UNIVERSITY POLITEHNICA OF BUCHAREST

FACULTY OF ENGINEERING IN FOREIGN LANGUAGES

Biomaterials for Tissue Engineering (BioTE)

PROJECT
DEBILITATING DISEASES OF TISSUES

~ Apoptosis ~

Student: Daniela-Constanta GHICA

Teacher: Anca HERMENEAN

Master, First Year - 2018/2019

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 UNIVERSITY POLITEHNICA OF BUCHAREST
FACULTY OF ENGINEERING IN FOREIGN LANGUAGES
Biomaterials for Tissue Engineering (BioTE)

INTRODUCTION

Apoptosis is a morphologically and biochemically distinct form of programmed cell death

that plays an essential role during embryologic development, after birth, and during adulthood.
However, deregulation of apoptosis is involved in the pathogenesis of a variety of human
diseases.

Toxicants also induce cell death via apoptosis, and in most cases this involves the activation
of cysteinyl aspartate-specific proteases (caspases).

Apoptosis is an orderly process in which the cell’s contents are packaged into small
packets of membrane for “garbage collection” by immune cells. Apoptosis removes cells during
development, eliminates potentially cancerous and virus-infected cells, and maintains balance in
the body.

Figure 1 - Programmed cell death and how it is different from necrosis (cell death due to injury)

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 UNIVERSITY POLITEHNICA OF BUCHAREST
FACULTY OF ENGINEERING IN FOREIGN LANGUAGES
Biomaterials for Tissue Engineering (BioTE)

DISCOVERY AND ETYMOLOGY

German scientist Karl Vogt was first to describe the principle of apoptosis in 1842.
In 1885, anatomist Walther Flemming delivered a more precise description of the process of
programmed cell death. However, it was not until 1965 that the topic was resurrected. While
studying tissues using electron microscopy, John Foxton Ross Kerr at the University of
Queensland was able to distinguish apoptosis from traumatic cell death. For many years, neither
"apoptosis" nor "programmed cell death" was a highly cited term. Two discoveries brought cell
death from obscurity to a major field of research: identification of components of the cell death
control and effector mechanisms, and linkage of abnormalities in cell death to human disease, in
particular cancer.

In Greek, apoptosis translates to the "falling off" of leaves from a tree. Cormack,
professor of Greek language, reintroduced the term for medical use as it had a medical meaning
for the Greeks over two thousand years before. Hippocrates used the term to mean "the falling
off of the bones". Galen extended its meaning to "the dropping of the scabs".

ACTIVATION MECHANISM

Because apoptosis cannot stop once it has begun, it is a highly regulated process.
Apoptosis can be initiated through one of two pathways. In the intrinsic pathway the cell kills
itself because it senses cell stress, while in the extrinsic pathway the cell kills itself because of
signals from other cells.

Intrinsic pathway

The mitochondria are essential to multicellular life. Without them, a cell ceases to respire
aerobically and quickly dies. This fact forms the basis for some apoptotic pathways. Apoptotic
proteins that target mitochondria affect them in different ways. They may cause mitochondrial
swelling through the formation of membrane pores, or they may increase the permeability of the
mitochondrial membrane and cause apoptotic effectors to leak out. They are very closely related
to intrinsic pathway, and tumors arise more frequently through intrinsic pathway than the
extrinsic pathway because of sensitivity.

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 UNIVERSITY POLITEHNICA OF BUCHAREST
FACULTY OF ENGINEERING IN FOREIGN LANGUAGES
Biomaterials for Tissue Engineering (BioTE)

Figure 2- Intrinsic pathway of apoptosis

Extrinsic pathway

Two theories of the direct initiation of apoptotic mechanisms in mammals have

been suggested: the TNF-induced (tumor necrosis factor) model and the Fas-Fas ligand-
mediated model, both involving receptors of the TNF receptor (TNFR) family coupled to
extrinsic signals. Death receptors are structurally defined by an intracellular protein-protein
interaction domain, called the death domain (DD), which is critically involved in apoptosis-
inducing signaling.

Some cells do not die in response to the extrinsic pathway alone and require an
amplification step that is induced by caspase-8. In this situation, capase-8 targets the BH3-only
protein Bid (BH3-interacting-domain death agonist) for cleavage and generate the activated
fragment t-Bid; t-Bid then directly activates pro-apoptotic multi-domain proteins to induce
mitochondrial outer membrane permeability (MOMP), so this co-engages the intrinsic pathway.

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 UNIVERSITY POLITEHNICA OF BUCHAREST
FACULTY OF ENGINEERING IN FOREIGN LANGUAGES
Biomaterials for Tissue Engineering (BioTE)

Figure 3 - Extrinsic Apoptosis Pathway (Signalling)

Regulation of apoptosis. Due to the irreversible consequence of apoptosis, both the intrinsic and
extrinsic pathways are under tight control. The major regulator of apoptosis is the Bcl (from B
cell lymphoma) family of proteins. The members of this group of proteins include proapoptotic
and antiapoptotic agents, which control the release of cytochrome c and other mitochondrial
proteins to the cytosol, regulating downstream caspase activation.

PATHOLOGIC APOPTOSIS

Abnormalities in cell death regulation can be a significant component of

diseases such as cancer, autoimmune lymphoproliferative syndrome, AIDS, ischemia, and
neurode-generative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s
disease, and Amyotrophic Lateral Sclerosis. Some conditions feature insufficient apoptosis
whereas others feature excessive apoptosis.
Cancer is an example where the normal mechanisms of cell cycle regulation
are dysfunctional, with either an overproliferation of cells and/or decreased removal of cells. In
fact, suppression of apoptosis during carcinogenesis is thought to play a central role in the

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 UNIVERSITY POLITEHNICA OF BUCHAREST
FACULTY OF ENGINEERING IN FOREIGN LANGUAGES
Biomaterials for Tissue Engineering (BioTE)

development and progression of some cancers. There are a variety of molecular mechanisms that
tumor cells use to suppress apoptosis. Tumor cells can acquire resistance to apoptosis by the
expression of anti-apoptotic proteins such as Bcl-2 or by the down-regulation or mutation of pro-
apoptotic proteins such as Bax.
Excessive apoptosis may also be a feature of some conditions such as
autoimmune diseases, neurodegenerative diseases, and ischemia-associated injury. Autoimmune
deficiency syndrome (AIDS) is an example of an autoimmune disease that results from infection
with the human immunodeficiency virus (HIV).

Alzheimer’s disease is a neurodegenerative condition that is thought to be

caused by mutations in certain proteins such as APP (amyloid precursor protein) and presenilins.
Presenilins are thought to be involved in the processing of APP to amyloid β.

Excessive apoptosis is also thought to play an important role in various

ischemia-associated injuries. One example is myocardial ischemia caused by an insufficient
blood supply, leading to a decrease in oxygen delivery to, and subsequent death of, the
cardiomyocytes. Although necrosis does occur, overexpression of BAX has been detected in
ischemic myocardial tissue and therapy aimed at reducing apoptosis has shown some success in
reducing the degree of tissue damage. One hypothesis is that the damage produced by ischemia is
capable of initiating apoptosis but if ischemia is prolonged, necrosis occurs. If energy production
is restored, as with reperfusion, the apoptotic cascade that was initiated by ischemia may
proceed.

Figure 4 – Cytology of apoptosis – The different stages of apoptotic cell death start by cellular

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 UNIVERSITY POLITEHNICA OF BUCHAREST
FACULTY OF ENGINEERING IN FOREIGN LANGUAGES
Biomaterials for Tissue Engineering (BioTE)

An important function of programmed cell death is the elimination of damaged cells,

especially those that have undergone changes in their DNA. These cells are dangerous as they
can accumulate mutations and become carcinogenic. In mammalian cells there are mechanisms
that prevent malignant transformation of cells. In response to DNA damage, these mechanisms
are mediated by the transcription factor of p53 (tumor suppressor protein) that induces
expression of cyclin inhibitors and stops cell cycle progression. In addition to this action, p53
also triggers apoptosis by inducing expression of protein BH3 of the intrinsic pathway.

MEDICAL IMPORTANCE

Many diseases are associated with disturbances in the regulation of apoptosis. For
example, in Alzheimer’s disease and other neurodegenerative diseases, abnormal apoptosis leads
to exacerbated neuronal destruction in specific regions of the brain. There is also increased
apoptotic activity in T lymphocytes in the acquired immunodeficiency syndrome (AIDS).

Other examples of increased cell destruction are heart attacks and strokes. In these cases, the
necrosis resulting from the lack of oxygen supply predominates, but some cells affected by
hypoxia undergo apoptosis. It is expected that the development of caspase inhibitor drugs will be
useful in these conditions.

Mutations in the genes encoding factors associated with programmed cell death result in
serious alterations. A failure of the gene that directs the synthesis of Fas death receptors, reduces
cell removal, leading to cell accumulation in spleen and lymph nodes, which is a cause of
autoimmune diseases.
Elimination of unwanted cells is impaired in some types of tumors. In lymphoma, there is a
chromosomal translocation that determines excessive production of Bcl-2 protein and inhibition
of apoptosis. In 50% of human cancers, mutations in the p53 gene have been shown. Some of the
drugs used in the treatment of neoplasias induce apoptosis and cell cycle arrest by a mechanism
dependent on p53. In cases in which the p53 gene is mutated, the cancer cells are not sensitive to
chemotherapy.

DIFFERENT INFORMATION
Apoptosis serves several important functions.

These include:

1. Elimination of unnecessary or damaged cells, or cells carrying alterations that make them
potentially dangerous to the body (i.e., cells which have been invaded by viruses or cancer cells).

2. Atrophy of certain tissues in organs that undergo cyclic changes induced by hormones (i.e.,
mammary gland at the end of lactation).

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 UNIVERSITY POLITEHNICA OF BUCHAREST
FACULTY OF ENGINEERING IN FOREIGN LANGUAGES
Biomaterials for Tissue Engineering (BioTE)

3. Removal of cells from the immune system that did not reach a satisfactory gene recombination
or whose antigen specificity makes them potentially reactive against own tissue structures.

4. Regression of embryonic structures, which should not persist in postnatal life (i.e., interdigital
membranes), or cells produced in excess (it is estimated that 50% of brain cells are removed
before birth).

In a normal adult, it is estimated that more than 10 billion cells are destroyed
by apoptosis each day. Cells sentenced to programmed cell death show a number of
characteristic morphological changes. Cell size is reduced due to cleavage of cytoskeletal
filament fibers, cell cytoplasm, and nucleus condense, DNA becomes fragmented by the action
of endonu-cleases into pieces of 200 (or multiples of 200) base pairs, cell organelles (Golgi
apparatus, en-doplasmic reticulum, and mitochondria) also become fragmented, the cell plasma
membrane displays a “blistered” like appearance, cells become round and separate from
neighboring cells. Finally, the cell is reduced to vesicular remnants that are phagocytosed by
neighboring cells and macrophages.

Figure 5 – Apoptosis – stapes of apoptosis

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 UNIVERSITY POLITEHNICA OF BUCHAREST
FACULTY OF ENGINEERING IN FOREIGN LANGUAGES
Biomaterials for Tissue Engineering (BioTE)

CONCLUSIONS
Intensive investigation in the last decades on the molecular mechanisms of
apoptosis in cancer cells has led to the identification of the several molecules involved in both
the intrinsic and the extrinsic apoptotic pathways.

Apoptosis is regarded as a carefully regulated energy-dependent process,

characterized by specific morphological and biochemical features in which caspase activation
plays a central role. Although many of the key apoptotic proteins that are activated or inactivated
in the apoptotic pathways have been identified, the molecular mechanisms of action or activation
of these proteins are not fully understood and are the focus of continued research. The
importance of understanding the mechanistic machinery of apoptosis is vital because
programmed cell death is a component of both health and disease, being initiated by various
physiologic and pathologic stimuli.

Understanding the mechanisms of apoptosis, and other variants of

programmed cell death, at the molecular level provides deeper insight into various disease
processes and may thus influence therapeutic strategy.

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 UNIVERSITY POLITEHNICA OF BUCHAREST
FACULTY OF ENGINEERING IN FOREIGN LANGUAGES
Biomaterials for Tissue Engineering (BioTE)

REFERENCES

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