¹
10. The cell - the principal part of the
organism. Tissues of the human
body.
Adjectives. The Degrees of comparison of
adjectives. Numerals. Cardinal
and ordinal numerals.
Drawing
of the structure of cork as it appeared under the microscope to Robert Hook
from Micrographia
which is the origin of the word "cell".
Cells in culture, stained for keratin
(red) and DNA
(green).
The cell is the
structural and functional unit of all living organisms,
and is sometimes called the "building block of life." Some organisms,
such as bacteria,
are unicellular
(consist of a single cell). Other organisms, such as humans, are multicellular.
(Humans have an estimated 100 trillion or 1014 cells; a typical cell
size is 10 µm; a typical cell mass is 1 nanogram.)
The largest known cell is an ostrich egg.
The cell theory,
first developed in 1839 by Matthias Jakob Schleiden and Theodor Schwann,
states that all organisms
are composed of one or more cells. All cells come from preexisting cells. Vital
functions of an organism occur within cells, and all cells contain the hereditary
information necessary for regulating cell functions and for
transmitting information to the next generation of cells.
The word cell comes
from the Latin cellula,
a small room. The name was chosen by Robert Hooke
when he compared the cork cells he saw to the small rooms monks
lived in.
Each cell is at least
somewhat self-contained and self-maintaining: it can take in nutrients, convert
these nutrients into energy, carry out specialized functions, and reproduce as
necessary. Each cell stores its own set of instructions for carrying out each
of these activities.
Mouse cells grown in a culture dish. These cells grow in large clumps, but
each individual cell is about 10 micrometres
across.
All cells share several
abilities:
·
Reproduction by cell division
(binary fission,
mitosis
or meiosis).
·
Use of enzymes and other proteins
coded for
by DNA genes and made via messenger RNA
intermediates and ribosomes.
·
Metabolism,
including taking in raw materials, building cell components, converting energy, molecules
and releasing by-products. The functioning of a cell depends upon its
ability to extract and use chemical energy stored in organic molecules. This
energy is derived from metabolic pathways.
·
Response to external and
internal stimuli such as changes in temperature, pH or nutrient levels.
·
Cell contents are contained
within a cell surface membrane that contains proteins and a lipid bilayer.
Some prokaryotic
cells contain important internal membrane-bound compartments, but eukaryotic
cells have a highly specialized endomembrane system characterized by regulated traffic
and transport
of vesicles.
There are two types of
cells: eukaryotic and prokaryotic. Prokaryotic cells are usually singletons,
while eukaryotic cells are usually found in multicellular organisms.
Diagram
of a typical prokaryotic cell
Prokaryotes
are distinguished from eukaryotes on the basis of nuclear organization,
specifically their lack of a nuclear membrane. Prokaryotes also lack most of
the intracellular organelles and structures that are characteristic of
eukaryotic cells (an important exception is the ribosomes, which are present in
both prokaryotic and eukaryotic cells). Most functions of organelles, such as
mitochondria, chloroplasts, and the Golgi apparatus, are taken over by the
prokaryotic plasma membrane. Prokaryotic cells have three architectural
regions: appendages called flagella and pili
— proteins attached to the cell surface; a cell envelope
consisting of a capsule, a cell wall, and a plasma membrane;
and a cytoplasmic region
that contains the cell genome
(DNA) and ribosomes and various sorts of inclusions. Other differences include:
·
The plasma membrane
(a phospholipid bilayer) separates the interior of the cell from its
environment and serves as a filter and communications beacon.
·
Most prokaryotes have a cell wall
(some exceptions are Mycoplasma (a bacterium) and Thermoplasma
(an archaeon)). It consists of peptidoglycan
in bacteria, and acts as an additional barrier against exterior forces. It also
prevents the cell from "exploding" (cytolysis)
from osmotic pressure against a hypotonic
environment. A cell wall is also present in some eukaryotes like plants
(cellulose) and fungi,
but has a different chemical composition.
·
A prokaryotic chromosome is
usually a circular molecule (an exception is that of the bacterium Borrelia
burgdorferi, which causes Lyme disease).
Even without a real nucleus, the DNA is condensed in a nucleoid.
Prokaryotes can carry extrachromosomal DNA elements called plasmids,
which are usually circular. Plasmids can carry additional functions, such as
antibiotic resistance.
Diagram
of a typical eukaryotic cell, showing subcellular components. Organelles:
(1) nucleolus
(2) nucleus
(3) ribosome
(4) vesicle (5) rough endoplasmic reticulum (ER) (6) Golgi apparatus
(7) Cytoskeleton
(8) smooth ER (9) mitochondria (10) vacuole
(11) cytoplasm
(12) lysosome
(13) centrioles
Eukaryotic
cells are about 10 times the size of a typical prokaryote and can be as much as
1000 times greater in volume. The major difference between prokaryotes and
eukaryotes is that eukaryotic cells contain membrane-bound compartments in
which specific metabolic activities take place. Most important among these is
the presence of a cell nucleus, a membrane-delineated compartment that houses
the eukaryotic cell's DNA. It is this nucleus that gives the eukaryote its
name, which means "true nucleus". Other differences include:
·
The plasma membrane
resembles that of prokaryotes in function, with minor differences in the setup.
Cell walls may or may not be present.
·
The eukaryotic DNA is
organized in one or more linear molecules, called chromosomes,
which are associated with histone proteins. All chromosomal DNA is stored in the cell nucleus,
separated from the cytoplasm by a membrane. Some eukaryotic organelles
also contain some DNA.
·
Eukaryotes can move using cilia
or flagella. The flagella are more complex than those of prokaryotes.
Table 1: Comparison of
features of prokaryotic and eukaryotic cells |
||
|
Prokaryotes |
Eukaryotes |
Typical organisms |
||
Typical size |
~ 1-10 µm |
~ 10-100 µm (sperm cells,
apart from the tail, are smaller) |
Type of nucleus |
nucleoid region; no real nucleus |
real nucleus with double membrane |
DNA |
circular (usually) |
linear molecules (chromosomes)
with histone proteins |
RNA-/protein-synthesis |
coupled in cytoplasm |
RNA-synthesis inside the nucleus |
50S+30S |
60S+40S |
|
Cytoplasmatic structure |
very few structures |
highly structured by endomembranes
and a cytoskeleton |
none |
one to several dozen (though some
lack mitochondria) |
|
none |
||
Organization |
usually single cells |
single cells, colonies, higher
multicellular organisms with specialized cells |
Binary fission (simple division) |
Table 2: Comparison of
structures between animal and plant cells |
||
|
Typical animal cell |
Typical plant cell |
Organelles |
·
Nucleus o
Nucleolus (within nucleus) ·
Rough endoplasmic reticulum (ER) ·
Smooth ER ·
Vesicles o
Vacuoles |
·
Nucleus o
Nucleolus (within nucleus) ·
Rough ER ·
Smooth ER ·
Golgi apparatus (dictiosomes)
·
Vesicles ·
Chloroplast and other plastids
o
Central vacuole(large) o
Tonoplast (central vacuole membrane) ·
Vacuoles |
Additional structures |
·
Cilium
|
·
Flagellum (only in gametes) |
The cells of eukaryotes (left) and prokaryotes (right).
All cells, whether prokaryotic
or eukaryotic,
have a membrane that envelops the cell, separates its interior from
its environment, regulates what moves in and out (selectively permeable), and
maintains the electric potential of the cell. Inside the
membrane, a salty cytoplasm
takes up most of the cell volume. All cells possess DNA, the hereditary
material of genes,
and RNA,
containing the information necessary to build
various proteins
such as enzymes,
the cell's primary machinery. There are also other kinds of biomolecules
in cells. This article will list these primary components of the cell, then
briefly describe their function.
The cytoplasm of a cell is
surrounded by a plasma membrane. The plasma membrane in plants and
prokaryotes is usually covered by a cell wall.
This membrane serves to separate and protect a cell from its surrounding
environment and is made mostly from a double layer of
lipids (hydrophobic fat-like molecules) and hydrophilic
phosphorus
molecules. Hence, the layer is called a phospholipid bilayer. It may also be called a
fluid mosaic membrane. Embedded within this membrane is a variety of protein
molecules that act as channels and pumps that move different molecules into and
out of the cell. The membrane is said to be 'semi-permeable', in that it can
either let a substance (molecule or ion)
pass through freely, pass through to a limited extent or not pass through at
all. Cell surface membranes also contain receptor proteins that allow cells to detect
external signalling molecules such as hormones.
The cytoskeleton acts to
organize and maintain the cell's shape; anchors organelles in place; helps
during endocytosis,
the uptake of external materials by a cell, and cytokinesis,
the separation of daughter cells after cell division;
and moves parts of the cell in processes of growth and mobility. The eukaryotic
cytoskeleton is composed of microfilaments, intermediate filaments and microtubules.
There is a great number of proteins associated with them, each controlling a
cell's structure by directing, bundling, and aligning filaments. The
prokaryotic cytoskeleton is less well-studied but is involved in the
maintenance of cell shape, polarity and cytokinesis.
Two different kinds of
genetic material exist: deoxyribonucleic
acid (DNA) and ribonucleic acid
(RNA). Most organisms use DNA for their long-term information storage, but some viruses
(e.g., retroviruses)
have RNA as their genetic material. The biological information contained in an
organism is encoded in its DNA or RNA sequence. RNA is also used for
information transport (e.g., mRNA)
and enzymatic
functions (e.g., ribosomal RNA) in organisms that use DNA for the genetic code
itself.
Prokaryotic genetic material
is organized in a simple circular DNA molecule (the bacterial chromosome)
in the nucleoid region of the cytoplasm. Eukaryotic
genetic material is divided into different, linear molecules called chromosomes
inside a discrete nucleus, usually with additional genetic material in some
organelles like mitochondria and chloroplasts
(see endosymbiotic theory).
A human cell has genetic
material in the nucleus (the nuclear
genome) and in the mitochondria (the mitochondrial genome). In humans the nuclear
genome is divided into 46 linear DNA molecules called chromosomes. The
mitochondrial genome is a circular DNA molecule separate from the nuclear DNA.
Although the mitochondrial genome is very small, it codes for some important
proteins.
Foreign genetic material
(most commonly DNA) can also be artificially introduced into the cell by a
process called transfection. This can be transient, if the DNA is not
inserted into the cell's genome,
or stable, if it is.
The human body contains many
different organs, such as the heart, lung, and kidney,
with each organ performing a different function. Cells also have a set of
"little organs," called organelles,
that are adapted and/or specialized for carrying out one or more vital
functions. Membrane-bound organelles are found only in eukaryotes.
Cell nucleus (a cell's information
center) The cell nucleus
is the most conspicuous organelle found in a eukaryotic
cell. It houses the cell's chromosomes, and is the place where almost all DNA replication and RNA synthesis
occur. The nucleus is spherical in shape and separated from
the cytoplasm by a double membrane called the nuclear envelope.
The nuclear envelope isolates and protects a cell's DNA from various
molecules that could accidentally damage its structure or interfere with its
processing. During processing, DNA is transcribed, or copied into a special RNA, called mRNA. This mRNA is then
transported out of the nucleus, where it is translated into a specific
protein molecule. In prokaryotes, DNA processing takes place in the cytoplasm.
|
|
Mitochondria and Chloroplasts (the
power generators) Mitochondria
are self-replicating organelles that occur in various
numbers, shapes, and sizes in the cytoplasm of all eukaryotic cells. As
mitochondria contain their own genome that is separate and distinct from the
nuclear genome of a cell, they play a critical role in generating energy in
the eukaryotic cell, they give the cell energy by the process of respiration,
adding oxygen
to food (typicially pertaining to glucose and ATP) to release energy. Organelles that are modified chloroplasts; they
are broadly called plastids,
and are often involved in storage. Since they contain their own genome, they
are thought to have once been separate organisms, which later formed a
symbiotic relationship with the cells. Chloroplasts are the counter-part of
the mitochondria. Instead of giving off CO2 and H2O
Plants give off glucose, oxygen, 6 molecules of water (compaired to |
|
Endoplasmic reticulum and Golgi
apparatus (macromolecule managers) The endoplasmic reticulum (ER) is the transport network for molecules targeted for certain
modifications and specific destinations, as compared to molecules that will
float freely in the cytoplasm. The ER has two forms: the rough ER, which has
ribosomes on its surface, and the smooth ER, which lacks them. Also the Golgi apparatus's
ends "pinch" off and become new vacuoles in the animal cell. |
|
Ribosomes (the protein production
centers in the cell) The ribosome is a large complex,
composed of many molecules, in prokaryotes only exist floating freely in the
cytosol, whereas in eukaryotes they can be found either free or bound to
membranes. |
|
Lysosomes and Peroxisomes
(of the eukaryotic cell) The cell could not house such
destructive enzymes if they were not contained in a membrane-bound system.
These organelles are often called a "suicide bag" because of their
ability to detonate and destroy the cell. |
|
Centrosome (the cytoskeleton
organiser) The centrosome
produces the microtubules of a cell - a key component of the cytoskeleton.
It directs the transport through the ER
and the Golgi apparatus.
Centrosomes are composed of two centrioles,
which separate during cell division and help in the formation of the mitotic spindle.
A single centrosome is present in the animal cells.
They are also found in some fungi and algae cells. |
|
Vacuoles Vacuoles store food and waste. Some
vacuoles store extra water. They are often described as liquid filled space
and are surrounded by a membrane. Some cells, most notably Amoeba have contractile
vacuoles, which are able to pump water out of the cell if there is too much
water. Cell functions
Cell growth and metabolism
Between
successive cell divisions, cells grow through the functioning of cellular
metabolism. Cell
metabolism is the process by which individual cells process nutrient
molecules. Metabolism has two distinct divisions: catabolism,
in which the cell breaks down complex molecules to produce energy and
reducing power, and anabolism, in which the cell uses energy and reducing power to construct
complex molecules and perform other biological functions. Complex sugars consumed
by the organism can be broken down into a less chemically-complex sugar
molecule called glucose.
Once inside the cell, glucose is broken down to make adenosine triphosphate (ATP), a form of energy, via two different pathways. The
first pathway, glycolysis, requires no oxygen and is referred to as anaerobic
metabolism. Each reaction is
designed to produce some hydrogen ions that can then be used to make energy
packets (ATP). In prokaryotes, glycolysis is the only method used for
converting energy. The
second pathway, called the Krebs cycle, or citric acid cycle, occurs inside the mitochondria and is capable of generating enough
ATP to run all the cell functions. An overview of protein synthesis. Creation of new cells
Cell
division involves a single cell (called a mother cell) dividing into
two daughter cells. This leads to growth in multicellular
organisms (the growth of tissue) and to procreation (vegetative
reproduction) in unicellular organisms. Prokaryotic
cells divide by binary fission. Eukaryotic
cells usually undergo a process of nuclear division, called mitosis, followed by division
of the cell, called cytokinesis. A diploid cell may also undergo meiosis to produce haploid
cells, usually four. Haploid
cells serve as gametes
in multicellular organisms, fusing to form new diploid cells. DNA replication,
or the process of duplicating a cell's genome, is required every time a cell
divides. Replication, like all cellular activities, requires specialized
proteins for carrying out the job. Protein synthesis
Cells
are capable of synthesizing new proteins, which are essential for the
modulation and maintenance of cellular activities. This process involves the
formation of new protein molecules from amino acid
building blocks based on information encoded in DNA/RNA. Protein synthesis
generally consists of two major steps: transcription and translation. Transcription
is the process where genetic information in DNA is used to produce a
complementary RNA strand. This RNA strand is then processed to give messenger RNA
(mRNA), which is free to migrate through the cell. mRNA molecules bind to
protein-RNA complexes called ribosomes located in the cytosol,
where they are translated into polypeptide sequences. The ribosome mediates
the formation of a polypeptide sequence based on the mRNA sequence. The mRNA
sequence directly relates to the polypeptide sequence by binding to transfer RNA
(tRNA) adapter molecules in binding pockets within the ribosome. The new
polypeptide then folds into a functional three-dimensional protein molecule. Origins of cells
The
origin of cells has to do with the origin of life, and was one of the most
important steps in evolution of life as we know it. The birth of the cell
marked the passage from prebiotic chemistry to biological life. Origin
of the first cell
If
life is viewed from the point of view of replicators,
that is DNA molecules in the
organism, cells satisfy two fundamental conditions: protection from the
outside environment and confinement of biochemical activity. The former
condition is needed to maintain the fragile DNA chains stable in a
varying and sometimes aggressive environment, and may have been the main
reason for which cells evolved. The latter is fundamental for the evolution
of biological complexity. If freely-floating DNA molecules that code for enzymes are not enclosed into
cells, the enzymes that benefit a given DNA molecule (for example, by
producing nucleotides) will automatically benefit the neighbouring DNA
molecules. This might be viewed as "parasitism
by default." Therefore the selection pressure on DNA molecules will be much lower, since there is not a definitive
advantage for the "lucky" DNA molecule that produces the better
enzyme over the others: All molecules in a given neighbourhood are almost
equally advantaged. If
all the DNA molecule is enclosed in a cell, then the enzymes coded from the
molecule will be kept close to the DNA molecule itself. The DNA molecule will
directly enjoy the benefits of the enzymes it codes, and not of others. This
means other DNA molecules won't benefit from a positive mutation in a
neighbouring molecule: this in turn means that positive mutations give
immediate and selective advantage to the replicator bearing it, and not on
others. This is thought to have been the one of the main driving force of
evolution of life as we know it. (Note. This is more a metaphor given for
simplicity than complete accuracy since the earliest molecules of life,
probably up to the stage of cellular life, were most likely RNA molecules that acted
as both replicators and enzymes: see RNA world hypothesis. However, the core of the reasoning is the same.) Biochemically,
cell-like spheroids formed by proteinoids
are observed by heating amino acids with phosphoric acid as a catalyst. They bear much of the basic features provided by cell membranes.
Proteinoid-based protocells enclosing RNA molecules could (but not
necessarily should) have been the first cellular life forms on Earth. Another
theory holds that the turbulent shores of the ancient coastal waters may have
served as a mammoth laboratory, aiding in the countless experiments necessary
to bring about the first cell. Waves breaking on the shore create a delicate
foam composed of bubbles. Winds sweeping across the ocean have a tendency to
drive things to shore, much like driftwood collecting on the beach. It is
possible that organic molecules were concentrated on the shorelines in much
the same way. Shallow coastal waters also tend to be warmer, further
concentrating the molecules through evaporation.
While bubbles comprised of mostly water tend to burst quickly, oily bubbles
happen to be much more stable, lending more time to the particular bubble to
perform these crucial experiments. The Phospholipid
is a good example of a common oily compound prevalent in the prebiotic seas.
Phospholipids can be constructed in one's mind as a hydrophilic
head on one end, and a hydrophobic tail on the other. Phospholipids also possess an important
characteristic, that is having the function to link together to form a bilayer
membrane. A lipid monolayer bubble can only contain oil, and is therefore not
conducive to harbouring water-soluble organic molecules. On the other hand, a
lipid bilayer bubble can contain
water, and was a likely precursor to the modern cell membrane. If a protein
came along that increased the integrity of its parent bubble, then that
bubble had an advantage, and was placed at the top of the natural selection waiting list. Primitive reproduction can be envisioned when the
bubbles burst, releasing the results of the experiment into the surrounding
medium. Once enough of the 'right stuff' was released into the medium, the
development of the first prokaryotes, eukaryotes,
and multi-cellular organisms could be achieved. This theory is expanded upon
in the book, The Cell: Evolution of the First Organism by Joseph Panno Ph. D. Origin of eukaryotic cells
The
eukaryotic cell seems to have evolved from a symbiotic community
of prokaryotic cells. It is almost certain that DNA-bearing organelles like
the mitochondria
and the chloroplasts
are what remains of ancient symbiotic oxygen-breathing bacteria
and cyanobacteria,
respectively, where the rest of the cell seems to be derived from an
ancestral archaean prokaryote cell – a
theory termed the endosymbiotic theory. There
is still considerable debate about whether organelles like the hydrogenosome
predated the origin of mitochondria, or viceversa: see the hydrogen hypothesis for the origin of eukaryotic cells. Sex,
as the stereotyped choreography of meiosis and syngamy that persists in
nearly all extant eukaryotes, may have played a role in the transition from
prokaryotes to eukaryotes. An 'origin of sex as vaccination' theory suggests
that the eukaryote genome accreted from prokaryan parasite genomes in
numerous rounds of lateral gene transfer. Sex-as-syngamy (fusion sex) arose
when infected hosts began swapping nuclearized genomes containing coevolved,
vertically transmitted symbionts that conveyed protection against horizontal
infection by more virulent symbionts. VIDEO Tissue in the human body Tissue is a cellular organizational level intermediate
between cells and a complete organism. A tissue is an ensemble of similar
cells and from the same origin, that together carry out a specific function.
These are called tissues because of their identical functioning. Organs are
then formed by the functional grouping together of multiple tissues. The study of tissue is known as histology or, in
connection with disease, histopathology. The classical tools for studying
tissues are the paraffin block in which tissue is embedded and then
sectioned, the histological stain, and the optical microscope. In the last
couple of decades, developments in electron microscopy, immunofluorescence,
and the use of frozen tissue sections have enhanced the detail that can be
observed in tissues. With these tools, the classical appearances of tissues
can be examined in health and disease, enabling considerable refinement of
clinical diagnosis and prognosis. Cross section of sclerenchyma fibers in plant ground tissue Microscopic view of a histologic specimen of human lung tissue stained
with hematoxylin and eosin Animal
tissues PAS diastase showing the fungus Histoplasma Animal tissues can be grouped into four basic
types: connective, muscle, nervous, and epithelial. Multiple tissue types
comprise organs and body structures. While all animals can generally be
considered to contain the four tissue types, the manifestation of these
tissues can differ depending on the type of organism. For example, the origin
of the cells comprising a particular tissue type may differ developmentally
for different classifications of animals. The epithelium in all animals is derived from the
ectoderm and endoderm with a small contribution from the mesoderm, forming
the endothelium, a specialized type of epithelium that comprises the vasculature.
By contrast, a true epithelial tissue is present only in a single layer of
cells held together via occluding junctions called tight junctions, to create
a selectively permeable barrier. This tissue covers all organismal surfaces
that come in contact with the external environment such as the skin, the
airways, and the digestive tract. It serves functions of protection,
secretion, and absorption, and is separated from other tissues below by a
basal lamina. Types
of Tissue: Epithelial tissue: Covering the external & internal body
surfaces. e.g. – Skin, internal covering of GIT. The epithelial tissues are formed by cells that cover the organ
surfaces such as the surface of the skin, the airways, the reproductive
tract, and the inner lining of the digestive tract. The cells comprising an
epithelial layer are linked via semi-permeable, tight junctions; hence, this
tissue provides a barrier between the external environment and the organ it
covers. In addition to this protective function, epithelial tissue may also
be specialized to function in secretion and absorption. Epithelial tissue
helps to protect organisms from microorganisms, injury, and fluid loss. Epithelium
is one of the four basic types of animal tissue, along with connective tissue,
muscle tissue and nervous tissue. Epithelial tissues line the cavities and
surfaces of structures throughout the body, and also form many glands.
Functions of epithelial cells include secretion, selective absorption,
protection, transcellular transport and detection of sensation. In Greek
"epi" means, "on, upon," and "thele" meaning
"nipple". Epithelial layers are avascular, so they must receive
nourishment via diffusion of substances from the underlying connective
tissue, through the basement membrane. Epithelia can also be organized into
clusters of cells that function as exocrine and endocrine glands. Structure Cells
in epithelium are very densely packed together like bricks in a wall, leaving
very little intercellular space. The cells and ca form continuous sheets
which are attached to each other at many locations by tight junctions and
desmosomes. Basement
membrane All
epithelial cells rest on a basement membrane, which acts as a scaffolding on
which epithelium can grow and regenerate after injuries. Epithelial tissue is
innervated, but avascular. This epithelial tissue must be nourished by
substances diffusing from the blood vessels in the underlying tissue, but
they don't have their own blood supply. The basement membrane acts as a
selectively permeable membrane that determines which substances will be able
to enter the epithelium. Cell
junctions Cell
junctions are especially abundant in epithelial tissues. They consist of
protein complexes and provide contact between neighbouring cells, between a
cell and the extracellular matrix, or they build up the paracellular barrier
of epithelia and control the paracellular transport.[citation needed] Cell
junctions are the contact points between plasma membrane and tissue cells.
There are mainly 5 different types of cell junctions. They are tight
junctions, adherens junctions, desmosomes, hemidesmosomes, and gap junctions.
Tight junctions are a pair of trans-membranar protein fused on outer plasma
membrane. Adherens junctions are a plaque (protein layer on the inside plasma
membrane) which attaches both protein and microfilaments. Desmosomes attach
to the microfilaments of cytoskeleton made up of keratin protein.
Hemidesmosomes resemble desmosomes on a section. They are made up of the
integrin (a transmembraner protein) instead of cadherin. They attach the
epithelial cell to the basement membrane. Gap junctions connect the cytoplasm
of two cells and are made up of proteins called connexins (six of which come
together to make a connexon). Classification Types
of epithelium Tissues
are generally classified by the morphology of their cells, and the number of
layers they are composed of. Epithelial tissue that is only one cell thick is
known as simple epithelium. If it is two or more cells thick, it is known as
stratified epithelium. However, when taller simple epithelial cells (see
columnar, below) are viewed in cross section with several nuclei appearing at
different heights, they can be confused with stratified epithelia. This kind
of epithelium is therefore described as "pseudostratified"
epithelium. There
are three principal morphologies associated with epithelial cells. Squamous
epithelium has cells which are wider than they are tall (flat and scale-like).
Cuboidal epithelium has cells whose height and width are approximately the
same (cube shaped). Columnar epithelium has cells taller than they are wide
(column shaped). In addition, the morphology of the cells in transitional
epithelium may vary from squamous to cuboidal, depending on the amount of
tension on the epithelium. Simple
epithelium Simple
epithelium is one cell thick, that is, every cell is in direct contact with
the underlying basement membrane. It is generally found where absorption and
filtration occur. The thinness of the epithelial barrier facilitates these
processes. Simple
epithelial tissues are generally classified by the shape of their cells. The
four major classes of simple epithelium are: (1) simple squamous; (2) simple
cuboidal; (3) simple columnar; (4) pseudostratified. Simple
squamous epithelium is found lining areas where passive diffusion of gases
occur. e.g. walls of capillaries, linings of the pericardial, pleural,and
peritoneal cavities, as well as the linings of the alveoli of the lungs. Functions The
primary functions of epithelial tissues are: (1) to protect the tissues that
lie beneath it from radiation, desiccation, toxins, invasion by pathogens,
and physical trauma; (2) the regulation and exchange of chemicals between the
underlying tissues and a body cavity; (3) the secretion of hormones into the
blood vascular system, and/or the secretion of sweat, mucus, enzymes, and
other products that are delivered by ducts glandular epithelium; (4) to
provide sensation. Secretory
epithelia As
stated above, secretion is one major function of epithelial cells. Glands are
formed from the invagination / infolding of epithelial cells and subsequent
growth in the underlying connective tissue. There are two major classifications
of glands: endocrine glands and exocrine glands. Endocrine glands secrete
their product into the extracellular space where it is rapidly taken up by
the blood vascular system. The exocrine glands secrete their products into a
duct that then delivers the product to the lumen of an organ or onto the free
surface of the epithelium. Sensing
the extracellular environment "Some
epithelial cells are ciliated, and they commonly exist as a sheet of
polarised cells forming a tube or tubule with cilia projecting into the
lumen." Primary cilia on epithelial cells provide chemosensation,
thermosensation and mechanosensation of the extracellular environment by
playing "a sensory role mediating specific signalling cues, including
soluble factors in the external cell environment, a secretory role in which a
soluble protein is released to have an effect downstream of the fluid flow,
and mediation of fluid flow if the cilia are motile." Embryological
development In
general, there are epithelial tissues deriving from all of the embryological
germ layers: from
ectoderm (e.g., the epidermis); from
endoderm (e.g., the lining of the gastrointestinal tract); from
mesoderm (e.g., the inner linings of body cavities). However,
it is important to note that pathologists do not consider endothelium and
mesothelium (both derived from mesoderm) to be true epithelium. This is
because such tissues present very different pathology. For that reason,
pathologists label cancers in endothelium and mesothelium sarcomas, whereas
true epithelial cancers are called carcinomas. Also, the filaments that
support these mesoderm-derived tissues are very distinct. Outside of the
field of pathology, it is, in general, accepted that the epithelium arises
from all three germ layers. Growing
in culture When
growing epithelium in culture, one can determine whether or not a particular
cell is epithelial by examining its morphological characteristics. Epithelial
cells tend to cluster together, and have a "characteristic tight
pavementlike appearance". But this is not always the case, such as when
the cells are derived from a tumor. In these cases, it is often necessary to
use certain biochemical markers to make a positive identification. The
intermediate filament proteins in the cytokeratin group are almost
exclusively found in epithelial cells, and so are often used for this
purpose. Location Epithelium
lines both the outside (skin) and the inside cavities and lumen of bodies.
The outermost layer of our skin is composed of dead stratified squamous,
keratinized epithelial cells. Tissues
that line the inside of the mouth, the esophagus and part of the rectum are
composed of nonkeratinized stratified squamous epithelium. Other surfaces
that separate body cavities from the outside environment are lined by simple
squamous, columnar, or pseudostratified epithelial cells. Other epithelial
cells line the insides of the lungs, the gastrointestinal tract, the
reproductive and urinary tracts, and make up the exocrine and endocrine
glands. The outer surface of the cornea is covered with fast-growing,
easily-regenerated epithelial cells. Endothelium (the inner lining of blood
vessels, the heart, and lymphatic vessels) is a specialized form of
epithelium. Another type, mesothelium, forms the walls of the pericardium,
pleurae, and peritoneum. Connective tissue: Connects different structures of the body &
also helps to provide framework of the body. e.g. – Blood, Bones. Connective
tissues are fibrous tissues. They are made up of cells separated by
non-living material, which is called extracellular matrix. Connective tissue
gives shape to organs and holds them in place. Both blood and bone are
examples of connective tissue. As the name. It supports and binds other
tissues. Unlike epithelial tissue, connective tissue typically has cells
scattered throughout an extracellular matrix2. All
CT has three main components: cells, fibers, and extracellular matrix, all
immersed in the body fluids. Connective
tissue can be broadly subdivided into connective tissue proper, special
connective tissue, and series of other, less classifiable types of connective
tissues. Connective tissue proper consists of loose connective tissue and
dense connective tissue (which is further subdivided into dense regular and
dense irregular connective tissues.) Special connective tissue consists of
reticular connective tissue, adipose tissue, cartilage, bone, and blood.
Other kinds of connective tissues include fibrous, elastic, and lymphoid
connective tissues. Fibroblasts
are the cells responsible for the production of some CT. Type-I
collagen, is present in many forms of connective tissue, and makes up about
25% of the total protein content of the mammalian body. Functions
of connective tissue Storage
of energy Protection
of organs Provision
of structural framework for the body Connection
of body tissues Connection
of epithelial tissues to muscle tissues [edit] Characteristics
of connective tissue and fiber types Characteristics
of CT: Cells
are spread through an extracellular fluid. Ground
substance - A clear, colorless, and viscous fluid containing
glycosaminoglycans and proteoglycans to fix the bodywater and the collagen
fibers in the intercellular spaces. Ground substance slows the spread of
pathogens. Fibers.
Not all types of CT are fibrous. Examples include adipose tissue and blood.
Adipose tissue gives "mechanical cushioning" to our body, among
other functions. Although there is no dense collagen network in adipose
tissue, groups of adipose cells are kept together by collagen fibers and
collagen sheets in order to keep fat tissue under compression in place (for
example, the sole of the foot). The matrix of blood is plasma. Both
the ground substance and proteins (fibers) create the matrix for CT. Types
of fibers: ·
Collagenous fibers . Collagen is a group of naturally
occurring proteins found in animals, especially in the flesh and connective
tissues of vertebrates. It is the main component of connective tissue, and is
the most abundant protein in mammals, making up about 25% to 35% of the
whole-body protein content. Collagen, in the form of elongated fibrils, is
mostly found in fibrous tissues such as tendon, ligament and skin, and is
also abundant in cornea, cartilage, bone, blood vessels, the gut, and
intervertebral disc. The fibroblast is the most common cell which creates
collagen. In muscle tissue, it serves as a major component of the endomysium.
Collagen constitutes one to two percent of muscle tissue, and accounts for 6%
of the weight of strong, tendinous muscles. Gelatin, which is used in food
and industry, is collagen that has been irreversibly hydrolyzed.
Tropocollagen triple helix History and background The molecular and packing structures of collagen have eluded
scientists over decades of research. The first evidence that it possesses a
regular structure at the molecular level was presented in the mid-1930s.
Since that time, many prominent scholars, including Nobel laureates Crick,
Pauling, Rich and Yonath, and others, including Brodsky, Berman, and
Ramachandran, concentrated on the conformation of the collagen monomer.
Several competing models, although correctly dealing with the conformation of
each individual peptide chain, gave way to the triple-helical
"Madras" model, which provided an essentially correct model of the
molecule's quaternary structure although this model still required some
refinement. The packing structure of collagen has not been defined to the
same degree outside of the fibrillar collagen types, although it has been
long known to be hexagonal or quasi-hexagonal. As with its monomeric
structure, several conflicting models alleged that either the packing
arrangement of collagen molecules is 'sheet-like' or microfibrillar. The
microfibrillar structure of collagen fibrils in tendon, cornea and cartilage
has been directly imaged by electron microscopy. The microfibrillar structure
of adult tendon, as described by Fraser, Miller, and Wess (amongst others),
was modeled as being closest to the observed structure, although it
oversimplified the topological progression of neighboring collagen molecules,
and hence did not predict the correct conformation of the discontinuous
D-periodic pentameric arrangement termed simply: the microfibril. Various
cross linking agents like dopaquinone, embelin, potassium embelate and
5-O-methyl embelin could be developed as potential
cross-linking/stabilization agent of collagen preparation and its application
as wound dressing sheet in clinical applications is enhanced. Chemistry Collagen is composed of a triple helix, which generally consists of
two identical chains (α1) and an additional chain that differs slightly
in its chemical composition (α2). The amino acid composition of collagen
is atypical for proteins, particularly with respect to its high
hydroxyproline content. The most common motifs in the amino acid sequence of
collagen are glycine-proline-X and glycine-X-hydroxyproline, where X is any
amino acid other than glycine, proline or hydroxyproline. Synthesis First, a three dimensional stranded structure is assembled, with the
amino acids lycine and proline as its principal components. This is not yet
collagen but its precursor, procollagen. A recent study shows that vitamin C
must have an important role in its synthesis. Prolonged exposure of cultures
of human connective-tissue cells to ascorbate induced an eight-fold increase
in the synthesis of collagen with no increase in the rate of synthesis of
other proteins (Murad et al., 1981). Since the production of procollagen must
precede the production of collagen, vitamin C must have a role in this step.
The conversion involves a reaction that substitutes a hydroxyl group, OH, for
a hydrogen atom, H, in the proline residues at certain points in the
polypeptide chains, converting those residues to hydroxyproline. This
hydroxylation reaction organizes the chains in the conformation necessary for
them to form a triple helix. The hydroxylation, next, of the residues of the
amino acid lysine, transforming them to hydroxylysine, is then needed to
permit the cross-linking of the triple helices into the fibers and networks
of the tissues. These hydroxylation reactions are catalyzed by two different enzymes:
prolyl-4-hydroxylase and lysyl-hydroxylase. Vitamin C also serves with them
in inducing these reactions. in this service, one molecule of vitamin C is
destroyed for each H replaced by OH. The synthesis of collagen occurs inside
and outside of the cell. The formation of collagen which results in
fibrillary collagen (most common form) is discussed here. Meshwork collagen,
which is often involved in the formation of filtration systems is the other
form of collagen. It should be noted that all types of collagens are triple
helixes, and the differences lie in the make-up of the alpha peptides created
in step 2. Transcription of mRNA: There are approximately 34 genes associated
with collagen formation, each coding for a specific mRNA sequence, and
typically have the " Pre-pro-peptide Formation: Once the final mRNA exits from the cell
nucleus and enters into the cytoplasm it links with the ribosomal subunits
and the process of translation occurs. The early/first part of the new
peptide is known as the signal sequence. The signal sequence on the
N-terminal of the peptide is recognized by a signal recognition particle on
the endoplasmic reticulum, which will be responsible for directing the
pre-pro-peptide into the endoplasmic reticulum. Therefore, once the synthesis
of new peptide is finished, it goes directly into the endoplasmic reticulum
for post-translational processing. Note that it is now known as
pre-pro-collagen. Alpha Peptide to Procollagen: Three modifications of the
pre-pro-peptide occurs leading to the formation of the alpha peptide.
Secondly, the triple helix known as procollagen is formed before being
transported in a transport vesicle to the golgi apparatus. 1) The signal
peptide on the N-terminal is dissolved, and the molecule is now known as
propeptide (not procollagen). 2) Hydroxylation of lysines and prolines on
propeptide by the enzymes prolyl hydroxylase and lysyl hydroxylase (to
produce hydroxyproline and hydroxylysine) occurs to aid crosslinking of the
alpha peptides. It is this enzymatic step that requires vitamin C as a
cofactor. In scurvy, the lack of hydroxylation of prolines and lysines causes
a looser triple helix (which is formed by 3 alpha peptides). 3) Glycosylation
occurs by adding either glucose or galactose monomers onto the hydroxy groups
that were placed onto lysines, but not on prolines. From here the
hydroxylated and glycosylated propeptide twists towards the left very tightly
and then three propeptides will form a triple helix. It is important to
remember that this molecule, now known as procollagen (not propeptide) is
composed of a twisted portion (center) and two loose ends on either end. At
this point the procollagen is packaged into a transfer vesicle destined for
the golgi apparatus. Golgi Apparatus Modification: In the golgi apparatus, the procollagen
goes through one last post-translational modification before being secreted
out of the cell. In this step oligosaccharides (not monosaccharides like in
step 3) are added, and then the procollagen is packaged into a secretory
vesicle destined for the extracellular space. Formation of Tropocollagen: Once outside the cell, membrane bound
enzymes known as collagen peptidases, remove the "loose ends" of
the procollagen molecule. What is left is known as tropocollagen. Defect in
this step produces one of the many collagenopathies known as Ehlers-Danlos
syndrome. This step is absent when synthesizing type III, a type of fibrilar
collagen. Formation of the Collagen Fibril: Lysyl oxidase and extracellular
enzyme produces the final step in the collagen synthesis pathway. This enzyme
acts on lysines and hydroxylysines producing aldehyde groups, which will
eventually undergo covalent bonding between tropocollagen molecules. This
polymer of tropocollogen is known as a collagen fibril. Action of lysyl oxidase Amino acids Collagen has an unusual amino acid composition and sequence: Glycine is found at almost every third residue Proline (Pro) makes up about 17% of collagen Collagen contains two uncommon derivative amino acids not directly
inserted during translation. These amino acids are found at specific
locations relative to glycine and are modified post-translationally by different
enzymes, both of which require vitamin C as a cofactor. Hydroxyproline (Hyp), derived from proline. Hydroxylysine (Hyl), derived from lysine ( Cortisol stimulates degradation of (skin) collagen into amino
acids.[28] Collagen I formation Most collagen forms in a similar manner, but the following process is
typical for type I: Inside the cell 1.
Two types of peptide chains are
formed during translation on ribosomes along the rough endoplasmic reticulum
(RER): alpha-1 and alpha-2 chains. These peptide chains (known as
preprocollagen) have registration peptides on each end and a signal peptide. 2.
Polypeptide chains are released
into the lumen of the RER. 3.
Signal peptides are cleaved inside
the RER and the chains are now known as pro-alpha chains. 4.
Hydroxylation of lysine and proline
amino acids occurs inside the lumen. This process is dependent on ascorbic
acid (Vitamin C) as a cofactor. 5.
Glycosylation of specific
hydroxylysine residues occurs. 6.
Triple ɣ helical structure is formed inside
the endoplasmic reticulum from each two alpha-1 chains and one alpha-2 chain. 7.
Procollagen is shipped to the Golgi
apparatus, where it is packaged and secreted by exocytosis. Outside the cell 1.
Registration peptides are cleaved
and tropocollagen is formed by procollagen peptidase. 2.
Multiple tropocollagen molecules
form collagen fibrils, via covalent cross-linking (aldol reaction) by lysyl
oxidase which links hydroxylysine and lysine residues. Multiple collagen
fibrils form into collagen fibers. 3.
Collagen may be attached to cell
membranes via several types of protein, including fibronectin and integrin. Synthetic pathogenesis Vitamin C deficiency causes scurvy, a serious and painful disease in
which defective collagen prevents the formation of strong connective tissue.
Gums deteriorate and bleed, with loss of teeth; skin discolors, and wounds do
not heal. Prior to the eighteenth century, this condition was notorious among
long duration military, particularly naval, expeditions during which
participants were deprived of foods containing Vitamin C. An autoimmune disease such as lupus erythematosus or rheumatoid
arthritis may attack healthy collagen fibers. Many bacteria and viruses have virulence factors which destroy
collagen or interfere with its production. Molecular structure The tropocollagen or collagen molecule is a subunit of larger collagen
aggregates such as fibrils. At approximately 300 nm long and 1.5 nm in
diameter, it is made up of three polypeptide strands (called alpha peptides,
see step 2), each possessing the conformation of a left-handed helix (its
name is not to be confused with the commonly occurring alpha helix, a
right-handed structure). These three left-handed helices are twisted together
into a right-handed coiled coil, a triple helix or "super helix", a
cooperative quaternary structure stabilized by numerous hydrogen bonds. With
type I collagen and possibly all fibrillar collagens if not all collagens,
each triple-helix associates into a right-handed super-super-coil referred to
as the collagen microfibril. Each microfibril is interdigitated with its
neighboring microfibrils to a degree that might suggest they are individually
unstable, although within collagen fibrils, they are so well ordered as to be
crystalline. A distinctive feature of collagen is the regular arrangement of amino
acids in each of the three chains of these collagen subunits. The sequence
often follows the pattern Gly-Pro-X or Gly-X-Hyp, where X may be any of
various other amino acid residues. Proline or hydroxyproline constitute about
1/6 of the total sequence. With glycine accounting for the 1/3 of the sequence,
this means approximately half of the collagen sequence is not glycine,
proline or hydroxyproline, a fact often missed due to the distraction of the
unusual GX1X2 character of collagen alpha-peptides. The high glycine content
of collagen is important with respect to stabilization of the collagen helix
as this allows the very close association of the collagen fibers within the
molecule, facilitating hydrogen bonding and the formation of intermolecular
cross-links. This kind of regular repetition and high glycine content is
found in only a few other fibrous proteins, such as silk fibroin. About
75-80% of silk is (approximately) -Gly- Because glycine is the smallest amino acid with no side chain, it
plays a unique role in fibrous structural proteins. In collagen, Gly is
required at every third position because the assembly of the triple helix
puts this residue at the interior (axis) of the helix, where there is no
space for a larger side group than glycine’s single hydrogen atom. For the
same reason, the rings of the Pro and Hyp must point outward. These two amino
acids help stabilize the triple helix—Hyp even more so than Pro; a lower
concentration of them is required in animals such as fish, whose body
temperatures are lower than most warm-blooded animals. Lower proline and
hydroxyproline contents are characteristic of cold-water, but not warm-water
fish; the latter tend to have similar proline and hydroxyproline contents to
mammals. The lower proline and hydroxproline contents of cold-water fish and
other poikilotherm animals leads to their collagen having a lower thermal
stability than mammalian collagen. This lower thermal stability means that
gelatin derived from fish collagen is not suitable for many food and
industrial applications. The tropocollagen subunits spontaneously self-assemble, with regularly
staggered ends, into even larger arrays in the extracellular spaces of
tissues. In the fibrillar collagens, the molecules are staggered from each
other by about 67 nm (a unit that is referred to as ‘D’ and changes depending
upon the hydration state of the aggregate). Each D-period contains four plus
a fraction collagen molecules, because 300 nm divided by 67 nm does not give
an integer (the length of the collagen molecule divided by the stagger
distance D). Therefore, in each D-period repeat of the microfibril, there is
a part containing five molecules in cross-section, called the “overlap”, and
a part containing only four molecules, called the "gap". The
triple-helices are also arranged in a hexagonal or quasihexagonal array in
cross-section, in both the gap and overlap regions. There is some covalent crosslinking within the triple helices, and a
variable amount of covalent crosslinking between tropocollagen helices
forming well organized aggregates (such as fibrils). Larger fibrillar bundles
are formed with the aid of several different classes of proteins (including
different collagen types), glycoproteins and proteoglycans to form the
different types of mature tissues from alternate combinations of the same key
players. Collagen's insolubility was a barrier to the study of monomeric
collagen until it was found that tropocollagen from young animals can be
extracted because it is not yet fully crosslinked. However, advances in
microscopy techniques (i.e. electron microscopy (EM) and atomic force microscopy
(AFM)) and X-ray diffraction have enabled researchers to obtain increasingly
detailed images of collagen structure in situ. These later advances are
particularly important to better understanding the way in which collagen
structure affects cell-cell and cell-matrix communication, and how tissues
are constructed in growth and repair, and changed in development and disease.
For example using AFM –based nanoindentation it has been shown that a single
collagen fibril is a heterogeneous material along its axial direction with
significantly different mechanical properties in its gap and overlap regions,
correlating with its different molecular organizations in these two regions. Collagen fibrils are semicrystalline aggregates of collagen molecules.
Collagen fibers are bundles of fibrils. Collagen fibrils/aggregates are arranged in different combinations and
concentrations in various tissues to provide varying tissue properties. In
bone, entire collagen triple helices lie in a parallel, staggered array. 40
nm gaps between the ends of the tropocollagen subunits (approximately equal
to the gap region) probably serve as nucleation sites for the deposition of
long, hard, fine crystals of the mineral component, which is (approximately)
Ca10(OH)2(PO4)6. Type I collagen gives bone its tensile strength. [edit] Types and associated disorders Collagen occurs in many places throughout the body. Over 90% of the
collagen in the body, however, is of So far, 28 types of collagen have been identified and described. The
five most common types are: ·
Collagen I: skin, tendon, vascular
ligature, organs, bone (main component of the organic part of bone) ·
Collagen II: cartilage (main
component of cartilage) ·
Collagen III: reticulate (main component
of reticular fibers), commonly found alongside type I. ·
Collagen IV: forms bases of cell
basement membrane ·
Collagen V: cell surfaces, hair and
placenta ·
Elastic fibers. Elastic fibers (or
yellow fibers) are bundles of proteins (elastin) found in extracellular
matrix of connective tissue and produced by fibroblasts and smooth muscle
cells in arteries. These fibers can stretch up to 1.5 times their length, and
snap back to their original length when relaxed. Elastic fibers include
elastin, elaunin and oxytalan. Elastic
tissue is classified as "connective tissue proper". The
elastic fiber is formed from the elastic microfibril (consisting of numerous
proteins such as microfibrillar-associated glycoproteins, fibrillin,
fibullin, and the elastin receptor) and amorphous elastin. The
microfibril scaffolds and organizes the deposition of amorphous elastin.
Amorphous elastin forms from monomers of soluble tropoelastin which is
insolubilized and crosslinked into amorphous elastin by lysyl oxidase. Lysyl
oxidase reacts with specific lysine residues and by oxidative deamination
generates reactive aldehydes and allysine. These
reactive aldehydes and allysines can react with lysine and other allysine
residues to crosslink and form desmosine, isodesmosine, and a number of other
polyfunctional crosslinks that join surrounding elastin molecules to build an
elastin matrix and elastic fiber. These unique crosslinks are responsible for
elastin's elasticity. Subcutaneous
tissue from a young rabbit. Highly magnified. (Elastic fibers labeled at
right. ) Histology Elastic
fibers stain well with aldehyde fuchsin, orcein, and Weigert's elastic stain
in histological sections. The
permanganate-bisulfite-toluidine blue reaction is a highly selective and
sensitive method for demonstrating elastic fibers under polarizing optics.
The induced birefringence demonstrates the highly ordered molecular structure
of the elastin molecules in the elastic fiber. This is not readily apparent
under normal optics. Defects
and disease There
is evidence to believe that certain defects of any components of the elastic
matrix may impair and alter the structural appearance of elastic and collagen
fibers. Cutis
laxa and Williams syndrome have elastic matrix defects that have been
directly associated with alterations in the elastin gene. Alpha-1
antitrypsin deficiency is a genetic disorder where elastin is excessively
degraded by elastase, a degrading protein released by neutrophils during the
inflammatory response. This leads most often to emphysema and liver disease
in affected individuals. Buschke-Ollendorff
syndrome, Menkes disease, pseudoxanthoma elasticum, and Marfan's syndrome
have been associated with defects in copper metabolism and lysyl oxidase or
defects in the microfibril (defects in fibrillin, or fibullin for example). Hurler
disease, a lysosomal storage disease, is associated with an altered elastic
matrix. Hypertension
and some congenital heart defects are associated with alterations in the great
arteries, arteries, and arterioles with alterations in the elastic matrix. ·
Reticular fibers. Reticular
fibers, reticular fibres or reticulin is a type of fiber in connective tissue
composed of type III collagen secreted by reticular cells. Reticular fibers
crosslink to form a fine meshwork (reticulin). This network acts as a
supporting mesh in soft tissues such as liver, bone marrow, and the tissues
and organs of the lymphatic system. A
liver biopsy stained with a reticulin stain demonstrating a normal hepatic
plate thickness and mild steatosis. History The
term reticulin was coined in 1892 by M. Siegfried. Today,
the term reticulin or reticular fiber is restricted to referring to fibers
composed of type III collagen. However, during the pre-molecular era, there
was confusion in the use of the term 'reticulin', which was used to describe
two structures: the
argyrophilic (silver staining) fibrous structures present in basement
membranes histologically
similar fibers present in developing connective tissue. The
history of the reticulin silver stain is reviewed by Puchtler et al. (1978).
The abstract of this paper says: Maresch
(1905) introduced Bielschowsky's silver impregnation technic for neurofibrils
as a stain for reticulum fibers, but emphasized the nonspecificity of such
procedures. This lack of specificity has been confirmed repeatedly. Yet,
since the 1920s the definition of "reticulin" and studies of its
distribution were based solely on silver impregnation technics. The chemical
mechanism and specificity of this group of stains is obscure. Application of
Gömöri's and Wilder's methods to human tissues showed variations of
staining patterns with the fixatives and technics employed. Besides reticulum
fibers, various other tissue structures, e.g. I bands of striated muscle,
fibers in nervous tissues, and model substances, e.g. polysaccharides, egg
white, gliadin, were also stained. Deposition of silver compounds on
reticulum fibers was limited to an easily removable substance; the remaining
collagen component did not bind silver. These histochemical studies indicate
that silver impregnation technics for reticulum fibers have no chemical
significance and cannot be considered as histochemical technics for
"reticulin" or type III collagen. Structure Reticular
fiber is composed of one or more types of very thin and delicately woven
strands of type III collagen. These strands build a highly ordered cellular
network and provide a supporting network. Many of these types of collagen
have been combined with carbohydrate. Thus, they react with silver stains and
with periodic acid-Schiff reagent but are not demonstrated with ordinary
histological stains such as those using hematoxylin. The 1953 Science article
mentioned above concluded that the reticular and regular collagenous
materials contains the same four sugars—galactose, glucose, mannose, and
fucose—but in a much greater concentration in the reticular than in the
collagenous material. In
a 1993 paper, the reticular fibers of the capillary sheath and splenic cord
were studied and compared in the pig spleen by transmission electron
microscopy. This paper attempted to reveal their components and the presence
of sialic acid in the amorphous ground substance. Collagen fibrils, elastic
fibers, microfibrils, nerve fibers, and smooth muscle cells were observed in
the reticular fibers of the splenic cord. On the other hand, only
microfibrils were recognized in the reticular fibers of the capillary sheath.
The binding of LFA lectin to the splenic cord was stronger than the capillary
sheath. These findings suggested that the reticular fibers of the splenic
cord include multiple functional elements and might perform an important role
during contraction or dilation of the spleen. On the other hand, the
reticular fiber of the capillary sheath resembled the basement membrane of
the capillary in its components. Muscular tissue: Muscular tissues make up the major part of the
soft tissues of the body & by means of its contraction power helps in
locomotion. e.g. – Skeletal muscle, cardiac muscle. Muscle cells form the active contractile tissue of the body known as
muscle tissue or muscular tissue. Muscle tissue functions to produce force
and cause motion, either locomotion or movement within internal organs.
Muscle tissue is separated into three distinct categories: visceral or smooth
muscle, which is found in the inner linings of organs; skeletal muscle, in
which is found attached to bone providing for gross movement; and cardiac
muscle which is found in the heart, allowing it to contract and pump blood
throughout an organism. Nervous tissue: Nervous tissue is highly specialized tissue
which controls & co-ordinates the body functions by forming nervous
system. e.g – Neuralgia, White matter, Grey matter. Cells comprising the central nervous system and peripheral nervous
system are classified as neural tissue. In the central nervous system, neural
tissue forms the brain and spinal cord and, in the peripheral nervous system
forms the cranial nerves and spinal nerves, inclusive of the motor neurons.
Nervous tissue functions to transmit messages in form of impulse. Tissue in the human body: 1.
Epithelial: Is made of cells arranged in a continuous sheet with one or more
layers, has apical & basal surfaces. o
A basement membrane is
the attachment between the basal surface of the cell & the underlying
connective tissue. o
Two types of epithelial
tissues: (1) Covering & lining epithelia and (2) Glandular Epithelium. o
The number of cell
layers & the shape of the cells in the top layer can classify epithelium. §
Simple Epithelium - one cell layer §
Stratified
epithelium - two or more cell layers §
Pseudostratified
Columnar Epithelium - When cells of an epithelial
tissue are all anchored to the basement Membrane but not all cells reach the
apical surface. §
Glandular
Epithelium – (1) Endocrine:
Release hormones directly into the blood stream and (2) Exocrine - Secrete
into ducts. 2.
Connective: contains many different
cell types including: fibroblasts, macrophages, mast cells, and adipocytes.
Connective Tissue Matrix is made of two materials: ground substance -
proteins and polysaccharides, fiber – reticular, collagen and elastic. o
oose Connective - fibers & many cell types in gelatinous matrix, found in skin,
& surrounding blood vessels, nerves, and organs. o
Dense Connective - Bundles of parallel collagen fibers& fibroblasts, found in
tendons& ligaments. o
Cartilage - Cartilage is made of collagen & elastin fibers embedded in a
matrix glycoprotein & cells called chondrocytes, which was found in small
spaces. o
Cartilage has three subtypes: §
Hyaline
cartilage – Weakest, most
abundant type, Found at end of long bones, & structures like the ear and
nose, §
Elastic
cartilage- maintains shape, branching
elastic fibers distinguish it from hyaline and §
Fibrous
Cartilage - Strongest type, has
dense collagen & little matrix, found in pelvis, skull & vertebral
discs. 3.
Muscle: is divided into 3 categories, skeletal, cardiac and smooth. o
Skeletal Muscle – voluntary, striated, striations perpendicular to the muscle fibers
and it is mainly found attached to bones. o
Cardiac Muscle – involuntary, striated, branched and has intercalated discs o
Smooth Muscle – involuntary, nonstriated, spindle shaped and is found in blood
vessels & the GI tract. 4.
Nervous: Consists of only two cell types in the central nervous system (CNS)
& peripheral nervous system (PNS): o
Neurons - Cells that convert stimuli into electrical impulses to the brain,
and Neuroglia – supportive cells. o
Neurons – are made up of cell body, axon and dendrites. There are 3 types of
neurons: §
Motor Neuron – carry impulses from CNS to muscles and glands, §
Interneuron - interpret input from sensory neurons and end responses to motor
neurons §
Sensory Neuron – receive information from environment and transmit to CNS. o
Neuroglia – is made up of astrocytes, oligodendrocytes, ependymal cells and microglia
in the CNS, and schwann cells and satellite cells in the PNS. Development: All tissues of the body develop from the three primary germ cell
layers that form the embryo:
Cell
Junctions:
|
An adjective
modifies a noun or
a pronoun
by describing, identifying, or quantifying words. An adjective usually precedes
the noun or the pronoun which it modifies.
In the following examples,
the highlighted words are adjectives:
The truck-shaped
balloon floated over the treetops.
Mrs. Morrison papered
her kitchen walls with hideous wall paper.
The small
boat foundered on the wine dark sea.
The coal
mines are dark and dank.
Many stores have already begun to play irritating Christmas
music.
A battered
music box sat on the mahogany sideboard.
The back room was
filled with large, yellow rain boots.
An adjective can be modified
by an adverb,
or by a phrase
or clause
functioning as an adverb. In the sentence
My husband knits
intricately patterned mittens.
for example, the adverb
``intricately'' modifies the adjective ``patterned.''
Some nouns, many pronouns,
and many participle phrases
can also act as adjectives. In the sentence
Eleanor listened to
the muffled sounds of the radio hidden under
her pillow.
for example, both highlighted
adjectives are past participles.
Grammarians also consider articles (``the,'' ``a,'' ``an'') to be
adjectives.
A possessive adjective (``my,''
``your,'' ``his,'' ``her,'' ``its,'' ``our,'' ``their'') is similar or
identical to a possessive pronoun;
however, it is used as an adjective and modifies a noun or a noun phrase,
as in the following sentences:
I can't complete my
assignment because I don't have the textbook.
In this sentence, the
possessive adjective ``my'' modifies ``assignment'' and the noun phrase ``my
assignment'' functions as an object.
Note that the possessive pronoun form ``mine'' is not used to modify a noun or
noun phrase.
What is your
phone number.
Here the possessive
adjective ``your'' is used to modify the noun phrase ``phone number''; the
entire noun phrase ``your phone number'' is a subject complement.
Note that the possessive pronoun form ``yours'' is not used to modify a noun or
a noun phrase.
The bakery sold his
favourite type of bread.
In this example, the
possessive adjective ``his'' modifies the noun phrase ``favourite type of
bread'' and the entire noun phrase ``his favourite type of bread'' is the direct object
of the verb
``sold.''
After many years, she
returned to her homeland.
Here the possessive
adjective ``her'' modifies the noun ``homeland'' and the noun phrase ``her
homeland'' is the object of the preposition
``to.'' Note also that the form ``hers'' is not used to modify nouns or noun
phrases.
We have lost our
way in this wood.
In this sentence, the
possessive adjective ``our'' modifies ``way'' and the noun phrase ``our way''
is the direct object of the compound verb
``have lost''. Note that the possessive pronoun form ``ours'' is not used to
modify nouns or noun phrases.
In many fairy tales,
children are neglected by their parents.
Here the possessive
adjective ``their'' modifies ``parents'' and the noun phrase ``their parents''
is the object of the preposition ``by.'' Note that the possessive pronoun form
``theirs'' is not used to modify nouns or noun phrases.
The cat chased its
ball down the stairs and into the backyard.
In this sentence, the
possessive adjective ``its'' modifies ``ball'' and the noun phrase ``its ball''
is the object of the verb ``chased.'' Note that ``its'' is the possessive
adjective and ``it's'' is a contraction
for ``it is.''
The demonstrative adjectives
``this,'' ``these,'' ``that,'' ``those,'' and ``what'' are identical to the demonstrative
pronouns, but are used as adjectives to modify nouns or noun
phrases, as in the following sentences:
When the librarian
tripped over that cord, she dropped a pile of books.
In this sentence, the
demonstrative adjective ``that'' modifies the noun ``cord'' and the noun phrase
``that cord'' is the object of the preposition ``over.''
This apartment needs to be fumigated.
Here ``this'' modifies
``apartment'' and the noun phrase ``this apartment'' is the subject
of the sentence.
Even though my friend
preferred those plates, I bought these.
In the subordinate clause,
``those'' modifies ``plates'' and the noun phrase ``those plates'' is the
object of the verb ``preferred.'' In the independent clause,
``these'' is the direct object of the verb ``bought.''
Note that the relationship
between a demonstrative adjective and a demonstrative pronoun is similar to the
relationship between a possessive adjective and a possessive pronoun, or to
that between a interrogative adjective and an interrogative
pronoun.
An interrogative adjective
(``which'' or ``what'') is like an interrogative pronoun, except that it
modifies a noun or noun phrase rather than standing on its own:
Which plants should be watered twice a week?
Like other adjectives,
``which'' can be used to modify a noun or a noun phrase. In this example,
``which'' modifies ``plants'' and the noun phrase ``which paints'' is the
subject of the compound verb ``should be watered'':
What book are you reading?
In this sentence, ``what''
modifies ``book'' and the noun phrase ``what book'' is the direct object of the
compound verb ``are reading.''
An indefinite adjective is
similar to an indefinite pronoun,
except that it modifies a noun, pronoun, or noun phrasé́́́́, as in the following sentences:
Many people believe
that corporations are under-taxed.
The indefinite adjective
``many'' modifies the noun ``people'' and the noun phrase ``many people'' is
the subject of the sentence.
I will send you any
mail that arrives after you have moved to Sudbury.
The indefinite adjective
``any'' modifies the noun ``mail'' and the noun phrase ``any mail'' is the
direct object of the compound verb ``will send.''
They found a few
goldfish floating belly up in the swan pound.
In this example the
indefinite adjective modifies the noun ``goldfish'' and the noun phrase is the
direct object of the verb ``found'':
The title of Kelly's
favourite game is ``All dogs go to heaven.''
Here the indefinite pronoun
``all'' modifies ``dogs'' and the full title is a subject complement.
́́́́ THE COMPARISON OF ADJECTIVES
There are
three degrees of comparison:
POSITIVE
degree, COMPARATIVE
degree, SUPERLATIVE
degree:
POSITIVE |
COMPARATIVE |
SUPERLATIVE |
cool |
cooler |
coolest |
intelligent |
more intelligent |
most intelligent |
01. COMPARATIVE OF EQUALITY
AS .... AS (for positive comparisons),
(NOT) SO
.... AS (for negative comparisons).
Her
pronunciation is AS good AS yours.
His pronunciation is NOT SO good AS yours.
Note: We may say NOT AS .... AS, especially after a
contracted form: Her pronunciation isn't AS good AS yours.
02. COMPARATIVE OF INFERIORITY
LESS ..... THAN
+ the adjective.
It is LESS cold
today THAN
it was yesterday.
Kelly is LESS
old THAN Sandra.
03. SUPERLATIVE OF INFERIORITY
THE LEAST ....... OF (or IN) + the adjective.
Sunday
was THE
LEAST cold day of the week.
Christina is THE
LEAST old girl in that class.
04. COMPARATIVE and SUPERLATIVE OF SUPERIORITY
a) Monosyllabic adjectives form their COMPARATIVE
and SUPERLATIVE
by adding - ER
and - EST
to the POSITIVE degree.
tall |
tallER THAN |
THE tallEST |
warm |
warmER THAN |
THE warmEST |
Exceptions:
just |
MORE just THAN |
THE MOST just |
right |
MORE right THAN |
THE MOST right |
real |
MORE real THAN |
THE MOST real |
wrong |
MORE wrong THAN |
THE MOST wrong |
b) Adjectives with more than two syllables
form their COMPARATIVE
and SUPERLATIVE
by putting MORE
and THE MOST
in front of the adjective.
difficult |
MORE difficult THAN |
THE MOST difficult |
important |
MORE important THAN |
THE MOST important |
c) Disyllabic
(two syllables) adjectives form their COMPARATIVE and SUPERLATIVE
in two
different ways:
1. Adjectives ending in ED, ING, RE, FUL, OUS
and those with the stress on the first syllable usually take MORE and THE MOST:
charming |
MORE charming THAN |
THE MOST charming |
famous |
MORE famous THAN |
THE MOST famous |
hopeful |
MORE hopeful THAN |
THE MOST hopeful |
learned |
MORE learned THAN |
THE MOST learned |
obscure |
MORE obscure THAN |
THE MOST obscure |
2. Adjectives ending in ER, Y, LE, OW and those with the stress on the second
syllable add ER and EST to the
POSITIVE degree.
clever |
cleverER THAN |
THE cleverEST |
narrow |
narrowER THAN |
THE narrowEST |
pretty |
prettiER THAN |
THE prettiEST |
polite |
politER THAN |
THE politEST |
simple |
simplER THAN |
THE simplEST |
Note: Adjectives ending in SOME and the words cheerful, common, cruel, pleasant, quiet,
civil may be compared by adding ER and EST or by MORE and MOST.
pleasant |
pleasantER THAN |
THE pleasantEST |
or
pleasant |
MORE
pleasant THAN |
THE MOST
pleasant |
05. ORTHOGRAPHIC NOTES
a) Add R and ST to
adjectives ending in E.
large |
largeR THAN |
THE largeST |
ripe |
ripeR THAN |
THE ripeST |
b) VOWEL SANDWICH
(VOWEL + CONSONANT + VOWEL) (THE LAST
VOWEL IS DOUBLED)
big |
bigGER THAN |
THE bigGEST |
fat |
fatTER THAN |
THE fatTEST |
NO SANDWICH (JUST THE SUFFIX)
small |
smallER THAN |
THE smallEST |
sweet |
sweetER THAN |
THE sweetEST |
c) Adjectives
ending in - y
preceded by
a consonant, change Y into I before ER and EST.
happY |
happIER THAN |
THE happIEST |
Exceptions:
shY |
shYER THAN |
THE shYEST |
gaY |
gaYER THAN |
THE gaYEST |
greY |
greYER THAN |
THE greYEST |
6. IRREGULAR COMPARISONS
good |
better than |
the best |
bad |
worse than |
the worst |
little |
less than |
the least |
much |
more than |
the most |
many |
more than |
the most |
far |
farther than |
the farthest |
far |
further than |
the furthest |
old |
older than |
the oldest |
old |
elder than |
the eldest |
NOTES:
1. FARTHER and FARTHEST
generally refer to distance; FURTHER and FURTHEST also refer to distance but
they may have the meaning of "additional".
I live farther from here than
you do.
Give me further details.
2.
OLDER and OLDEST refer to persons or things; ELDER and ELDEST can only be used
for members of the same family:
My elder sister is afraid of
mice.
My older friend is afraid of
wasps.
but
ELDER can
not be placed before THAN so OLDER is used:
My sister is two years older
than I am.
7. CONSTRUCTIONS WITH
COMPARATIVES
a) Gradual increase:
Those exercises are getting EASIER AND EASIER.
OR
Those exercises are getting MORE AND MORE EASY.
The
weather is getting NICER AND NICER. OR
The weather is getting MORE AND MORE NICE.
The
rent of our flat is getting MORE AND MORE EXPENSIVE.
B) Parallel increase: (THE +
comparative ...... THE + comparative).
THE MORE I see you THE MORE I want you.
THE HOTTER,
THE BETTER.
THE MORE
he studies, THE
BETTER he becomes.
COMPARISON OF ADVERBS
1. COMPARATIVE and SUPERLATIVE of
SUPERIORITY.
a) Monosyllabic adverbs from their
comparative and superlative of superiority in the same way
as monosyllabic
adjectives.
high |
highER THAN |
THE highEST |
soon |
soonER THAN |
THE soonEST |
fast |
fastER THAN |
THE fastEST |
b) Adverbs of more than one syllable
take MORE
and MOST.
quickly |
MORE quickly THAN |
THE MOST quickly |
slowly |
MORE slowly THAN |
THE MOST slowly |
seldom |
MORE seldom THAN |
THE MOST seldom |
Exception:
early |
earliER THAN |
THE earliEST |
2. IRREGULAR COMPARISONS
well |
better than |
the best |
badly |
worse than |
the worst |
little |
less than |
the least |
much |
more than |
the most |
late |
later than |
the last |
Biological tissue is a collection of interconnected cells
that perform a similar function within an organism.
The study of tissue is known
as histology,
or, in connection with disease, histopathology.
The classical tools for
studying the tissues are the wax block, the tissue stain, and the optical microscope,
though developments in electron microscopy, immunofluorescence, and frozen sections have
all added to the sum of knowledge in the last couple of decades.With these
tools, the classical appearances of the tissues can be examined in health and
disease, enabling considerable refinement of clinical diagnosis and prognosis.
There are four basic types of tissue in the body of all animals, including
the human body and lower multicellular organisms such as insects. These
compose all the organs, structures and other contents.
·
Epithelium - Tissues composed of layers of cells that cover organ surfaces such as
surface of the skin and inner lining of digestive tract: the tissues that serve
for protection, secretion, and absorption.
·
Connective tissue - As the name suggests, connective tissue holds everything together. Some
people consider blood a
connective tissue. It should be noted that blood is not 'considered' connective
tissue, it is connective tissue. (i.e. cells of connective tissue (blood)
separated by an inorganic material (plasma). Plasma is the extracellular matrix
that includes everything but the red/white blood cells. These tissues contain
extensive extracellular matrix.
·
Muscle tissue - Muscle cells contain contractile filaments that move past each other and
change the size of the cell. Muscle tissue also is separated into three
distinct categories: visceral or smooth muscle,
which is found in the inner linings of organs; skeletal muscle,
which is found attached to bone in order for mobility to take place; and cardiac muscle
which is found in the heart.
·
Nervous tissue - Cells forming the brain,
spinal cord
and peripheral nervous system.
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In developmental
biology, cellular differentiation is
the process by which a less specialized cell becomes a more specialized cell
type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of tissues and cell types. Differentiation is a common process in adults as well: adult stem cells divide
and create fully differentiated daughter
cells during tissue repair and during normal cell turnover. Differentiation
dramatically changes a cell's size, shape, membrane potential, metabolic
activity, and responsiveness to signals. These changes are largely due to
highly controlled modifications in gene
expression. With a few exceptions, cellular differentiation almost never
involves a change in the DNA sequence itself. Thus, different cells can have very different physical
characteristics despite having the same genome.
A cell that is able to differentiate into all
cell types of the adult organism is known as pluripotent. Such cells are called embryonic stem cells in
animals and meristematic cells in
higher plants. A cell that is able to differentiate into all cell types, including the placental tissue, is known as totipotent. In mammals, only the zygote and
subsequent blastomeric are totipotent, while in plants many differentiated cells can become
totipotent with simple laboratory techniques. In cytopathology, the level of cellular differentiation is used as a measure of cancer progression. "Grade" is a marker of how differentiated a cell in
a tumor is.
Three basic categories of cells make up the
mammalian body: germ cells, somatic cells, and stem
cells. Each of the approximately 100 trillion (1014) cells in an adult
human has its own copy or copies of the genome except certain cell types, such as red
blood cells, that lack nuclei in their fully differentiated state. Most cells
are diploid; they have two copies of each chromosome. Such cells, called somatic cells, make up most of the human
body, such as skin and muscle cells. Cells differentiate to specialize for
different functions.
Germ line cells are any line of cells that
give rise to gametes—eggs and sperm—and thus are continuous through the generations. Stem
cells, on the other hand, have the ability to divide for indefinite periods and
to give rise to specialized cells. They are best described in the context of
normal human development.
Development begins when a sperm fertilizes an egg and creates a single cell that has the potential to form an entire
organism. In the first hours after fertilization, this cell divides into
identical cells. In humans, approximately four days after fertilization and
after several cycles of cell division, these cells begin to specialize, forming
a hollow sphere of cells, called a blastocyst.
The blastocyst has an outer layer of cells, and inside this hollow sphere,
there is a cluster of cells called the inner
cell mass. The cells of the inner cell mass go on to form virtually all of the
tissues of the human body. Although the cells of the inner cell mass can form
virtually every type of cell found in the human body, they cannot form an
organism. These cells are referred to as pluripotent.
Pluripotent stem cells undergo further specialization
into multipotent progenitor cells that
then give rise to functional cells. Examples of stem and progenitor cells
include:
·
Hematopoietic stem cells (adult stem cells) from the bone
marrow that give rise to red
blood cells, white blood cells, and platelets
·
Mesenchyme stem cells (adult stem cells) from the bone
marrow that give rise to stromal cells, fat cells, and types of bone cells
·
Epithelial stem cells (progenitor
cells) that give rise to the various types of skin cells
·
Muscle satellite cells (progenitor
cells) that contribute to differentiated muscle tissue.
A pathway that is guided by the cell adhesion
molecules consisting of four amino acids, arginine, glycine, asparagine, and serine,
is created as the cellular blastomere differentiates from the single-layered blastula to the three primary layers
of germ cells in mammals, namely the ectoderm, mesoderm and endoderm (listed from most distal (exterior) to proximal (interior)). The ectoderm
ends up forming the skin and the nervous system, the mesoderm forms the bones
and muscular tissue, and the endoderm forms the internal organ tissues.
Micrograph of a lip sarcoma with some dedifferentiation, that is not identifiable as a liposarcoma,
(left edge of image) and a differentiated component (with lip oblasts and increased vascularity (right of image)). Fully differentiated (morphologically benign)adipose
tissue (center of the image) has few blood vessels. H&E stain.
Dedifferentiation is a cellular process often
seen in more basal life forms such as worms and amphibians in which a partially or terminally differentiated cell reverts to an
earlier developmental stage, usually as part of a regenerative process. Dedifferentiation also occurs in plants. Cells in cell culture can
lose properties they originally had, such as protein expression, or change
shape. This process is also termed dedifferentiation.
Some believe dedifferentiation is an
aberration of the normal development cycle that results in cancer, whereas others believe it to be a natural part of the immune response lost
by humans at some point as a result of evolution.
A small molecule dubbed riverine, a purine analog, has been discovered that has proven to induce dedifferentiation in my tubes. These dedifferentiated cells were then able to redifferentiate
into osteoblasts and adipocytes.
Dedifferentiation to totipotency or pluripotency: an overview of methods.'Various methods exist to revert adult somatic cells to pluripotency or
totipotency. In the case of totipotency, reprogramming is mediated through a
mature metaphase II oocyte as in somatic cell nuclear transfer (Wilmut et al.,
1997). Recent work has demonstrated the feasibility of enucleated zygotes or
early blastomeres chemically arrested during mitosis, such that nuclear
envelope break down occurs, to support reprogramming to totipotency in a
process called chromosome transfer (Egli and Eggan, 2010). Direct reprogramming
methods support reversion to pluripotency; though, vehicles and biotypes vary
considerably in efficiencies (Takahashi and Yamanaka, 2006). Viral-mediated
transduction robustly supports dedifferentiation to pluripotency through
retroviral or DNA-viral routes but carries the onus of insertional inactivation.
Additionally, epigenetic reprogramming by enforced expression of OSKM through
DNA routes exists such as plasmid DNA, minicircles, transposons, episomes and
DNA mulicistronic construct targeting by homologous recombination has also been
demonstrated; however, these methods suffer from the burden to potentially
alter the recipient genome by gene insertion (Ho et al., 2010). While
protein-mediated transduction supports reprogramming adult cells to
pluripotency, the method is cumbersome and requires recombinant protein
expression and purification expertise, and reprograms albeit at very low
frequencies (Kim et al., 2009). A major obstacle of using RNA for reprogramming
is its lability and that single-stranded RNA biotypes trigger innate antiviral
defense pathways such as interferon and NF-κB-dependent pathways. In vitro
transcribed RNA, containing stabilizing modifications such as 5-methylguanosine
capping or substituted ribonucleobases, e.g. pseudouracil, is 35-fold more
efficient than viral transduction and has the additional benefit of not
altering the somatic genome (Warren et al., 2010).
Mechanisms
of cellular differentiation
Each specialized cell type in an organism expresses a subset of all the genes that constitute the genome of that species. Each cell type is defined by its particular pattern of regulated gene expression. Cell differentiation is thus a transition of a
cell from one cell type to another and it involves a switch from one pattern of
gene expression to another. Cellular differentiation during development can be
understood as the result of a gene
regulatory network. A regulatory gene and its cis-regulatory modules are nodes
in a gene regulatory network; they receive input and create output elsewhere in
the network. The systems biology approach
to developmental biology emphasizes the importance of investigating how
developmental mechanisms interact to produce predictable patterns
(morphogenesis). (However, an alternative view has been proposed recently.
Based on stochastic gene expression, cellular differentiation is the result of
a Darwinian selective process occurring among cells. In this frame, protein and
gene networks are the result of cellular processes and not their cause. See:
Cellular)
A few evolutionarily conserved
types of molecular processes are often involved in the cellular mechanisms that
control these switches. The major types of molecular processes that control
cellular differentiation involve cell
signaling. Many of the signal molecules that convey information from cell to cell
during the control of cellular differentiation are called growth factors. Although the details of specific signal transduction
pathways vary, these pathways often share the following general steps. A ligand
produced by one cell binds to a receptor in the extracellular region of another
cell, inducing a conformational change in the receptor. The shape of the
cytoplasmic domain of the receptor changes, and the receptor acquires enzymatic
activity. The receptor then catalyzes reactions that phosphorylate other
proteins, activating them. A cascade of phosphorylation reactions eventually
activates a dormant transcription factor or cytoskeletal protein, thus
contributing to the differentiation process in the target cell. Cells and tissues can vary in competence, their ability to respond to
external signals.
Signal Induction refers to cascades of signaling events, during which a cell or tissue
signals to another cell or tissue to influence its developmental fate. Yamamoto and Jeffery investigated
the role of the lens in eye formation in cave- and surface-dwelling fish, a
striking example of induction. Through
reciprocal transplants, Yamamoto and Jeffery found that the lens vesicle of surface fish can induce other parts of the
eye to develop in cave- and surface-dwelling fish, while the lens vesicle of
the cave-dwelling fish cannot.
Other important mechanisms fall under the
category of asymmetric cell divisions, divisions that give rise to daughter cells with
distinct developmental fates. Asymmetric cell divisions can occur because of
asymmetrically expressed maternal cytoplasmic
determinants or
because of signaling. In the former mechanism, distinct daughter cells are
created during cytokinesis because of an uneven
distribution of regulatory molecules in the parent cell; the distinct cytoplasm
that each daughter cell inherits results in a distinct pattern of
differentiation for each daughter cell. A well-studied example of pattern
formation by asymmetric divisions is body
axis patterning in Drosophila. RNA molecules are an important type of intracellular differentiation control
signal. The molecular and genetic basis of asymmetric cell divisions has also
been studied in green algae of the genus Volvos, a model system for studying how unicellular
organisms can evolve into multicellular organisms. In Volvox carteri, the 16 cells in the anterior
hemisphere of a 32-cell embryo divide asymmetrically, each producing one large
and one small daughter cell. The size of the cell at the end of all cell
divisions determines whether it becomes a specialized germ or somatic cell.
Since each cell, regardless of cell type,
possesses the same genome,
determination of cell type must occur at the level of gene expression. While the regulation of gene expression can
occur through cist- and trans-regulatory elements including
a gene’s promoter and enhancers, the problem arises to how this expression pattern is maintained
over numerous generations of cell
division. As it turns out, epigenetic processes play a crucial role in regulating the decision to adopt a stem,
progenitor, or mature cell fate. This section will focus primarily on mammalian stem cells.
The first question that can be asked is the
extent and complexity of the role of epigenetic processes in the determination
of cell fate. A clear answer to this question can be seen in the 2011 paper by
Lister R, et al. on aberrant epigenomic programming in human induced. As induced pluripotent stem cells (iPSCs) are thought to
mimic embryonic stem cells in
their pluripotent properties, few epigenetic differences should exist between
them. To test this prediction, the authors conducted whole-genome profiling of DNA methylation patterns
in several human embryonic stem cell (ESC), iPSC, and progenitor cell lines.
Female adipose cells, lung fibroblasts, and foreskin fibroblasts were reprogrammed into induced
pluripotent state with the OCT4,SOX2, KLF4, and MYC genes. Patterns of DNA methylation in ESCs, iPSCs, somatic cells were
compared. Lister R, et
al. observed significant resemblance in methylation levels between embryonic
and induced pluripotent cells. Around 80% of CG dinucleotide in ESCs
and iPSCs were methylated, the same was true of only 60% of CG dinucleotides in
somatic cells. In addition, somatic cells possessed minimal levels of cytosine
methylation in non-CG dinucleotides, while induced pluripotent cells possessed
similar levels of methylation as embryonic stem cells, between 0.5 and 1.5%.
Thus, consistent with their respective transcriptional activities, DNA
methylation patterns, at least on the genomic level, are similar between ESCs
and iPSCs.
However, upon examining methylation patterns
more closely, the authors discovered 1175 regions of differential CG
dinucleotide methylation between at least one ES or iPS cell line. By comparing
these regions of differential methylation with regions of cytosine methylation
in the original somatic cells, 44-49% of differentially methylated regions
reflected methylation patterns of the respective progenitor somatic cells,
while 51-56% of these regions were dissimilar to both the progenitor and
embryonic cell lines. In
vitro-induced differentiation of iPSC lines saw transmission of 88% and 46% of
hyper and hypo-methylated differentially methylated regions, respectively.
Two conclusions are readily apparent from
this study. First, epigenetic processes are heavily involved in cell fate
determination, as seen from the similar levels of cytosine methylation between
induced pluripotent and embryonic stem cells, consistent with their respective
patterns of transcription. Second, the mechanisms of de-differentiation (and by
extension, differentiation) are very complex and cannot be easily duplicated,
as seen by the significant number of differentially methylated regions between
ES and iPS cell lines. Now that these two points have been established, we can
examine some of the epigenetic mechanisms that are thought to regulate cellular
differentiation.
Three transcription factors, OCT4, SOX2, and NANOG – the first two of which are used in iPSC reprogramming – are highly
expressed in undifferentiated embryonic stem cells and are necessary for the
maintenance of their pluripotency. It is thought that they achieve this through alterations in chromatin structure, such as histone
modification and DNA methylation, to restrict or permit the transcription of target
genes.
In the realm of gene silencing, Polycomb
repressive complex 2, one of two classes of the Polycomb group (PcG)
family of proteins, catalyzes the di- and tri-methylation of histone H3 lysine
27 (H3K27me2/me3). By binding to the H3K27me2/3-tagged nucleosome, PRC1 (also a
complex of PcG family proteins) catalyzes the mono-ubiquitinylation of histone
H2A at lysine 119 (H2AK119Ub1), blocking RNA polymerase II activity
and resulting in transcriptional suppression. PcG knockout ES cells do not differentiate efficiently into the three germ
layers, and deletion of the PRC1 and PRC2 genes leads to increased expression
of lineage-affiliated genes and unscheduled differentiation Presumably, PcG complexes are responsible for transcriptionally repressing
differentiation and development-promoting genes.
Alternately, upon receiving differentiation
signals, PcG proteins are recruited to promoters of pluripotency transcription
factors. PcG-deficient ES cells can begin differentiation but are unable to
maintain the differentiated phenotype. Simultaneously, differentiation and
development-promoting genes are activated by Trithorax group (TrxG) chromatin
regulators and lose their repression. TrxG
proteins are recruited at regions of high transcriptional activity, where they
catalyze the trimethylation of histone H3 lysine 4 (H3K4me3) and promote gene
activation through histone acetylation. PcG and TrxG complexes engage in direct competition and are thought to be
functionally antagonistic, creating at differentiation and development-promoting
loci what is termed a “bivalent domain” and rendering these genes sensitive to
rapid induction or repression.
Regulation of gene expression is further
achieved through DNA methylation, in which the DNA methyltransferase-mediated methylation of cytosine residues in CpG
dinucleotides maintains heritable repression by controlling DNA accessibility.
The majority of CpG sites in embryonic stem cells are unmethylated and appear
to be associated with H3K4me3-carrying nucleosomes. Upon differentiation, a small number of genes, including OCT4 and NANOG, are methylated and their promoters repressed to prevent their further
expression. Consistently, DNA methylation-deficient embryonic stem cells
rapidly enter apoptosis upon in vitro differentiation.
A final question to ask concerns the role of cell signaling in
influencing the epigenetic processes governing differentiation. Such a role
should exist, as it would be reasonable to think that extrinsic signaling can
lead to epigenetic remodeling, just as it can lead to changes in gene
expression through the activation or repression of different transcription
factors. Interestingly, little direct data is available concerning the specific
signals that influence the epigenome,
and the majority of current knowledge consist of speculations on plausible
candidate regulators of epigenetic remodeling. We will first discuss several major candidates thought to be involved in
the induction and maintenance of both embryonic stem cells and their
differentiated progeny, and then turn to one example of specific signaling
pathways in which more direct evidence exists for its role in epigenetic
change.
The first major candidate is Wnt signaling pathway. The Wnt pathway is involved in all stages of
differentiation, and the ligand Wnt3a can substitute for the overexpression of
c-Myc in the generation of induced pluripotent stem cells. On the other hand, disruption of ß-catenin,
a component of the Wnt signaling pathway, leads to decreased proliferation of
neural progenitors.
Growth factors comprise the second major set of candidates of epigenetic regulators of
cellular differentiation. These morphogens are crucial for development, and
include bone morphogenetic proteins,transforming growth factors (TGFs), and fibroblast growth factors (FGFs).
TGFs and FGFs have been shown to sustain expression of OCT4, SOX2, and NANOG by
downstream signaling to Smad proteins. Depletion of growth factors promotes the differentiation of ESCs,
while genes with bivalent chromatin can become either more restrictive or
permissive in their transcription.
Several other signaling pathways are also
considered to be primary candidates. Cytokine leukemia inhibitory factors are
associated with the maintenance of mouse ESCs in an undifferentiated state.
This is achieved through its activation of the Jak-STAT3 pathway, which has
been shown to be necessary and sufficient towards maintaining mouse ESC
pluripotency. Retinoic acid can
induce differentiation of human and mouse ESCs, and Notch signaling is
involved in the proliferation and self-renewal of stem cells. Finally, Sonic hedgehog, in addition to its role as a morphogen, promotes embryonic
stem cell differentiation and the self-renewal of somatic stem cells.
The problem, of course, is that the candidacy
of these signaling pathways was inferred primarily on the basis of their role
in development and cellular differentiation. While epigenetic regulation is
necessary for driving cellular differentiation, they are certainly not
sufficient for this process. Direct modulation of gene expression through
modification of transcription factors plays a key role that must be
distinguished from heritable epigenetic changes that can persist even in the
absence of the original environmental signals. Only a few examples of signaling
pathways leading to epigenetic changes that alter cell fate currently exist,
and we will focus on one of them.
Expression of Shh (Sonic hedgehog)
upregulates the production of Bmi1, a component of the PcG complex that
recognizes H3K27me3. This occurs in a Gli-dependent manner, as Gli1 and Gli2 are downstream effectors of the Hedgehog
signaling pathway. In culture, Bmi1 mediates the Hedgehog pathway’s ability to
promote human mammary stem cell self-renewal. In both humans and mice,
researchers showed Bmi1 to be highly expressed in proliferating immature
cerebellar granule cell precursors. When Bmi1 was knocked out in mice, impaired
cerebellar development resulted, leading to significant reductions in postnatal
brain mass along with abnormalities in motor control and behavior. A separate
study showed a significant decrease in neural stem cell proliferation along
with increased astrocyte proliferation in Bmi null mice.
In summary, the role of signaling in the
epigenetic control of cell fate in mammals is largely unknown, but distinct
examples exist that indicate the likely existence of further such mechanisms.
Tissue stress (tissue adaptive syndrome) is an unspecific adaptive reaction universal for
all tissues of adult organism which forms in tissue as a response to various
external influences. The latter are tissue cells’ damage, overload of their
specialized functions or regulatory influences.
According to tissue adaptive syndrome (TAS)
concept, this adaptive mechanism (see adaptation) comes into effect in damaged
tissue (see Tissue (biology)) as a result of concurrence of two events. The first one
is accumulation of TAS effectors in tissue (comutons, chalones, and
contactines), which possess a unique feature of tissue specificity in their
action on homologous tissue cells without species specificity. The second one
is increase in sensitivity of damaged cells to these regulators, as it was
demonstrated on the example of comuton. These effectors cause tissuespecific
self-damage of homologous cells via disturbance of their ion homeostasis and
energy-production processes. As a result, unspecific reaction to damage (CURD)
is activated in the cells. This universal physiological reaction plays a role
of TAS executive mechanism. Thus, the adaptive function of tissue stress is
brought into action using such CURD properties as increase of cell unspecific
resistance, as well as influence on the rate of cell metabolic processes. It is
obvious that in the case of TAS these changes have to be tissuespecific, since
they are initiated by way of cell self-damage under tissuespecific influence of
TAS effectors.
As is well known the CURD consists of two
phases. In the process of a slight damage of the cell the phase of metabolism
stimulation is forming in it. When the cell is slightly damaged, it begins to
form the phase of metabolism stimulation. Strong damaging influences initiate
the CURD phase of metabolism inhibition in the cell.
According to the TAS concept, the protective
effect of the tissue stress is realized in the case of forming of CURD
metabolism stimulation phase by TAS effectors as a result of acceleration of
reparative processes in the damaged cell. In the process of forming of CURD
phase of metabolism inhibition by the above effectors the protective influence
of tissue stress develops a result of cell reactivity decrease in response to
the external damaging influences.
The main feature of the tissue stress is its
formation with participation of the tissuespecific effectors of intratissue
intercellular interactions – comutons, chalones and contactins, which are
produced by the cells of a tissue under a stressor’s influence. This
distinguishes the tissue stress from the general adaptive syndrome, which is
realized via hormones – effectors of interorgan interactions (see Stress (biological)). Regional (local) stress forms with participation of
not one but several tissues making up an organ or a body part. This is why it
can be believed that regional stress-reaction is realized with the
participation of effectors of intraorgan intertissue interactions. Finally, the
cell stress is realized via intracellular mechanisms, without any participation
of intercellular interactions. In the latter case the CURD formation and
synthesis of heat shock proteins act as “self-defense” mechanism of the cell.
Another distinctive feature of tissue stress
is the principle of formation of its executive mechanism, the CURD, via
tissuespecific self-damage of homologous tissue cells. Despite the fact that
TAS, just as the cell stress, is realized via CURD, the TAS has a variety of
features which distinguish it from the cell stress, the key one being the
tissue-selectivity of CURD initiation under TAS effectors influence. In
addition, under cell stress the cell protection is realized with CURD
participation only via “passive” mechanism. It consists in the formation of the
protective phase of this physiological reaction. Meanwhile, under tissue
stress, its protective function may be carried out both the “passive” and
“active” CURD-induced mechanisms. Thus, the cell stress mechanism is just one
of the two instruments with which TAS protects the cells of homologous tissue.
The third difference between tissue and cell stresses lies in ability of the
former not only to increase but also to decrease the unspecific resistance of
the cells. Meanwhile, the cell stress concept considers only the first
possibility.
At the present moment, two physiological
functions of tissue stress, which are realized in the process of participation
of its adaptive mechanism, can be considered. One of them is expressed in an
increase of cell specialized functions stability in the conditions of prolonged
functional load. Another tissue stress function is to regulate homologous
tissue cell mass in various physiological conditions.
It is well known that only some part of
tissue functional units participate in its cells specialized functions
realization (Barcroft, 1937). Because of universality of this phenomenon it was
named “the law of intermittent activity of functioning structures”
(Kryshanovskii, 1973; Kryshanovskii, 1974). According to this law, functional
units of actively functioning tissue (or cells) form two populations where one
is in “intensive functioning” state and the other one – is in “resting” state.
Thereat the “rest” is not a passive state since there active reparation of
cellular structures occurs damaged in the course of specialized functions
performing by cells. “Intermittent” pattern of tissue cells specialized
functions realization is that the cells pass from one population to another
when the tissue is in intensive functioning mode. In such a way the cells
damaged in consequence of intensive functioning gain an offing to recover in
“resting” population. Meanwhile, recovered cells pass from the “resting”
population into “intensively functioning” one. It is safe to say that such organization
of tissue functioning favors stability of its cells functions performance. Yet,
the mechanisms which regulate cells passage from one population to another on
intratissue level are unknown.
Considering the law of “intermittent activity
of functioning structures” one can talk about two results of the TAS mechanism
action on the cells of actively functioning tissue. In conditions where the TAS
effector (effectors) forms CURD phase of metabolism stimulation one should
expect an acceleration of reparative processes in the cells of “resting”
population. Obviously that will promote accelerated recovery of such cells and
their pass to intensively functioning cell population. In case if TAS mechanism
forms the CURD phase of metabolism inhibition in intensively functioning cells
population this will lead to cell signaling inhibition and promote cells
“autonomy” from other external influences. Such autonomy may provoke an
inhibition of cell’s specialized functions in mentioned population in case if
they are stimulated by external regulatory influences. An inhibition of cells
specialized functions by the TAS mechanism may promote defense of intensively
functioning cells from self-damage and also their pass into the “resting”
state. Thus, the properties of tissue stress executive mechanism – CURD – allow
it to raise tissue functions stability in conditions of continuous intensive
activity in many ways.
According to the TAS concept, tissue stress possess
the ability to regulate the cell mass of homologous tissue via executive
mechanism described above – the CURD. As in the case of cells specialized
functions regulation there are two ways of tissue-specific control of
homologous tissue cell mass. These are cells unspecific resistance modulation
and influencing the speed of physiological processes occurring in the cell.
Tissue stress mechanism able to control
tissue cell mass influencing both its mitotic and apoptotic (see Apoptosis) activities tissue-specifically. In case if TAS effectors form
CURD phase of metabolism stimulation one should expect acceleration of
proliferative (see Proliferation)
pool cells passage through mitotic cycle (MC). Herewith there will be also an
acceleration of cells maturation and ageing. This will provoke an increase of
both mitotic and apoptotic activity in tissue. On the contrary, formation of
CURD phase of metabolism protective inhibition should result in opposite
results – an inhibition of all mentioned processes and, as a result, to
inhibition of both mitotic and apoptotic activities. One cannot exclude the
possibility that tissue stress mechanism considered able to regulate apoptosis
through inhibition of its energy-dependent stage. As concerns the modulation of
cells unspecific resistance by tissue stress mechanism, this property of CURD
allows to regulate cells entrance into MC as well as their entrance into
apoptosis.
Regulation of tissue cell mass by the TAS
mechanism can be carried out in two physiological regimes – ether by formation
of “conservative” or “dynamic” phase of this adaptive reaction. TAS
conservative phase is forming under the influence of “weak” unspecific external
damaging or “load” influences on cells specialized functions. Here tissue
stress provides intratissue adaptation by preservation of the existing cell
population in the tissue. It is achieved by raise of cells unspecific
resistance under the influence of tissue-specific self-damage of cells by TAS
effectors. This prevents entrance of postmitotic cells both into MC and
apoptosis. The TAS dynamic phase forms under “strong” external unspecific
damaging or “loading” influences on cells specialized functions. According to
TAS concept in dynamic phase of tissue stress a summation of damaging influence
of stressor (stressors) with cells self-damage by TAS effectors occurs. This
leads to stimulation of proliferation (see Proliferation) and to an increase of apoptotic activity (see Apoptosis) simultaneously. Thus, in above case adaptive function of tissue
stress realizes by replacement of damaged, dying cells by descendents of cells
more resistant to stressor(s) influence.
As is clear from the foregoing according the
TAS concept tissue stress mechanism effect on homologous tissue cells is
multifarious. It may protect them against the unspecific damaging influences as
well as to increase stability of tissue specialized functions in the conditions
of prolonged intensive functional activity. Simultaneously, the same mechanism
performs intratissue control of cell mass of homologous tissue.
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