William A Beresford MA, D Phil ©
Professor of Anatomy
Anatomy Department, West Virginia University, Morgantown, USA
This account deals, by custom, with a generic cell. For a similar story based
on specific working cell types - the poster-cell approach - try the
Medical Cytology Module.
A CELL MEMBRANE OR PLASMALEMMA.
1 Although looking trilaminar in routine EM, it behaves as if it comprises a
double layer of lipid molecules, in which proteins are distributed
asymmetrically in a mobile mosaic pattern. Thus, some proteins span the width of the
membrane, and may vary rates of transport by changes in their conformation.
Others, as enzymes, receptors, or adhesion molecules, etc. have active domains
at the surface held in correct position by intramembranous domains imbedded in
the lipid layer, and intracellular domains to engage in events inside the cell.
A sometimes fuzzy-looking coat of glycoprotein - glycocalyx - sticks to the external face of the membrane.
2 Functions of the membrane are:
- Firm attachment to other cells or a basal lamina; membrane
specializations for this are: (a) junctional complexes, (b) gap junctions/
nexuses, (c) desmosomes, (d) hemi-desmosomes, (e) intercalated discs, and (f)
membrane interdigitations; more details Chapter 4.D.l.
- Movement of the cell itself by pseudopodial, filipodial, or
lamellipodial extensions (think karate: fist, finger, or side of the hand)
and the release of any firm attachments, or by flagellate activity, e.g., by
sperm. (Microspikes and ruffles are alternative names for filopodia and
- Movement of materials outside the cell by the activity of cilia,
e.g., ciliated epithelia of the respiratory tract and uterine tube. The
wide-spread occurrence of solitary cilia (flagella), e.g., on neurons,
adrenal cells, smooth muscle, may involve a vestigial body or one still
functional. The stereocilia of the male reproductive tract are
non-motile, clumped, long microvilli, probably absorptive.
- Transport of materials in and out of the cell served by:
(a) permeability (selective) of the membrane, (b) active transport
through the membrane, (c) endocytosis, and its more scaled-up forms -
pinocytosis and phagocytosis, (d) exocytosis; and increased exchange surface
area by (e) microvilli (thousands on a cell), and (f) infoldings of membrane.
- Communication and transduction. Each cell collaborates with both
adjacent cells, and those of the whole body, for development, growth,
homeostasis, regeneration, and its own particular task. The importance of the
cell membrane in receiving and sending the necessary signals is stressed by
the number of examples given:
(a) The binding of hormones to receptors on the membrane.
(b) The binding of the lymphocyte's membrane receptor to an antigen.
(c) Transmitter chemicals depolarize neurons and muscle cells.
(d) Excitable tissues propagate action potentials along the membranes.
(e) Schwann cells wrap their membranes many times round an axon's to make
myelin sheath segments for faster signalling.
(f) Chemical stimuli are transduced into nerve impulses in chemoreceptors;
mechanical stimuli in mechanoreceptors.
(g) Gap junctions permit ions and excitation to spread from cell to cell, and
unify and synchronise actions of many cells/cell assemblies.
(h) In development, epithelial and mesenchymal cells interact in sequence to
induce cell differentiations, e.g., in tooth and glands.
(i) Cells attract and fuse with one another to form multinucleated cells, e.g.,
skeletal muscle and osteoclasts.
(j) Chemotactic agents act on phagocytic cells to attract them to their targets.
(k) Keratinocytes of the skin phagocytose melanin pigment offered to them in
the processes of melanocytes.
(l) Macrophages detect spent or abnormal red blood cells, and hold and engulf
either the whole cell, or the part holding an unwanted body.
3 Molecules Wherever such actions are described, special molecules
are acting, by binding to each other, changing their conformation, or some
other means. Examples are:
.. (a) Spectrin/fodrin provides a subplasmalemmal skeleton attached to the
cell membrane by ankyrin, and to actin of the cytoskeleton, to permit control
of the membrane's shape and movement.
.. (b) Cell adhesion molecules (CAMs) allow cells to attach to only
certain cell types or substrates.
.. (c) Integrins are cell-surface-membrane dimeric molecules (an
alpha with a beta), by which cells choose to which extracellular matrix (ECM)
components they wish to fasten, e.g., laminin.
.. (d) Connexins are proteins that combine as hexamers to form
connexons - the gap-junction channels, allowing ions and small molecules to
pass between cells. Connexins and the transports allowed vary among liver
cells, neurons, etc.
.. (e) Occludins are responsible for the seal preventing passage of
materials past inter-epithelial tight junctions.
B INTERNAL (CYTO-) MEMBRANE SYSTEMS
l Nuclear membrane is a doubled membrane with pores
that separates off genetic material and influences its degree and kind of
interaction with the cytoplasm. The membrane sometimes has deep infoldings.
(The rare annulate lamellae are parallel membranes with pores, and
closely resemble nuclear membranes, but are stacked in the cytoplasm.)
2 Granular endoplasmic reticulum (ergastoplasm) is a membrane system
providing some communication with the nucleus via the latter's outer membrane.
Both have ribosome particles studding their outer sufaces, i.e., those
facing outwards towards the cytoplasm. The membranes and ribosomes, in
association with the nucleus, are concerned with protein synthesis.
Some proteins pass into the sacs or cisternae, formed between the double
membrane layers, for folding and processing. Membrane vesicles holding the
protein bud off and travel along microtubules to the cis (receiving) face of
the Golgi complex.
. Endosomes are the natural transport vesicles moving from the donor
membrane compartment to the acceptor compartment. Endosomes require active
mechanisms for: membrane budding, separation, transport, targetting &
sorting, docking, and fusion. The donor and acceptor compartments may be the
plasmalemma (via endocytotic vesicles), the Golgi complex, lysosomes, or the
Some materials, e.g., receptors, are in a constant cycle between cell membrane, early
endosomes, and late endosomes, with branch points for materials to come or go to the
Golgi complex, lysosomes, or elsewhere in the cell.
[Note that microsomes are small bodies formed during separation by biochemical
cell fractionation techniques: morphologically they are artefacts. They are
derived from broken parts of the smooth or granular ER whose membranes 'heal'
to form small vesicles, with or without ribosomes.]
3 Golgi apparatus serves as a hub for traffic out of, into, and around
the cell. It is a complex transit region (there may be more than one in large
cells) occupied by smooth-surfaced tubules, sacs and flatter chambers varying
considerably in size. It concentrates, modifies and packages
certain secretory products to await transport to the cell membrane for
release, or application to some intracellular purpose. Vesicles depart from
the trans or releasing face. Also, the Golgi is where glycoconjugates are
finished by adding the remaining sugars (using glycosyltransferases),
e.g., in cartilage cells and mucus-secreting goblet cells. Glyco
4 Many inclusions - structures not actively participating in the
metabolism of the cell at the time of observation - are products bound
in membranes by the Golgi apparatus, e.g., melanosomes, zymogen granules.
Other inclusions, e.g., glycogen granules, form in the cytoplasm without
any enclosing membrane.
5 Smooth endoplasmic reticulum resembles the granular form in
sometimes having systems of parallel membranes following the curvature
of nearby structures, but it usually exists in tubular and vesicular
forms. Its functions are varied and include:
- Acting as a source or reserve for membranes of new structures, e.g., Golgi
body, GER; and cell membrane, as for the gastric oxyntic cell's canaliculi,
and in the megakaryocyte's formation of platelets.
- It is prominent in cells involved in cholesterol metabolism, e.g.,
liver cells and cells making steroid hormones. It seems to interact with lipid
droplets, also present, in the synthesis of the steroids.
- Smooth ER in liver cells is the site of enzymes detoxifying
phenobarbital and other foreign chemical materials. It is also concerned
there with the formation of plasma lipoprotein as a normal responsibility.
- A smooth membrane system is found in muscle fibres as the
sarcoplasmic reticulum. It synchronizes contractions and relaxations throughout the
fibre, by moving calcium ions to and from the sarcoplasm.
l These are complex bodies with a double membrane, the inner
membrane extending inwards as sheets or tubules called cristae.
2 The inside of the mitochondrion is occupied by a matrix in which dense
bodies may sometimes be found.
3 Enzymes of oxidation and energy-release, and for some syntheses,
are present; some associated with the crista membranes or with the external/
outer limiting membrane, others and coenzymes are in the matrix.
4 Mitochondria of steroid cells are distinctive in having tubular
5 Mitochondria are able to reproduce themselves. Also, they contain circular DNA for
13 respiratory-chain proteins. One rare mitochondrial genetic disorder of this
DNA causes, for example, a muscle disease with mitochondrial inclusion bodies.
6 Apoptosis involves mitochondria. Increased permeability of the outer mitochondrial
membrane allows the release of inter-membrane factors, e.g., cytochrome c, that help
start the caspase enzymatic cascade.
l They are roughly spherical with a single enclosing membrane.
2 The storage/primary form is derived from the Golgi apparatus and contains
3 whose access to other intracellular materials is controlled by the
enclosing membrane and processes of membrane fusion. The stability of the
membrane can be influenced by vitamin A and glucocorticoid hormones.
4 Lysosomes fuse with endosomes, phagosomes, surplus
secretory granules or expended organelles, which they destroy.
Multivesicular bodies are endosomes on their way to meet lysosomes, but
containing distinct vesicles within them, probably as a way to keep membrane
separate and salvageable.
5 The form of lysosomes changes from round and fairly homogeneous to varied
secondary kinds including myelin figures and residual bodies.
Some residual bodies become yellow or brown lipofuscin/lipochrome
6 In autophagy, the lysosome fuses with the autophagosome, consisting of a double membrane wrapped around the target organelles and cytoplasm to be broken down. . Autophagy PowerPoint
7 Lysosomal enzymes are also used in the turnover of extra- and
intra-cellular materials. In lysosomal deficiency diseases, the inherited
absence of an enzyme causes the massive accumulation of the material, e.g.,
glycogen, normally broken down. (Excess storage, hence "storage disease".)
8 A devastating storage disease is Hurler's, where a deficiency in lysosomal
a -L-iduronidase causes intra- and extra-cellular excess accumulations of dermatan-sulphate
and heparan-sulphate glycosaminoglycans. Aside from the dwarfism and mental retardation,
the many cardiovascular defects bring about early death.
8 Peroxisomes/Microbodies are widespread, but particularly in
hepatocytes and renal proximal tubule cells. They have a dense matrix
enclosed by a single membrane, and hold enzymes involved in the beta
oxidation of certain fatty acids. Catalase is a useful marker enzyme for
peroxisomes. The congenital lack of peroxisomes causes a fatal syndrome with
brain, liver and kidney dysfunctions.
C CYTOSKELETAL (FILAMENTO-TUBULAR) SYSTEM
The three components of the cytoskeleton - actin-myosin,
microtubules, and intermediate filaments - are functionally linked as
the dynamic organizer of the cellular domain, controlling cell shape,
cell locomotion, where materials move in the cell, and hence cell polarity.
- Several kinds of filaments, derived from unpolymerized precursors, attach
to the plasmalemma, and to structures within the cell in order to change their
form and position as the cell works.
- Subdivision of filaments is by: (a) size - thick myosin (l5 nm
diameter) and thin actin (6 nm) versus intermediate (l0 nm),
roughly contractile versus noncontractile (also labile versus insoluble);
and (b) by distribution - general versus tissue-specific.
- Relatively tissue-specific intermediate filaments are: keratin in
epithelia; desmin in muscle cells; neurofilaments in neurons;
and glial filaments of acidic protein (GFAP) in certain glia.
Immunostaining for these filament types gives some idea of the cellular
origin of, and prognosis for, tumours.
- Nestin is a protein closely associated with intermediate filaments in stem and progenitor cells of tissues generally, and serves as a stem-cell marker.
- More generally distributed filaments are: (a) vimentin
(intermediate) in connective tissue and other cells of mesenchymal origin,
and in muscle, glia, and sometimes epithelia; (b) actin (thin); and (c) myosin,
often not easily demonstrable as filaments.
- In motile cells, e.g., white blood cells/leucocytes, the peripheral zone
of cytoplasm clear of organelles and inclusions in phase-contrast microscopy,
and used to extend pseudopodia, is the ectoplasm. This zone is now
known as the actin cortex because of the actin filaments attached to the cell
membrane for locomotion and changes in cell shape.
- In absorptive and secretory epithelia, actin filaments are a major
component of the apical terminal web inserting into junctional complexes and
running up inside the microvilli. The actin is responsible for the
movement involved in endocytosis and exocytosis.
- Isoforms of actin (at least seven) have roles in striated muscle, smooth
muscle, and non-muscle cells; and several proteins interact with these actins
to achieve their controlled rapid reorganization for movement, e.g., profilin,
a-actinin, filamin, severin, villin, etc.
Each microtubule is built of 13 tubulin filaments. The dimers constructing
the filaments confer a repeated polarisation along the tubule so that one end
is 'plus', the other 'minus' - a difference that tells the attached
microtubule motor proteins which end to head for.
In conclusion, filaments and microtubules give support, and both participate
in various kinds of movement.
- Microtubules, not in a doublet or triplet formation, are supporting
or cytoskeletal elements used, for instance: (a) to give some
shape to platelets, (b) to cause and orient the elongation of
cells, e.g., ameloblasts, (c) to allow neurons and glia to grow long
processes and keep them patent; (d) microtubules are responsible for
axoplasmic flow. (e) Microtubules direct certain materials to
regions of the cell membrane, e.g., basolateral, creating cell
Microtubules are dynamic structures in themselves and their construction and
disassembly from tubulin dimers are under constant control.
- Centrioles are cylinders open at one end with a wall composed of
microtubules disposed longitudinally as nine triplets. The centrioles
and additional microtubules direct and move the chromosomes
along the mitotic spindle in cell division.
- Cilia have, at their base, basal bodies, each identical
with a centriole and often developing from one. Of the triplet, two microtubules extend up inside the cilium which thus has a core
of nine peripheral doublets, plus an additional central pair.
The doublets, by a sliding-tubule action using dynein arms, move
the cilium to beat strongly in one direction by a bending-wave
- Flagellum (tail) of the spermatozoon uses a cilium-like array of
microtubules, aided by very thick fibres, for powerful swimming.
- Intracellular movement of vesicles by microtubules is achieved by
a repeating detachment and re-attachment of motor proteins - kinesin
and/or cytoplasmic dynein - to the microtubule, energized by an
ATPase. Two different motor proteins can achieve movement in opposing
directions, as in axons, although the microtubules are polarised (+ & -) only
- Sensory cilia containing microtubules occur on cells in the
special sense organs, e.g., olfactory, and play some role in sensory
D NUCLEAR-CYTOPLASMIC SYSTEM
l Access: Through the nuclear pores: the complex of glycoproteins at
the pore - the pore complex - permits the diffusion of materials of Mr
greater than 40-60 kDa and actively transports macromolecules.
2 Protein synthesis is the primary cell activity influenced by the
nucleus. Proteins, as enzymes, transcription factors, receptors, and so on,
are the key to the particular cell's character (Chapter 32).
3 Nuclear constituents are:
- Chromatin - mainly DNA and dispersed at interphase (except
for one female X chromosome); has a fine granular appearance in routine EM,
but is fibrillar; some RNA is present.
- Nucleolus/nucleoli - dense clumped granules; nucleic acid is
mainly RNA, but some DNA is there. Peri-nucleolar/nucleolus-associated
chromatin has a special relation to the nucleolus. A range in the number of
nucleoli present usually exists, e.g., in the liver cells with one nucleus, l
to 6, with 2 the modal value. Removal of DNA by DNase allows one to see
nucleoli in the very dense nuclei of lymphocytes and some other cells.
- Nuclear proteins - histones and non-histone proteins are
associated with the DNA and RNA. A nucleosome comprises a length of
DNA wrapped around a core of histones. The proteins mostly leave the nucleus
during cell division.
- Nuclear skeleton and karyoplasm/nuclear sap - A fibrous lamina is
attached to the inner nuclear membrane, and supports the DNA periodically,
creating intervening loops of DNA. The sap contains the more labile
- Histological methods for the nucleus:
- Nuclear structure is seen in TEM.
- Radioautography for rates of cell division uses tritium-labelled
precursors of nucleotides, e.g., thymidine and cytidine. Bromodeoxyuridine
(BrdU) is incorporated in place of thymidine, so that cells synthesizing DNA
prior to division can be revealed by a labelled antibody to the BrdU.
- Chromosomes and their banding patterns are studied in cytogenetics;
see Chapter 30.
- Fluorescent in-situ hybridisation/FISH uses
'coloured' nucleotide probes to identify a particular chromosome and, on it,
the gene of clinical interest - normal, mutated, translocated, deleted,
duplicated, truncated, etc.
- Silver staining reveals the nucleolar organizer regions (NORs) as
intranuclear black dots, because it marks the acidic proteins binding to the
genes coding for ribosomal RNA located on certain chromosomes. An increase in
the number of NORs so shown (AgNORs) correlates with dysplastic (abnormal)
growth, and may indicate malignant tendencies in epithelial cells.
4 Protein synthesis (also Chapter 32)
- Is controlled by messenger RNA, synthesized by transcription
from the chromatin DNA, and leaving via the nuclear pores.
- The nucleolus is a staging post for ribosomal RNA,
- before it passes out to the cytoplasmic ribosomes, free or
attached to membranes. Ribosomes are held in clusters by mRNA.
- Transfer RNA brings to the ribosomes
- activated amino acids for linking together according to the
messenger RNA`s molecule (the translation step),
- thus producing specific chains - a polypeptide or protein, with a
sequence and length specified in the first instance by the transcribed nuclear
Cell fusion techniques, using the Sendai virus or chemicals, to produce hybrid
cells have revealed that the cytoplasmic environment can alter the activity
of the nucleus. Thus, a dense and inaccessible chromatin in a nucleus may be
transformed by new cytoplasmic surroundings to one that is looser, paler and
more reactive, as is seen in the small lymphocyte after antigenic stimulation.
Cell fusion can also be between a nucleated cell and one made nucleus-free - a
E CYTOPLASM (cytosol/cell sap)
Structureless at the EM level, but of vital biochemical and physiological
importance with its water, electrolytes, soluble proteins, amino acids, sugars,
enzymes, etc. It is in continuous interaction with the filamentous and
membrane-enclosed systems. Unwanted or defective proteins to be destroyed are
conjugated with ubiquitin , which takes them to chemically
structured concentrations - proteasomes - of proteolytic cytoplasmic