative oncogene activated by chromosome translocations often found in follicular lymphoma. Unlike other cancer genes, which promote cancer by stimulating cell proliferation, BCL2 promoted cancer by stopping lymphoma cells from being able to kill themselves.[5]

PCD has been the subject of increasing attention and research efforts. This trend has been highlighted with the award of the 2002 Nobel Prize in Physiology or Medicine to Sydney Brenner (United Kingdom), H. Robert Horvitz (US) and John E. Sulston (UK).[6]

Apoptosis is the process of programmed cell death (PCD) that may occur in multicellular organisms.[8]Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation. It is now thought that- in a developmental context- cells are induced to positively commit suicide whilst in a homeostatic context; the absence of certain survival factors may provide the impetus for suicide. There appears to be some variation in the morphology and indeed the biochemistry of these suicide pathways; some treading the path of "apoptosis", others following a more generalized pathway to deletion, but both usually being genetically and synthetically motivated. There is some evidence that certain symptoms of "apoptosis" such as endonuclease activation can be spuriously induced without engaging a genetic cascade, however, presumably true apoptosis and programmed cell death must be genetically mediated. It is also becoming clear that mitosis and apoptosis are toggled or linked in some way and that the balance achieved depends on signals received from appropriate growth or survival factors.[9]

Macroautophagy, often referred to as autophagy, is a catabolic process that results in the autophagosomic-lysosomal degradation of bulk cytoplasmic contents, abnormal protein aggregates, and excess or damaged organelles.

Autophagy is generally activated by conditions of nutrient deprivation but has also been associated with physiological as well as pathological processes such as development, differentiation, neurodegenerative diseases, stress, infection and cancer.

A critical regulator of autophagy induction is the kinase mTOR, which when activated, suppresses autophagy and when not activated promotes it. Three related serine/threonine kinases, UNC-51-like kinase -1, -2, and -3 (ULK1, ULK2, UKL3), which play a similar role as the yeast Atg1, act downstream of the mTOR complex. ULK1 and ULK2 form a large complex with the mammalian homolog of an autophagy-related (Atg) gene product (mAtg13) and the scaffold protein FIP200. Class III PI3K complex, containing hVps34, Beclin-1, p150 and Atg14-like protein or ultraviolet irradiation resistance-associated gene (UVRAG), is required for the induction of autophagy.

The ATG genes control the autophagosome formation through ATG12-ATG5 and LC3-II (ATG8-II) complexes. ATG12 is conjugated to ATG5 in a ubiquitin-like reaction that requires ATG7 and ATG10. The Atg12Atg5 conjugate then interacts non-covalently with ATG16 to form a large complex. LC3/ATG8 is cleaved at its C terminus by ATG4 protease to generate the cytosolic LC3-I. LC3-I is conjugated to phosphatidylethanolamine (PE) also in a ubiquitin-like reaction that requires Atg7 and Atg3. The lipidated form of LC3, known as LC3-II, is attached to the autophagosome membrane.

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