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33
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Euchromatin
Chapter
Nuclear
envelope
Nuclear
lamina
Heterochromatin
3
Nucleus
Nucleolus
Nuclear pore
Endoplasmic
reticulum
Ribosomes
Figure 3.6 Nucleus. (From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 52.)
Transcription Nucleus
Nucleolus
rRNA
Ribosomal
proteins
synthesized
in cytoplasm
Large
Immature ribosomal subunit
subunits composed
of rRNA and ribosomal
proteins Small
subunit
Subunits combine
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on mRNA to become
functional ribosomes
mRNA
Figure 3.7 Ribosome formation. (Modified from Alberts B, Bray D, Lewis J, et al: Molecular Biology of the Cell, 3rd ed. New York,
Garland Publishing, 1994.)
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Cell Cycle The four classes of cyclins and the CDKs with
34 which they complex are as follows:
The cell cycle, a series of sequential cellular events in
• G1 cyclins: Cyclin D, early in the G1 phase, binds
preparation for cell division, is composed of inter-

to CDK4 and to CDK6.
phase, when the cell becomes larger and duplicates
• G1/S cyclins: Cyclin E is synthesized late in the
its genetic material, and mitosis, a process that
G1 phase and binds to CDK2. These three
Chapter
results in the formation of two identical daughter

complexes, along with other intermediaries,
cells. The cell cycle is usually described as beginning
permit the cell to enter and progress through the
at the end of cell division when the cell is entering
S phase.
interphase (Fig. 3.8).
• S cyclins: Cyclin A binds to CDK2 and CDK1
3 • Certain cells that are highly differentiated (e.g.,
muscle cells and neurons) cease to continue to
forming complexes that permit the cell to leave
the S phase and enter the G2 phase and induce
go through mitosis and remain in a resting stage the formation of cyclin B.
Nucleus
G0 (G zero) phase. • M cyclins: Cyclin B binds to CDK1, and this

• Other cells, such as peripheral lymphocytes, enter complex allows the cell to leave the G2 phase
the G0 phase temporarily and at a later time they and enter the M phase.
may again enter the cell cycle.
When the functions of the cyclins have been com-
Events such as mechanical forces, ischemia, or pleted, they are degraded to prevent their interfer-
death of cells in a particular cell line may induce sig- ence with the proper sequence of events.
naling cells to release growth factors that induce the
expression of proto-oncogenes, which prompt the Interphase
proliferative pathways of the cell. This process acti-
vates the release of a cascade of cytoplasmic protein Interphase is subdivided into three phases: G1 (gap)
kinases triggering a series of nuclear transcription phase, when the cell prepares to synthesize DNA; S
factors regulating the expression of proto-oncogenes (synthetic) phase, when DNA is replicated; and G2
that result in cell division. Many cancers are the result phase, when the cell prepares for the mitotic event
of mutations in the proto-oncogenes that permit the (see Fig. 3.8).
uncontrolled proliferation of the mutated cell.
• G1 phase: At the conclusion of mitosis, the newly
A group of proteins known as cyclins, by complex-
formed daughter cells enter the G1 phase of the
ing with specific cyclin-dependent kinases (CDKs),
cell cycle, a stage characterized by the synthesis
not only activate them, but also guide them to target
of the regulatory proteins necessary for DNA
proteins and, in that fashion, control the entry and
replication, the restoration of the nucleoli and of
advance of the cell through the cell cycle. There are
the original cell volume of the daughter cell, and
three principal checkpoints where the control system
the initiation of centriole duplication.
can prevent the cell from entering or continuing the
• S phase: The S phase is the synthetic phase
cell cycle. At each checkpoint, the cell may commit to
where the genome is duplicated. At this point,
finish the cell cycle, pause temporarily, or withdraw
the cell’s normal complement of DNA has
completely. These checkpoints are the:
doubled from the normal (2n) to (4n) in
• Start/restriction point in gap 1, which permits preparation for the mitotic event.
chromosome duplication and the entry into • G2 phase: The interval between the end of DNA
gap 2; synthesis and the beginning of mitosis is known
• G2/M checkpoint, which initiates the as the gap 2 phase; during this phase, the RNA,
condensation of chromosomes and other events tubulin, and additional proteins required for cell
necessary to permit the beginning of mitosis; and division are synthesized. Additionally, adenosine
• Metaphase/anaphase checkpoint, which permits triphosphate (ATP) reserves are increased, and
the separation of sister chromatids, the comple the newly synthesized DNA is checked for
tion of the M phase, and the process of cytokinesis. possible errors and, if present, corrected.
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35
I II III IV V VI
Chapter
Mitosis G0
Division
3
Nucleus
G2
G1
Interphase
Figure 3.8 The cell cycle in an actively dividing cell. Nondividing cells such as neurons exit the cell cycle to enter the G0 phase
(resting phase). Other cells such as lymphocytes may return to the cell cycle. (From Gartner LP, Hiatt JL: Color Textbook of
Histology, 3rd ed. Philadelphia, Saunders, 2007, p 61.)
CLINICAL CONSIDERATIONS
Cancer chemotherapy has been enhanced by a
more complete understanding of the cell cycle
and mitosis. Certain drugs can be employed
at specific times to arrest cell proliferation by
disrupting certain stages of the cell cycle.
Vincristine disrupts the mitotic spindle
arresting the cell in mitosis. Colchicine, a plant
alkaloid, is used to produce the same effect
and is used for individual chromosome studies
and for karyotyping. Methotrexate, a drug that
inhibits purine synthesis, and 5-fluorouracil, a
drug that inhibits pyrimidine synthesis, act
during the S phase of the cell cycle, preventing
cell division, and are used in chemotherapy
treatment.
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Account: ns014207
Mitosis plate (metaphase plate) of the mitotic spindle in
36 such a fashion that each chromatid lies parallel
Mitosis is the component of the cell cycle that follows
to the cell’s equator.
the G2 phase and results in the formation of two
• Anaphase begins when the cohesion proteins that

smaller but identical daughter cells from a single cell.
attach the sister chromatids to each other at the
The first event in this process is called karyokinesis,
centromere disappear, and the sister chromatids
the division of the nuclear material, and is followed
Chapter
(chromosomes) start to be pulled apart. The

by cytokinesis, cytoplasmic division. Although the
chromosomes seem to play a passive role in the
process of mitosis is a continuous one, for conve-
process of migration to the opposite poles of the
nience of the student it is divided into five stages:
cell. The depolymerization of the mitotic spindle
prophase, prometaphase, metaphase, anaphase, and
3
microtubules in association with dynein is the
telophase (Fig. 3.9).
responsible agent in the chromosome migration.
• The first phase of mitosis, prophase, is During the latter part of anaphase, a cleavage
characterized by condensing chromosomes, the furrow develops indicating that the plasmalemma
Nucleus
disappearance of the nucleolus, the beginning of is beginning to anticipate cytokinesis.

the disruption of the nucleus, and the division of • By telophase, the chromosomes have reached
the centrosome into two halves migrating away the opposite poles of the cell, and the nuclear
from each other toward the opposite poles of the envelope is reformed because of the
cell. Each half of the centrosome has a centriole dephosphorylation of the nuclear lamins. The
and a microtubule organizing center (MOC). As chromosomes begin to uncoil, and the nucleolar
the chromosomes, each composed of two sister organizing regions of five pairs of chromosomes
chromatids held together at the centromere by are unfolded.
cohesin (a chromatin binding protein), continue • Although cytokinesis (the division of the
to condense, another MOC, the kinetochore, cytoplasm into two halves, forming two
develops, and the formation of the mitotic daughter cells) began during anaphase, it is
spindle apparatus is initiated. This mitotic completed in telophase.
spindle apparatus is responsible for directing • As the cleavage furrow deepens in 360 degrees
the sister chromatids in their migration to the around the periphery of the cell, the cell
opposing poles of the nucleus. resembles a dumbbell where the two spheres
• During prometaphase, the nuclear envelope are very close to each other.
disappears secondary to the phosphorylation of • Eventually, only the midbody, the polar
the nuclear lamins. The chromosomes continue microtubules surrounded by a very thin rim of
to condense and are randomly oriented within cytoplasm, connects the cytoplasm of the two
the cytoplasm. The mitotic spindle apparatus daughter cells to each other.
becomes defined by microtubules attached to • Within each daughter cell, a contractile ring,
the kinetochores, known as mitotic spindle composed of actin and myosin, is responsible
microtubules, and polar microtubules that for the constriction process, which is
extend between the two centrosomes, known as completed when the midbody’s microtubules
polar microtubules. The former function in are depolymerized.
directing the chromosomes to their proper • When the two daughter cells are completely
orientation, and the latter are believed to separated from each other, the spindle
maintain the correct space between the two apparatus also becomes depolymerized and
centrosomes. cytokinesis is completed.
• At metaphase, the maximally condensed • The two diploid (2n) daughter cells are
chromosomes become aligned on the equatorial identical to each other.
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Account: ns014207
37
Chapter
Interphase Prophase Prometaphase Metaphase
Nucleus
Cytokinesis Telophase Anaphase
Figure 3.9 Stages of mitosis in a cell containing a diploid number of six chromosomes. (From Gartner LP, Hiatt JL: Color Textbook
of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 64.)
Observations of a karyotype may indicate that control cell division. Proto-oncogenes exhibit
aneuploidy—an abnormal number of four regulatory mechanisms of cell growth,
chromosomes. An example of this condition is in including growth factors, growth factor receptors,
Down syndrome, in which the individual has an signal transduction molecules, and nuclear
extra chromosome 21 (trisomy 21). Individuals transcription factors. Oncogenes may result from
with this condition exhibit stubby hands, mental a viral infection or random genetic accidents.
retardation, a malformed heart, and many other When present in a cell, oncogenes dominate
congenital malformations. Klinefelter syndrome genes over the normal proto-oncogene alleles,
is an example of aneuploidy of the sex causing unregulated cell division and proliferation.
chromosomes. These individuals are males but Examples of cancer cells arising from oncogenes
possess an extra X chromosome (XXY). They include bladder cancer and acute myelogenous
exhibit the male phenotype, but do not develop leukemia. Burkitt’s lymphoma develops from a
secondary sex characteristics and are usually proto-oncogene located on chromosome 8 that
sterile. Individuals possessing less than the normal gets transformed onto chromosome 14, causing
number of chromosomes exhibit monosomy. it to be detached from its normal regulatory
Turner syndrome (XO) is an example. These element. Burkitt’s lymphoma is endemic in some
individuals are mentally retarded females parts of Africa, affecting children and young
exhibiting undeveloped ovaries and breasts and adults; it affects the maxilla and mandible.
a small uterus. Burkitt’s lymphoma responds to chemotherapy.
Oncogenes are mutated forms of normal genes
called proto-oncogenes, which code for proteins
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Meiosis Meiosis II (Equatorial Division)
38
Meiosis is a special type of cell division in which a The equatorial division is not preceded by another
single diploid (2n) cell produces four haploid (1n) S phase. Meiosis II resembles mitosis and is subdi-
germ cells. In females, one of the four haploid cells vided into prophase II, metaphase II, anaphase II,
is known as an ovum, and the other three haploid and telophase II. Chromosomes, still composed of
cells are polar bodies that disintegrate. In males, sister chromatids, become arranged along the equa
Chapter
the four haploid cells are spermatozoa. Meiosis— tor, and attached kinetochore microtubules pull the
divided into two separate events, meiosis I and sister chromatids apart and draw them to opposite
meiosis II—reduces the genetic complement of the poles of the cell. When the chromosomes reach the
germ cells, ensures genetic recombination by redis- opposing poles, each daughter cell formed in meiosis
3 tribution of genes, and introduces variability to the
gene pool.
I is subdivided into two new daughter cells via cyto-
kinesis, resulting in the formation of four genetically
unique haploid cells (Fig. 3.11).
Nucleus
Meiosis I (Reductional Division)

During the cell cycle preceding meiosis, DNA in the Apoptosis
germ cells is doubled to (4n) in the S phase, but the
chromosome number remains at (2n) (Fig. 3.10). When cells die because they no longer receive nutri-
ents or are exposed to sudden trauma, they undergo
• Prophase I is subdivided into the following five necrosis, a process that initiates an inflammatory
phases: response. Most cells kill themselves in a genetically
• Leptotene: Chromosomes begin condensing. determined manner, however, known as apoptosis,
• Zygotene: Homologous chromosomes align in the best understood form of programmed cell
gene-to-gene register to form synaptonemal death. Some cells undergo apoptosis because of spe-
complexes. cific environmental conditions, such as overcrowd-
• Pachytene: Homologous chromosomes ing; others undergo apoptosis because of their age;
continue to condense; crossing-over sites and others, such as virally transformed cells, are
(chiasmata) are formed between nonsister forced into apoptosis by cells of the immune sys
chromatids resulting in random exchange of tem. During apoptosis, cells undergo morphologic
genetic material. changes: the cell shrinks, there is breakdown of the
• Diplotene: Chromosomes continue to cytoskeleton, the nuclear envelope disassembles,
condense, followed by disjunction of the and nuclear chromatin breaks up into fragments.
homologous pairs. These events are followed by the cell remnants
• Diakinesis: As the chromosomes condense becoming membrane-enclosed apoptotic bodies
maximally, the synaptonemal complex that are phagocytosed by macrophages. The process
disassembles, the nucleolus and the nuclear of apoptosis is regulated by caspases, proteolytic
envelope disappear, and chromosomes are enzymes that act at particular aspartate residues of
now free in the cytoplasm. A microtubule their target proteins. Each cell possesses the inactive
spindle begins to form. form, procaspases, some of which become activated
• Metaphase I: Homologous chromosomes align to form initiator caspases, which induce a cascade
in random order on the equatorial plate, forming activated executioner procaspases and
ensuring a shuffling of the maternal and paternal target proteins within the cell, initiating the mor-
chromosomes. Kinetochore microtubules attach phological events listed earlier. Signals external to
to the kinetochores. the cell activate membrane bound death receptors,
• Anaphase I: Homologous chromosomes, still which activate the caspase system to drive the cell
composed of two sister chromatids, migrate to into the extrinsic pathway of apoptosis. The intrin-
opposite poles. sic pathway of apoptosis is initiated by mitochon-
• Telophase I: Telophase I of meiosis I is similar dria that release cytochrome c into the cytosol. This
to telophase of mitosis. Chromosomes complete molecule binds with apoptotic procaspase-activat-
the migration to opposite poles, nuclei are ing adaptor protein (Apaf1), which combines with
reformed, and cytokinesis divides the one cell other Apaf1 units to form a wheel-like apoptosome
into two daughter cells, each with the (1n) that induces a caspase cascade resulting in pro-
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number of chromosomes (23 chromosomes, but grammed cell death. Because the extrinsic pathway
each composed of two chromatids, accounting is unable to generate a sufficient caspase cascade by
for the (2n) amount of DNA) (see Fig. 3.10). The itself, it must activate the intrinsic pathway to induce
daughter cells now enter meiosis II. a complete apoptosis cascade.
Account: ns014207
39
Chapter
Prophase I Metaphase I Anaphase I Telophase I
Chromosomes that have Tetrads are held together Homologous chromosomes The chromosomes have
been replicated condense by chiasmata. Chromosomes separate and migrate to formed two groups. The cell
3
and pair with homologues arrange themselves on the opposite poles of the cell. begins to constrict across
to form tetrads. equator of the spindle. the middle. Separates into
two daughter cells.
Figure 3.10 Stages of meiosis in a cell containing a diploid (2n) number of 4 chromosomes. Meiosis I. (From Gartner LP, Hiatt
Nucleus
JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 66.)
Prophase II Metaphase II Anaphase II Telophase II

The chromosomes of The chromosomes then The newly separated The cells constrict across
the two daughter cells migrate to the equator. chromosomes of the two the nuclear membrane. Four
condense again in daughter cells move to haploid nuclei are formed,
preparation for a opposite poles of their each with one member of each
second meiotic division. spindle. pair of chromosomes from the
original nucleus.
Figure 3.11 Meiosis II. (From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 67.)
During meiosis I, when the homologous pairs of
chromosomes normally separate and migrate to
opposite poles (anaphase I), nondisjunction
may occur—one daughter cell contains both
homologous chromosomes resulting in 24
chromosomes, whereas the other daughter cell
is totally without that chromosome, resulting in
22 chromosomes. At normal fertilization, one
zygote has 47 chromosomes (trisomy), whereas
the other zygote has 45 chromosomes
(monosomy). Down syndrome is an example
of trisomy 21. Nondisjunction occurs more
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frequently in chromosomes 8, 9, 13, 18, and

21, each producing unique characteristics.
Nondisjunction occurs more frequently in
women older than 35 years of age.
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4 Extracellular
Matrix
Cells with similar structural and functional charac Because these macromolecules are
teristics assemble to form tissues that perform par usually attached to protein cores,
ticular functions. The four tissues of they tend to be very closely
the mammalian body are epithelium, Key Words packed, which makes them not
connective tissue, muscular tissue, and only resist compression but also
nervous tissue. Each tissue is com
• Ground substance quite slippery.
posed not only of cells, but also of non • Collagen • With the exception of hyaluronic
living material, the extracellular matrix • Collagen synthesis acid, a massive GAG composed of
(ECM), whose two components are • Elastic fibers more than 10,000 disaccharides,
ground substance and fibers (Fig. 4.1). all GAGs are sulfated.
• Basement
ECM is manufactured by cells and • The most common GAGs (keratan
membrane
delivered by them into the extracellular sulfate, chondroitin 4-sulfate,
space and was believed to function • Basal lamina chondroitin 6-sulfate, heparan
only in the capacity of physical support. • Integrins sulfate, heparin, and dermatan
ECM has been shown, however, to sulfate) are composed of
have numerous additional responsi approximately 300 disaccharides,
bilities, such as: are synthesized in the Golgi apparatus,
and are covalently bound to a linear protein
• Influencing cell development, migration, mitosis,
core.
morphology, and function, and
• Hyaluronic acid is synthesized by the enzyme
• Permitting cells to migrate along it.
hyaluronan synthase on the cytoplasmic
Fluid that escapes from blood vessels, known as surface of the plasmalemma and is translocated
extracellular fluid, carries nutrients, oxygen, and sig- into the extracellular space to become
naling molecules to the cells of the body, and the incorporated into ECM. A single hyaluronic
same fluid returns waste products, oxygen, and other acid molecule can be 20 µm long.
cellular products to the bloodstream. Cells also leave • Proteoglycans are very large macromolecules
the bloodstream and make their way through ECM that are composed of a protein core to which
to eliminate toxic elements, antigens, microorgan- sulfated GAGs are covalently bound (see
isms, debris of dead cells, and other unwanted mate- Fig. 4.1). A proteoglycan resembles a bottlebrush,
rial located in ECM. where the protein core is the wire stem and
the GAGs comprise the bristles. These
Ground Substance macromolecules vary in composition and
in size:
Ground substance is a gel that consists of glycos • Decorin is about 50 kDa with only a
aminoglycans (GAGs), proteoglycans, and glycopro single GAG bound to its protein core,
teins. whereas
• Aggrecan, with 200 GAGs, is 3 million Da.
• GAGs are long, unbranched, negatively charged • Because all of the GAGs are hydrated, each
polysaccharide chains composed of repeating proteoglycan occupies a very large domain.
units of disaccharides, one of which is always • Many proteoglycans, such as aggrecan, are
a uronic acid (iduronic acid or glucuronic attached to hyaluronic acid, forming enormous
acid) and the other an amino sugar proteoglycans. These macromolecules may be
(N-acetylglucosamine or N-acetylgalactosamine) several hundred million daltons and possess a
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(Table 4.1). huge domain that is responsible for the gel

• Their negative charge attracts Na+ ions, which state of the ground substance.
attract water molecules from the extracellular • Functions of proteoglycans include resisting
fluid, making all GAGs highly hydrated. compression, binding signaling molecules and
40 EBSCO Publishing : eBook Collection (EBSCOhost) - printed on 10/10/2023 8:00 PM via SAINT JAMES SCHOOL OF MEDICINE
Account: ns014207
Collagen fibrils Hyaluronic acid
molecule 41
Chapter
4
Extracellular Matrix
Hyaluronic acid
Link protein
Core protein
Chondroitin sulfate
Proteoglycan
Collagen (type II)
Figure 4.1 Diagrammatic representation of ECM. Top, Lower magnification showing the banded collagen fibers with the adherent
proteoglycans. Bottom, GAGs attached to their protein core and the link proteins that attach them to hyaluronic acid, forming
huge macromolecules that may be hundreds of million daltons in size. (Adapted from Fawcett DW: Bloom and Fawcett’s A
Textbook of Histology, 11th ed. Philadelphia, Saunders, 1986.)
Table 4.1 TYPES OF GLYCOSAMINOGLYCANS (GAGs)

GAG Mass (Da) Repeating Disaccharides Location in Body
Hyaluronic acid 107–108 d-glucuronic acid-β-1,3-N-acetyl-d-glucosamine Most connective tissue,
synovial fluid, cartilage,
dermis
Keratan sulfate I 10,000–30,000 Galactose-β-1,4-N-acetyl-d-glucosamine-6-SO4 Cornea (keratan sulfate I),
and II cartilage (keratan sulfate
II)
Heparan sulfate 15,000–20,000 d-glucuronic acid-β-1,3-N-acetyl galactosamine Blood vessels, lung, basal
l-iduronic acid-2 or -SO4-β-1,3-N-acetyl-d-galactosamine lamina
Heparin (90%) 15,000–20,000 l-iduronic acid-β-1,4-sulfo-d-glucosamine-6-SO4 Mast cell granule, liver,
(10%) d-glucuronic acid-β-1,4-N-acetylglucosamine-6-SO4 lung, skin
Chondroitin 10,000–30,000 d-glucuronic acid-β-1,3-N-acetylgalactosamine-6-SO4 Cartilage, bone, cornea,
4-sulfate blood vessels
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Chondroitin 10,000–30,000 d-glucuronic acid-β-1,3-N-acetylgalactosamine-6-SO4 Cartilage, Wharton’s jelly,

6-sulfate blood vessels
Dermatan 10,000–30,000 l-iduronic acid-α-1,3-N-acetylglucosamine-4-SO4 Heart valves, skin, blood
sulfate vessels
Adapted from Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 71.
Account: ns014207
Ground Substance (cont.) Collagen, constituting about 25% of the proteins
42 of the body, is inelastic, and in noncalcified connec-
facilitating cell movement, impeding spread of tive tissue it resists tensile forces. Based on their
infection, and assisting in the formation of amino acid sequences, there are about 25 different
collagen. When attached to the cell membrane, collagens, classified into three categories according to
proteoglycans can assist in binding the cell to the manner in which they polymerize—fibril-form-
Chapter
ECM and can act as a receptor molecule. ing, fibril-associated, and network-forming. Some
• Glycoproteins (cell adhesive glycoproteins) are authors also recognize collagen-like proteins.
large protein molecules with some carbohydrate
moieties linked to them. They possess several • Fibril-forming collagens (the most common
binding domains that are specific for certain ones are types I, II, III, V, and XI) assemble into
4 integrins and for ECM molecules, permitting the ropelike molecules that congregate to form
flexible, cable-like structures, whose tensile
adherence of cells and elements of the ECM to
each other. The best known glycoproteins are: strength exceeds that of stainless steel. Because
• Fibronectin, a large V-shaped dimer of they are white, they are also called white fibers.
approximately 440,000 Da manufactured by • Fibril-associated collagens (types are IX and XII)
connective tissue cells such as fibroblasts, has are located on the surface of collagen fibrils and
binding sites for numerous ECM components facilitate collagen fibrils to be bound to other
and for integrin molecules, facilitating the collagen fibrils and to elements of ECM.
adhesion of cells to ECM. Plasma fibronectin, • Network-forming collagens (types IV and VII)
a soluble form of fibronectin, is present in do not form ropelike structures; instead they
blood where it aids in coagulation, aggregate to form a feltlike meshwork that
phagocytosis, and wound healing. constitutes the major component of the lamina
• Laminin, a very large epithelially produced densa of the basal lamina (type IV) and
glycoprotein (950,000 Da), consists of three anchoring fibrils (type VII) that aid in anchoring
polypeptide chains. It is almost always located the basal lamina to the lamina reticularis of the
on the epithelial aspect of the basal lamina connective tissue.
and has binding sites for basal lamina • Collagen-like proteins include type XVII,
components and for the integrins. associated with hemidesmosomes, and type
• Entactin (nidogen), binds to laminin and type XVIII localized to the basal laminae of blood
IV collagen, facilitating an adherence between vessels.
laminin and the basal lamina.
• Tenascin is a large glycoprotein (1700 kDa) Structure of Fibril-forming Collagen
composed of six polypeptides that resembles a Unstained collagen fibers are colorless when viewed
spider with only six legs projecting outward under the microscope and are very long, but only
from a central mass and has binding sites for about 10 µm in diameter. Viewed with the electron
fibronectin and syndecan, a transmembrane microscope, these fibers exhibit a characteristic 67-
proteoglycan. It is usually limited to nm cross-banding and longitudinal striations indi-
embryonic connective tissue, where it cating that they are formed by collections of thinner
delineates pathways along which embryonic fibrils that are 10 to 300 nm in diameter. These
cells can migrate. thin fibrils are composed of tropocollagen:
• Osteopontin is localized to bone where it aids
calcification and binds to osteoclast integrins. • Many tropocollagen subunits are aligned head
• Chondronectin and osteonectin resemble to toe and side by side.
fibronectin but are present in cartilage and • A tropocollagen molecule, 280 nm long and
bone, respectively. They have binding sites for 1.5 nm in diameter, is composed of three alpha
the cells of cartilage and bone and for the chains coiled about one another (Fig. 4.2).
components of their particular ECMs. • An alpha chain is composed of about 1000
amino acids; every third amino acid in the chain
Fibers is glycine.
• The alpha chains are rich in hydroxyproline
Historically, collagen, reticular, and elastic fibers to hold the three alpha chains together;
copyright law.
have been described to constitute the fibers of ECM, hydroxylysine, holding adjacent tropocollagen
although it is now known that reticular fibers are type molecules to each other; and proline, which
II of collagen fibers. usually follows glycine.
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43
Tendon
Chapter
Bundle
Muscle
Fiber 4
Fibril Tropocollagen
triple helix
Overlapping
region Gap
region
Packing of tropocollagen molecules
Figure 4.2 Components of type I collagen fiber. The arrangement of the gap and overlap regions of the adjoining tropocollagen
molecules gives rise to the characteristic 67-nm cross-banding noted in electron micrographs. (From Gartner LP, Hiatt JL: Color
Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 74.)
Collagenous colitis affects mostly middle-aged Alcoholic hepatitis is frequently accompanied by
and elderly women, who present with loose, collagen deposition in the region of the central
watery diarrhea with a relatively thick layer of vein of the hepatic lobule. If the condition is not
acellular collagen just deep to the lining epithelium alleviated by the cessation of alcohol abuse, the
of the large intestine. Histologically, the epithelium patient may progress to a more serious state,
of affected individuals is infiltrated by lymphocytes central hyaline sclerosis, in which the inlet
and neutrophils. The cause of collagenous colitis venule and the perivenular sinusoids are
is unknown, although an autoimmune component surrounded by a dense collagenous connective
has been postulated. The common treatment for tissue, reducing blood flow and portal
this disease is administration of antidiarrheal or hypertension results. Patients with this disease
copyright law.
anti-inflammatory drugs or both. If infection is present with fever, pain in the upper right
suspected, antibiotics may also alleviate the quadrant of the abdomen, and jaundice; in 20%
condition. to 25% of cases, the condition may progress to
liver failure and death.
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Collagen Synthesis molecules; they are unable to assemble into
44 collagen fibers, and instead they form dimers
Collagen is synthesized on the rough endoplasmic
that establish a feltlike meshwork.
reticulum (RER) as individual preprocollagen chains
• In some lymph nodes, the spleen, bone marrow,

coded for by individual mRNA molecules (Fig. 4.3).
and thymus reticular fibers (type III collagen)
• The amino and carboxyl terminals of these newly are synthesized by specialized reticular cells that
Chapter
synthesized polypeptides possess extra form a cellular sheath around these thin,
propeptides. branching, argyrophilic fibers to isolate them
• Within the RER cisterna, not only is the signal from their environment. In most other areas of
peptide removed, but also some of the proline the body, they are manufactured by fibroblasts or
and lysine residues are hydroxylated by peptidyl
4
smooth muscle cells (in blood vessels) and
proline hydroxylase and peptidyl lysine Schwann cells (in peripheral nerves).
hydroxylase, respectively.
• Additional post-translational modifications Elastic Fibers
include selective glycosylation of some lysine

residues. In contrast to collagen fibers, which are inelastic,
• After the modifications, the three preprocollagen elastic fibers may be stretched to 150% of their
molecules use the propeptides to align with each resting length, and when the tensile force is removed
other and form a tight helical configuration, but they return to their original length.
the propeptides do not wrap around each other. • Elastic fibers, also known as yellow fibers because
• The three preprocollagen chains together are of their color in their fresh state, are present in
known as procollagen, which resembles a short most noncalcified connective tissue elements of
rope with two frayed ends. The procollagen the body (manufactured by fibroblasts), and they
molecules do not adhere to each other, probably are located in blood vessels (manufactured by
because of the propeptides, but leave the RER to smooth muscle cells) and elastic cartilage
enter the Golgi apparatus where oligosaccharides (synthesized by cartilage cells).
are added. • These fibers may be present as very fine thin
• They are packaged into coatomer protein (COP) filaments, or they may be gathered into thick,
I–coated vesicles and leave the trans-Golgi coarse bundles. They are rarely visible in
network and are transported out of the cell along hematoxylin and eosin (H&E) dyed tissue
the constitutive pathway. sections, but become clearly evident with the use
• As the procollagen molecules are released into of special stains. Elastic fibers are composed of
the extracellular space, their propeptides are an amorphous elastin core surrounded by
cleaved by the membrane bound enzyme, microfibrils (Fig. 4.4).
procollagen peptidase, forming tropocollagen • Elastin is a glycine-rich protein (72 kDa) that
molecules (see Fig. 4.3). also has an abundance of alanine, lysine,
• The absence of the propeptides permits the proline, and valine, with a notable absence of
tropocollagen molecules to self-assemble and hydroxylysine.
form type I collagen. The formation of type I • Four lysine molecules of different chains of
collagen requires the presence of type XI this protein form highly deformable covalent
collagen, which forms the core of type I collagen. bonds, known as desmosine cross-links, with
Additionally, types III and V collagens are each other. These desmosine cross-links
interspersed within the substance of the type I provide the elasticity inherent to elastic fibers.
collagen fibrils. The alignment of the • The microfibrils that surround the desmin
tropocollagen molecules and the shape of the core are composed of fibrillin, a 350-kDa
collagen fiber that is being formed are glycoprotein.
determined by the cell that is synthesizing the • During the synthesis of elastic fibers, the cell
collagen fiber. produces the microfibrils first and then
• Network-forming collagens (types IV and VII) deposits the amorphous elastin component
retain the propeptides of their procollagen into the region surrounded by the microfibrils.
copyright law.
Account: ns014207
Nucleus Elastin
DNA
1 Transcription in core 45
mRNA nucleus
mRNA
Chapter
2 Translation of
preprocollagen in
RER
3 Hydroxylation (
in RER
)
4
Microfibrils
Figure 4.4 Elastic fiber. The amorphous elastin core is
4 Glycosylation ( ) surrounded by microfibrils. (From Gartner LP, Hiatt JL: Color
in RER Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007,
p 80.)
5 Formation of
procollagen triple
helix in RER
6 Secretion of
procollagen via trans-
Golgi network
7 Cleavage of
propeptides to form
tropocollagen
molecule
8 Spontaneous self-
assembly of
tropocollagen to
form collagen fibril
Figure 4.3 Type I collagen synthesis and assembly. Types III,

V, and XI are not shown in this diagram. (From Gartner LP,
Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia,
Saunders, 2007, p 77.)
Solar elastosis is a skin condition resulting from Scurvy is a condition that is due to the lack of
excess exposure to sun and ultraviolet rays in vitamin C, a substance that is necessary for the
tanning salons. The sun-damaged skin is more hydroxylation of the proline moieties of
wrinkled than normal, appears sagging, and looks preprocollagen. The paucity of hydroxyproline
and feels leathery. This condition is due to the prevents tropocollagen molecules from
damaged dermis, which has a decrease in assembling in a normal manner; tissues with a
collagen and increase in elastic fiber content. The high turnover of collagen lead to loose teeth and
copyright law.
elastic fibers lose some of their elasticity probably bleeding gingivae. The consumption of vitamin
because their fibrillin components appear in C–rich foods corrects the problem.
disarray. This condition may progress to frank
malignancy.
Account: ns014207
Basement Membrane type IV collagen of the lamina densa, the epithelium
46 is securely anchored to the basal lamina. The lamina
Viewed with the light microscope, connective tissue densa is firmly bound to the underlying lamina retic-
and epithelium are always separated from each other ularis by means of fibronectin, type VII collagen
by a narrow acellular zone, known as the basement (anchoring fibrils), and microfibrils (fibrillin), ensur-
membrane. On electron micrographs, the basement ing the firm attachment of the epithelium not
Chapter
membrane can be seen to have two components: only to the basal lamina, but also to the lamina
reticularis.
• Very narrow, epithelially produced basal lamina
The basal lamina functions:
• Thicker, connective tissue–derived lamina
reticularis (Fig. 4.5) • In ensuring epithelial attachment
4 It is evident on electron micrographs that the
• As a molecular filter owing to its type IV collagen
component and to the negative charge of its
basal lamina is also composed of two layers: heparan sulfate molecules
• A 50-nm-thick clear region, known as the lamina • In enhancing mitotic activity of cells
lucida, abutting the basal cell membranes of the • In binding signaling molecules
epithelial sheet • In facilitating rearrangement of integral cell
• A 50-nm-thick dense, matlike layer, known as membrane proteins
the lamina densa, which occupies the region • As an aid in the re-epithelialization of wounds
between the lamina lucida and the lamina and in the regeneration of myoneural junctions
reticularis The lamina reticularis (see Fig. 4.5), composed of
Some investigators suggest, however, that the lamina types I and III collagens, is synthesized by fibroblasts.
lucida is a fixation artifact, and that the basal lamina It is of variable thickness, depending on the abrasive
is composed only of the lamina densa. In addition forces acting on the epithelium superficial to it; it is
to separating epithelium from connective tissue, thick deep to the epithelium of the palms of the hand
basal laminae, referred to as external laminae, are and soles of the foot and thin beneath the epithelium
also noted to surround Schwann cells, skeletal and of the lung tissue. The collagens of the lamina reticu-
smooth muscle cells, and fat cells. A thickened basal laris arise from and are continuous with the colla-
lamina is present in the glomerulus of the kidney. gens of the connective tissue, forming a secure bond
not only between the basal lamina and the lamina
reticularis, but also between the connective tissue
Basal Lamina and Lamina Reticularis
and the lamina reticularis, and in that fashion firmly
The lamina lucida component (whether or not pre securing the epithelium to the connective tissue.
sent as a morphological entity) of the basal lamina
(see Fig. 4.5) houses the extracellular portions Integrins and Dystroglycans
of the integral cell membrane proteins, integrin and
dystroglycan, both of which are laminin receptors. Integrins are transmembrane proteins whose extra-
Additionally, laminin and entactin, two structural cellular moiety binds, in the presence of divalent
glycoproteins, form a thin sheath on the surface of cations, with certain ligands present in ECM, and
the lamina densa, the dense-appearing matlike com- their intracellular carboxyl ends bind to talins and
ponent of the basal lamina whose main constituent a-actinins of the cytoskeleton. Integrins are able
is type IV collagen (see Fig. 4.5). The lamina lucida to transduce extracellular signals into intracellular
and the lamina reticularis–facing surfaces of the molecular events that result in cell division or regula-
lamina densa are coated with the heparan sulfate– tion of gene expression or both.
rich proteoglycan, perlacan. Additionally, the lamina Dystroglycans are also heterodimer transmem-
reticularis–facing surface of the lamina densa is rich brane proteins whose extracellular moiety binds to a
in fibronectin. particular site on laminin, whereas their intracellular
Because laminin binds to integrins and dystrogly- moiety binds with dystrophin, an actin-binding pro
cans of epithelial cells and to heparan sulfate and tein that forms a bond with the cytoskeleton.
copyright law.
Account: ns014207
47
Epithelial cell
Lamina
lucida
Chapter
Basal
Lamina lamina
densa
Reticular fibers
(type III collagen) 4
Anchoring fibrils
(type VII collagen) Lamina
Anchoring plaque reticularis
(type IV collagen)
Figure 4.5 The basement membrane has two components, the basal lamina and the lamina reticularis. (Adapted from Fawcett
DW: Bloom and Fawcett’s a Textbook of Histology, 12th ed. New York, Chapman & Hall, 1994.)
Goodpasture syndrome is an autoimmune Alport syndrome (hereditary nephritis) is a
condition that involves the kidneys and the lungs. genetic disease caused by a mutation in the
If only the kidneys are involved, the condition is COL4A5 gene responsible for the coding for type
referred to as anti–glomerular basement IV collagen; these patients do not form normal
membrane antibody glomerulonephritis. In basal laminae. The glomerular basal lamina of
either condition, the autoimmune reaction is these patients is abnormally thick and appears to
against the type IV collagen of the basal lamina. split into interweaving layers as if it were
The onset of Goodpasture syndrome is usually composed of blisters. The syndrome is more
subsequent to a respiratory tract infection, and the prevalent and severe in males, although both
lung involvement is related to smoking. Patients sexes are affected. The disease progresses to
are usually young men, although both sexes and end-stage renal failure by the fifth decade of life in
all ages have been affected. The disease can most men and in about 20% of women.
rapidly progress to renal failure and the need for Additionally, at least 50% of patients of both
renal transplant. Treatment in the early stages is sexes experience progressive hearing loss and
with corticosteroids, the administration of damage to the lenses of the eyes.
cytotoxic compounds, and plasmapheresis.
Frequently, the disease is fatal, and even with
aggressive treatment the survival rate is only 50%
within 2 years of the onset of the disease.
Some cases of osteoarthritis are treated by
repeated injections of hyaluronic acid, a
component of synovial fluid, directly into the
joint to lubricate it providing relief for a
copyright law.
prolonged period.
Account: ns014207
5 Epithelium and
Glands
The human body consists of more than 200 cell types closely packed cells, held together by junctional com
organized into the four basic tissues: epithelium, plexes, with little intervening extracellular space
connective tissue, muscle, and nervous tissue. Com- and a scant amount of extracellular matrix. The two
binations of these tissues form func- tissues are separated from each other
tional entities known as organs, which Key Words by the epithelially derived basal lamina.
are combined into organ systems. Epithelial tissue functions in:
• Epithelium
• Simple epithelium • Protection of the tissues that it
Epithelial Tissue covers or lines,
• Stratified
• Transcellular transport of
Epithelial tissue can exist as sheets epithelium
molecules across epithelial sheets,
of adjoining cells covering or lining • Microvilli • Secretion of various substances by
the body surface or as glands, secre-
• Junctional complex glands,
tory organs derived from epithelial
cells. Most epithelia originate from • Unicellular exocrine • Absorption (e.g., intestinal tract
glands and kidney tubules),
ectoderm and endoderm, although
• Multicellular • Control of movement of ions
mesoderm also gives rise to some epi
and molecules via selective
thelia. exocrine glands
permeability, and
• Ectoderm gives rise to the • Endocrine glands • Detection of sensations (e.g.,
epidermis of the skin, lining of the taste, sight, hearing).
mouth and nasal cavity, cornea, sweat and
sebaceous glands, and mammary glands. Classification of Epithelial Membranes
• Endoderm gives rise to the lining of the
The epithelium can be classified based on the number
gastrointestinal and respiratory systems and to
of layers of cells between the basal lamina and the
the glands of the gastrointestinal system.
free surface and the morphology of the cells. A single
• Mesoderm gives rise to the uriniferous tubules of
layer of epithelial cells is called simple epithelium,
the kidney, the lining of the reproductive and
whereas two or more layers constitute a stratified
circulatory systems, and the lining of the body
epithelium. The epithelial cells abutting the free sur
cavities.
face may be squamous (flat), cuboidal, or columnar,
Epithelium, an avascular tissue organized into giving rise to the various types of epithelia (Table 5.1
sheets, receives its nutrients from the vascular supply and Fig. 5.1). Two additional types of epithelia are
of the adjacent connective tissue. It is composed of pseudostratified columnar and transitional.
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Account: ns014207
Simple Pseudostratified
49
Squamous Cuboidal Columnar Pseudostratified
Chapter
columnar
Stratified Transitional
Figure 5.1 Types of epithelia.
(From Gartner LP, Hiatt JL:
5
Color Textbook of Histology, 3rd
ed. Philadelphia, Saunders, 2007,
p 87.)
Squamous Cuboidal Transitional Transitional
Epithelium and Glands

nonkeratinized (relaxed) (distended)
Keratinized Columnar
Table 5.1 CLASSIFICATION OF EPITHELIA

Type Shape of Surface Cells Sample Locations Functions
Simple
Simple squamous Flattened Lining: pulmonary alveoli, loop of Limiting membrane, fluid
Henle, parietal layer of Bowman’s transport, gaseous
capsule, inner and middle ear, exchange, lubrication,
blood and lymphatic vessels, reducing friction (aiding
pleural and peritoneal cavities movement of viscera),
lining membrane
Simple cuboidal Cuboidal Ducts of many glands, covering of Secretion, absorption,
ovary, form kidney tubules protection
Simple columnar Columnar Lining: oviducts, ductuli efferentes of Transportation,
testis, uterus, small bronchi, much absorption, secretion,
of digestive tract, gallbladder, and protection
large ducts of some glands
Pseudostratified All cells rest on basal Lining: most of trachea, primary Secretion, absorption,
lamina, but not all bronchi, epididymis and ductus lubrication, protection,
reach epithelial deferens, auditory tube, part of transportation
surface; surface cells tympanic cavity, nasal cavity,
are columnar lacrimal sac, male urethra, large
excretory ducts
Stratified
Stratified squamous Flattened (with nuclei) Lining: mouth, epiglottis, esophagus, Protection, secretion
(nonkeratinized) vocal folds, vagina
Stratified squamous Flattened (without Epidermis of skin Protection
(keratinized) nuclei)
Stratified cuboidal Cuboidal Lining: ducts of sweat glands Absorption, secretion
Stratified columnar Columnar Conjunctiva of eye, some large Secretion, absorption,
excretory ducts, portions of male protection
urethra
Transitional Dome-shaped (relaxed), Lining: urinary tract from renal calyces Protection, distensible
copyright law.
flattened (distended) to urethra
From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 86.
Account: ns014207
Polarity and Cell Surface Specializations cells of the cochlea (inner ear), are called
50 stereocilia. They function in increasing surface
Epithelial cells generally possess specific regions—
to facilitate absorption in the epididymis,
domains—that impart a distinct polarity to the cell.
whereas in the ear they assist the hair cells in

These domains are defined by their location at the
signal generation.
apex or at the basolateral region of the cell. Tight
• Cilia (Fig. 5.3) are long (7 to 10 µm in length
junctions, which are a specialization of the cell mem-
Chapter
and 0.2 µm in diameter), finger-like structures

brane, encircle the apex of the cell, separating the
projecting from the apical domain of the cell.
two domains from each other and imparting a
They are highly conserved structures that are
polarity to the cell. Each domain possesses specific
present in unicellular organisms, in plants, and
modifications.
5
in all members of the animal kingdom. Cilia
are contractile structures that allow unicellular
Apical Domain
organisms to move through water; in higher
The apical domain, the region of the epithelial cell animals, where an epithelial sheet, such as that
facing the free surface, has an abundance of ion chan- lining the respiratory tract, can have 2 billion
nels, carrier proteins, H+-ATPase, aquaporins, glyco- cilia/cm2, their coordinated action can propel a
proteins, and hydrolytic enzymes. Additionally, it fluid along an epithelial sheet.
serves as the region where regulated secretory prod- • The core of the cilium, known as the axoneme,
ucts leave the cell to enter the extracellular space. is a highly organized longitudinal arrangement
Surface modifications of the apical domain, such as of nine doublets surrounding two singlet
microvilli and associated glycocalyx, cilia, stereocilia, microtubules, dynein, and associated elastic
and flagella, assist in performing many of the cell’s proteins.
functions. • Each doublet comprises a whole microtubule
• Microvilli (Fig. 5.2) are 1- to 2-µm-long (subunit A), which is composed of 13
membrane-bound, finger-like projections of the protofilaments, and a partial microtubule
apical cell surfaces of simple cuboidal and simple (subunit B), which has 10 protofilaments
columnar epithelia. They represent the striated and shares 3 protofilaments of the whole
and brush borders of light microscopy and, when microtubule.
closely packed, may increase the surface area as • Subunit A of each doublet possesses dynein
much as 20-fold. arms located at prescribed intervals of 24 nm
• The core of each microvillus is composed of along its entire length, resembling the legs of a
25 to 30 actin filaments that are held to each millipede. The free ends of these arms possess
other by villin and fimbrin; those at the adenosine triphosphate (ATP)–dependent
periphery of the bundle adhere to the binding sites for subunit B.
plasmalemma via calmodulin and myosin I. • The elastic proteins associated with the
• The plus ends of the actin filaments reach the axoneme are arranged in the following
tip of the microvillus, where they are manner: the two central singlets are
embedded in an amorphous substance. surrounded by a central sheath, and a radial
• The cytoplasmic ends of the actin bundle are spoke projects toward the central sheath from
fixed to the terminal web and composed of each subunit A.
intermediate filaments, spectrin, actin, and • Additionally, subunit A of one doublet is
other cytoskeletal components. connected to subunit B of the adjacent
• The extracellular aspect of the microvillar doublets by a nexin bridge.
membrane is coated with a glycocalyx whose • Viewed in three dimensions, the central sheet
composition depends on the location and is a cylinder around the singlets; each nexin
function of the cell. bridge and each radial arm is a quadrilateral
• Long, nonmotile, rigid microvilli, present sheet of elastic material.
only in the epididymis and on the sensory hair
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Account: ns014207
51
Villin
Chapter
Actin
filaments
Plasmalemma
Fimbrin
5

Linkage Lateral
to cell extension
membrane
Intermediate Actin cortex

filaments linked by spectrin
Figure 5.2 Structure of a microvillus. (From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007,
p 94.)
Plasma
membrane
Shared
B A heterodimers
Peripheral Dynein
microtubule
doublet
Plasmalemma
Radial
spokes
Nexin
Central Central
microtubule sheath
pair
Microtubule
triplet
copyright law.
Basal body
Plasma
membrane
Figure 5.3 Structure of a cilium with its basal body. (From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia,
Saunders, 2007, p 95.)
Account: ns014207
Ciliary Movement, Basal Body, and Flagella cialized junctional complexes and signal receptors,
52 ion channels, and Na+,K+-ATPase abound in these
During ciliary movement in the presence of ATP, the
regions, which also function as sites for constitutive
dynein arms fleetingly attach to and detach from
secretion.
subunit B of the adjacent doublet climbing up toward
the cilium tip. Nexin and the radial spokes tend to
Lateral Membrane Specializations
restrain the climbing action, however, and the cilium
Chapter
bends instead. Terminal bars, as viewed by light microscopy, are

sites of apparent attachment of epithelial cells that
• The bending of the cilium (a process that have been shown to be structures that are continuous
requires ATP) stretches the elastic proteins; around the circumference of the entire cell. Terminal
5 however, when the dynein arms cease their
climbing action, the elastic proteins return to
bars occupy restricted regions of the cell located in
the vicinity of its apex. When examined with the
their normal length, and the cilium resumes electron microscope, the terminal bars were resolved
its straight position (an ATP-independent
to be junctional complexes that facilitate the adher-

process). ence of contiguous cells to each other (Fig. 5.5).
• Alternating these two processes in rapid Three types of cell junctions constitute the terminal
progression permits the cilia to propel substances bar: the apicalmost zonula occludens and just basal
along the epithelial surface. to it, the zonula adherens, both of which are con-
The axoneme arrangement ceases at the base of tinuous, beltlike junctions around the circumference
the cilium where it is attached to the basal body (Fig. of the cell, and the maculae adherentes (desmo-
5.4), a structure composed of nine triplet microtu- somes), which are spot junctions rather than con-
bules (subunits A, B, and C) with no central singlets. tinuous around the cell’s perimeter. Additional types
The basal body resembles a centriole and develops of cell junctions are located in regions of the cell
from procentriole organizers. other than at terminal bars and do not belong
to the junctional complex. These are gap junctions,
• Subunits A and B of the cilium are continuous desmosomes, hemidesmosomes, and actin-linked
with subunits A and B of the basal body. cell-matrix adhesions. From a functional perspec
• Subunit C of the basal body does not continue tive, there are three types of epithelial cell junctions:
into the cilium.
Certain cells, including fibroblasts, neurons, and • Occluding junctions (zonulae occludentes)
certain epithelial cells such as those of kidney tu provide an impermeable, or selectively
bules, may possess a single nonmotile cilium whose permeable, barrier that prevents material from
axoneme has no dynein arms. These are known as traversing an epithelial membrane between
primary cilia, and they are believed to function as adjoining cells (paracellular route).
sensory organs or signal receptors. • Anchoring junctions (zonulae adherentes,
Flagella, present only on spermatozoa in humans, maculae adherentes, hemidesmosomes, actin-
are modified cilia that possess an axoneme and a linked cell-matrix adhesions) permit epithelial
robust elastic protein complex that is designed to cells to adhere to each other or to the basal
propel the spermatozoa along the female reproduc- lamina or both.
tive tract. Flagella are described in Chapter 21. • Communicating junctions (gap junctions)
permit the transcytoplasmic movement of
Basolateral Domain ions and small molecules between adjacent
Two regions constitute the basolateral domain of epi- cells, coupling them electrically and
thelia, the lateral and basal plasma membranes. Spe- metabolically.
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Account: ns014207
Plasma
membrane
Shared 53
B A heterodimers
Peripheral Dynein
microtubule
doublet
Plasmalemma
Chapter
Radial
spokes
Nexin Figure 5.4 Structure of a cilium with its basal body. (From Gartner LP,
Central Central Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007,
microtubule sheath
p 95.)
pair
Microtubule
5
triplet

Basal body
Plasma
membrane
Strands of Zonulae occludentes

transmembrane Extend along entire
proteins circumference of the cell.
Extracellular Prevent material from taking
space paracellular route in passing
from the lumen into the
Adjacent plasma membranes connective tissues.
Extracellular
space Zonulae adherentes
Basal to zonulae
occludentes.
E-cadherins bind to each
other in the intercellular
Actin filaments space and to actin
filaments, intracellularly.
Intermediate
filaments
Plaque
Maculae adherentes
E-cadherins are associated
with the plaque; intermediate
filaments form hairpin loops.
Desmogleins
Adjacent plasma membranes

Extracellular
space Gap junctions
Communicating junctions
for small molecules and
Connexons ions to pass between cells.
Couple adjacent cells
metabolically and
electrically.
copyright law.
Hemidesmosomes
Integrins Attach epithelial cells to
(transmembrane underlying basal lamina.
receptor proteins)
Figure 5.5 Junctional complexes. (From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007,
p 97.)
Account: ns014207
Lateral Membrane Specializations (cont.) (see Fig. 5.6). These adhesion junctions rely on cal-
54 cium-dependent transmembrane linker proteins,
Zonulae occludentes (tight junctions), the most
cadherins, to hold adjacent cells to one another.
apical component of the junctional complex, are
The calcium-sensitive moiety of cadherins is extra-

formed by the fusion of the outer leaflets of adjacent
cellularly located and is a flexible, hingelike struc
cell membranes (Fig. 5.6). The fusion extends along
ture.
the entire circumference of epithelial cells and, when
Chapter
viewed with freeze fracture electron microscopy, • In the presence of Ca++, the hinge region is
fusion strands, linear arrangements of transmem- unable to flex, and as it extends, it contacts and
brane proteins, are evident on the P-face, and con- binds to the extended moiety of the cadherin
comitant linear grooves are noted on the E-face. of the adjacent cell, but the two membranes
5 • Depending on the integrity of the tight junction,
cannot be more than 15 to 20 nm apart. The
intracellular moieties of cadherins are affixed to
several instances of fusion may be present, actin filament bundles that course parallel to the
resembling a diverging system of fusion strands,
cell membrane.
so that some zonulae occludentes are more • The links to the actin filaments occur via
leaky, having fewer fusion strands, or less leaky, catenins, vinculin, and α-actinin. In this fashion,
possessing more fusion strands. the transmembrane linker cadherins attach the
• These transmembrane proteins are present in the cytoskeleton of one cell to the cytoskeleton of its
membranes of both cells, and they contact each neighboring cell. As in the zonulae occludentes,
other, in a calcium-independent manner, in the an afadin-nectin complex reinforces this
extracellular space, obliterating that space. There adhesion junction.
are three types of transmembrane proteins • Adherens junctions may also be ribbonlike
present in tight junctions: attachments, as in capillary endothelia, where
• Claudins are the most important of the three they do not encircle the perimeter of the cell;
components; this protein blocks the here these junctions are known as fasciae
extracellular space when two cells contact one adherentes.
another.
• Tricellulin, instead of claudin, is present in Other weldlike cell junctions, known as desmo-
regions where three cells contact each other. somes (approximately 400 × 250 × 10 nm), appear
• Occludins are the third type of protein; their to be haphazardly located on the basolateral plasma-
function is not understood. lemmae of cells of simple epithelia and on the adja-
• Tight junctions are reinforced by the other two cent cell membranes of stratified squamous epithelia,
components of the junctional complex, zonulae such as that of the epidermis (see Fig. 5.6). Each half
adherentes and maculae adherentes. of a desmosome pairs up on the intracellular surfaces
• Three cytoplasmic scaffolding proteins—tight of the membranes of adjoining epithelial cells.
junction proteins (zonula occludens) ZO1,
ZO2, and ZO3—ensure the proper alignment • Desmoplakins and pakoglobins function as
of the claudins, occludins, and tricellulins of attachment proteins composing each plaque.
cells facing each other, but the mechanism of • Cytokeratin filaments (intermediate filaments)
their actions is not understood. are thought to reduce the shearing forces on the
• Attached to the ZO1 protein is another cell as they penetrate the plaque and turn back
complex of molecules, afadin-nectin complex, on themselves to reenter the cytoplasm.
which is believed to meet its counterpart from • The intercellular space between opposing
the adjoining cell and reinforce the adherence desmosome plaques (approximately 30 nm in
of the claudins to each other. width) contains filamentous Ca++-dependent
transmembrane linker proteins of the cadherin
Tight junctions limit or prevent paracellular move- family, desmoglein and desmocollin.
ment of material across the epithelial sheet, and pre • If Ca++ is present, the transmembrane linker
vent the migration of integral proteins between the proteins of each cell form a bond with each
apical and basolateral domains of the cell mem other. When calcium is unavailable, the bond is
brane. broken, and the two halves of the desmosome
Zonulae adherentes, similar to zonulae occlu- are unable to maintain their firm contact, and
copyright law.
dentes, are beltlike junctions that encircle the cell the cells become detached from each other.
Account: ns014207
55

connective tissues.
Chapter
Extracellular
Basal to zonulae
occludentes.
Actin filaments
space and to actin
5

Intermediate
filaments
Plaque
Maculae adherentes
with the plaque; intermedi-
ate filaments form hairpin
loops.
Desmogleins

Extracellular
space Gap junctions
Communicating junctions for
small molecules and ions to
Connexons pass between cells. Couple
adjacent cells metabolically
and electrically.
Hemidesmosomes
receptor proteins)
p 97.)
Pemphigus vulgaris is an autoimmune disease
of the skin in which antibodies are produced
against desmosomal proteins. Antibodies bind
to the desmosomal proteins disturbing cell
adhesion. This disturbance leads to blistering of
the epidermis causing loss of tissue fluids. If
this condition is left untreated, death occurs.
Systemic steroids and immunosuppressants are
used to control this disease.
copyright law.
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Gap Junctions and the underlying connective tissue, was
56 The most abundant of the junctional complexes, gap discussed in Chapter 4.
junctions, are present in most epithelial tissues and • Basal plasma membrane enfoldings of
neurons and in cardiac and smooth muscle cells. Gap epithelial cells, especially those concerned with
junctions are sites of intercellular communication ion transport, increase plasmalemma surface area
because they permit small molecules to pass through and compartmentalize the basal cytoplasm into
Chapter
the narrow (2 to 4 nm) wide intercellular space. mitochondria-housing segments. The presence of
These gap junctions couple cells chemically and elec- mitochondria coupled with the plicated plasma
trically to each other, facilitating intercellular com- membrane makes the cell appear striated when
munications in adult and embryonic tissues. viewed by light microscopy.
5
• Hemidesmosomes appear to be half of a
• Six connexins, transmembrane channel–forming desmosome and are located on the basal plasma
proteins, gather to form aqueous channels, known membrane. They assist in the attachment of the
as connexons, in the cell membrane (Fig. 5.7). basal plasmalemma to the basal lamina,
• The number of connexons that are present in a facilitating the anchoring of the cell to the
gap junction varies from a few to several thousands. underlying connective tissue.
• Connexons of one side of the gap junction that • Located on the cytoplasmic side of the plasma
are in register with connexons on the opposing membrane, hemidesmosomes display
side of the gap junction bind to each other attachment plaques composed of
forming a hydrophilic communication channel, desmoplakins, plectin, and other minor
1.5 to 2 nm in diameter, through which proteins, into which the terminal ends of
molecules less than 1 kDa in size can pass keratin intermediate filaments
between adjoining cells. (tonofilaments) are embedded.
• Although the manner in which passage of • Transmembrane linker proteins, which are
material through gap junctions is not integrins, a family of extracellular matrix
understood, it is known that an increase in receptors, penetrate the plaque on the
cytosolic Ca++ concentrations or a decrease in cytoplasmic side and pass through the cell
cytosolic pH closes gap junctions, whereas gap membrane; their extracellular moiety binds to
junctions open if the cytoplasmic pH is high, or laminin and type IV collagen present in the
Ca++ concentration is low. basal lamina.
Basal Surface Specializations Renewal of Epithelial Cells

Basal lamina, cell membrane plications, and hemides There is a high replacement rate for cells of an epi-
mosomes are the three principal specializations of thelium, but this rate is faster in some organs, as in
the basal surfaces of epithelial cells (see Fig. 5.7). the lining of the gastrointestinal tract, and slower in
Hemidesmosomes, located on the basal surface of other regions, as in the epidermis of skin. The renewal
the cell, contribute to anchoring the basal plasma rate for a particular organ is generally constant,
membrane to the underlying basal lamina. however. In the event that numerous cells are lost
because of infection or injury, mitotic activity is
• The basal lamina, a product of the epithelium increased to restore the cell population to normal
located at the interface between the epithelium levels.
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57

connective tissues.
Chapter
Extracellular
Basal to zonulae
occludentes.
Actin filaments
space and to actin
5

Intermediate
filaments
Plaque
Maculae adherentes
with the plaque; intermedi-
ate filaments form hairpin
loops.
Desmogleins

Extracellular
space Gap junctions
Communicating junctions for
small molecules and ions to
Connexons pass between cells. Couple
adjacent cells metabolically
and electrically.
Hemidesmosomes
receptor proteins)
p 97.)
Nonsyndromic deafness and the skin disease epithelium) of a heavy smoker may undergo
erythrokeratodermia variabilis are the result of squamous metaplasia resulting in an epithelial
connexin gene mutations. Mutations of connexin transformation to a stratified squamous epithelium,
genes are also associated with aberrant migration restricting function. This transformation may be
of neural crest cells leading to developmental reversed after the environmental insult is removed.
defects in the pulmonary vessels of the heart.
Epithelial cell tumors may be benign or malignant.
Diverse populations of epithelial cells display their The malignant tumors that arise from epithelia are
own distinctive characteristics that are based on known as carcinomas. Malignant tumors of
many factors, including location and environment, glands are called adenocarcinomas. Cancers
but all are related to function. Under certain in children younger than 10 years are least
copyright law.
pathological conditions, epithelial cells may be likely to be derived from epithelia, whereas
transformed into another epithelial type via a adenocarcinomas are most prominent in adults.
process called metaplasia. The respiratory About 90% of all cancers in adults older than 45
epithelium (pseudostratified ciliated columnar years originate in epithelia.
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Glands • Unicellular—a single cell is the entire gland
58 (e.g., goblet cell)
During the development of certain regions of the • Multicellular—the gland is composed of more
body, epithelial cells invade the underlying connec- than just a single cell (e.g., submandibular gland).
tive tissue, form the parenchyma (secretory units and
Additional classifications are based on the type of
ducts) of glands, and surround themselves with a
secretion the gland produces:
Chapter
basal lamina that they secrete. The surrounding con-

nective tissue, referred to as the stroma, supports the • Serous—watery (e.g., parotid gland)
parenchyma of the gland by providing vascular and • Mucous—viscous (e.g., minor salivary glands of
neural supplies, and its structural elements such as the palate)
capsules, which envelop the entire gland, and septa, • Mixed—serous and mucous (e.g., sublingual
5 which subdivide the gland into lobes and lobules. gland)
The individual cells of the gland’s secretory units
Still other classifications are based on the mechanism
synthesize secretory products and store them in intra-
whereby the cells of the gland release their secretory

cellular compartments known as secretory granules
products (Fig. 5.8):
until the secretion is released. Depending on the
gland, these secretory products may be as varied as: • Merocrine—only the secretory product is
released (as in the parotid gland)
• A hormone, such as insulin from the islets of
• Apocrine—a small piece of the cell’s cytoplasm
Langerhans;
accompanies the secretory product (as, perhaps,
• An enzyme, such as salivary amylase from the
in the lactating mammary gland)
parotid gland, or a bicarbonate-rich fluid from
• Holocrine—the entire cell dies and becomes the
Brunner’s glands of the duodenum; or
secretion (as in the sebaceous gland)
• A tear, a watery secretion from the lacrimal gland.
Two principal categories of glands exist based on Unicellular Exocrine Glands
the manner of delivery of their secretory products: The goblet cell, located in the epithelial lining of the
• Exocrine glands possess ducts through which small and large intestines and of the conducting
their secretory products are delivered onto an portion of the respiratory tract, is the principal example
epithelial surface. of a unicellular exocrine gland (Fig. 5.9). The narrow
• Endocrine glands are ductless; consequently, base of the goblet cell, known as the stem, contacts the
their secretory product is delivered directly into basal lamina. The theca, the apical portion of the cell,
the bloodstream or lymphatic vessels. expanded by the numerous mucinogen-containing
secretory granules, abuts the lumen of the intestine or
Frequently, cells communicate with each other by that of the conducting portion of the respiratory sys
releasing cytokines, which are signaling molecules tem. Mucinogen, released as a result of noxious chem
designed to act on specific cells known as target cells. ical stimulation or by neurotransmitter substances
Cells secreting cytokines are known as signaling derived from the parasympathetic nervous system,
cells, and their signaling molecules bind to receptors is hydrated to form the viscous slippery substance
inducing these target cells to perform a specific func- known as mucin, which, when mixed with other com-
tion (see Chapter 2). The effects of cytokines may be ponents located in the lumen, is known as mucus.
classified into three categories, based on the distance
between the signaling cell and the target cell:
• Autocrine: The signaling cell and the target cell CLINICAL CONSIDERATIONS
are the same—the cell stimulates itself. Sjögren syndrome is a chronic inflammatory
• Paracrine: The target cell and signaling cell are autoimmune disease of the salivary and lacrimal
near each other, so the cytokine can diffuse to glands in which the secretory units of these
the target cell. exocrine glands are rendered unable to release
• Endocrine: A great enough distance separates the their secretions, resulting in dry mouth and dry
signaling cell from the target cell so that the eyes. This condition may occur in isolation, or it
cytokine has to enter the blood or lymphatic may be associated with underlying disorders,
system to reach its destination. such as rheumatoid arthritis, lupus, and
copyright law.
scleroderma; it is also associated with the

Exocrine Glands development of lymphoma. Sjögren syndrome
affects women nine times more frequently than
Exocrine glands may be classified by the number of men. Currently, this disease is incurable.
cells that compose the gland:
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A B C
59
Secretion
Disintegrating
cell and its
contents Intact cell
Chapter
(secretion)
New cell
5
Pinched off
portion of cell

(secretion)
Figure 5.8 Modes of glandular secretion. A, Holocrine. B, Merocrine. C, Apocrine. (From Gartner LP, Hiatt JL: Color Textbook of
Histology, 3rd ed. Philadelphia, Saunders, 2007, p 105.)
Microvilli
Theca
Mucinogen
droplets
Nucleus
Stem
Figure 5.9 Ultrastructure of a goblet cell. (From Lentz TL: Cell Fine Structure: An Atlas of Drawings of Whole-Cell Structure.
Philadelphia, Saunders, 1971.)
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Multicellular Exocrine Glands ulation or a signaling molecule. Endocrine glands of
60 the cord arrangement include the parathyroid and
Secretory cells that are grouped together and orga
suprarenal glands and the anterior lobe of the pitu-
nized to act as secretory organs are multicellular
itary gland. Endocrine glands of the follicle arrange-

exocrine glands. Some multicellular glands display
ment possess follicular cells (secretory cells) that
a simple structure (e.g., gastric mucosa and in the
surround a depression or a cavity, and because they
uterus), or they may be complex structures that ex
Chapter
do not store the secretory product, they release it into

hibit assorted types of secretory units along with
the cavity where it is stored. On receiving the proper
compound branching (e.g., submandibular gland).
signal, the stored hormone is resorbed from the
Multicellular glands are classified according to the
cavity by the follicular cells and then released into
shape and organization of their secretory units and
5
blood capillaries located within the associated con-
their duct components. They may be classified as:
nective tissue (e.g., the thyroid gland).
• Simple, where the ducts do not branch, or Other glands of the body are mixed—that is, they
• Compound, where the ducts branch. contain exocrine and endocrine secretory units. The
The morphology of the secretory units on the com- pancreas, ovaries, and testes each possess both kinds
pound ducts is classified as acinar (alveolar), tubular, of glands. The exocrine portion empties its secretion
or tubuloalveolar (Fig. 5.10). into a duct, and the endocrine portion empties its
Collagenous connective tissue forms capsules that secretion into the bloodstream.
encase large multicellular glands and form strands
Diffuse Neuroendocrine System
called septa that add structural support to the gland
by subdividing the gland into lobes and lobules (Fig. Endocrine cells are also scattered among the epithe-
5.11). Nerves, blood vessels, and ducts access and lial cells lining the digestive tract and the respiratory
exit the glands via the passageways of the septa. system. These particular endocrine cells represent
Myoepithelial cells—cells of epithelial origin that the diffuse neuroendocrine system (DNES). Certain
possess the ability to contract—are present in major paracrine and endocrine hormones are products of
salivary glands and sweat glands, where they share these DNES cells. The DNES designation has replaced
the same basal lamina as the glandular acini. Glan- the terms argentaffin cells, argyrophil cells, and
dular acini and small ducts are wrapped by fibrillar APUD cells (see Chapter 17).
strands of cytoplasm that extend from these myoepi-
thelial cells. Contractions of these cells squeeze the
acini and small ducts, assisting them in delivering
their secretory product.
Endocrine Glands
Carcinoid tumors originate from DNES cells
The endocrine glands include the suprarenal (adre mostly in the digestive system. Before 2000,
nal), thyroid, pituitary, parathyroid, ovaries, testes, this name was applied to benign and malignant
placenta, and pineal glands. Because these glands are forms of DNES growths. Since that year, benign
ductless, they must release their secretions (hor- DNES growths are known as neuroendocrine
mones) into the blood or into the lymphatic vessels tumors, but if they migrate to other parts of the
so that they can be distributed to the target organs. body, they are called carcinoids. The following
Certain of these endocrine glands (e.g., the islets of terms apply to cancers: neuroendocrine
Langerhans of the pancreas and the interstitial cells cancers (carcinomas), well differentiated (less
of Leydig in the testes) are simply composed of clus- aggressive), and poorly differentiated (more
aggressive). Many physicians still prefer to use
ters of cells embedded within the connective tissue
the term carcinoid for benign and well-
stroma of those organs.
differentiated cancers. These DNES tumors and
Hormones secreted by endocrine glands include
cancers release hormone-like substances as
proteins, peptides, steroids, modified amino acids, they grow and spread causing face flushing,
and glycoproteins (see Chapter 13). Endocrine secre- wheezing, diarrhea, and rapid heartbeat; these
tory cells are arranged as cords or as follicles. Cords, symptoms are called carcinoid syndrome.
the most common, frequently anastomose around Additionally, these tumors and cancers can
capillaries or blood sinusoids. Their hormone, stored cause symptoms throughout the body.
copyright law.
within the cell, is released on receiving a neural stim-
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61
Secretory
portion
Chapter
Simple tubular Simple branched Simple coiled Simple acinar Simple branched
tubular tubular acinar
Duct
5

Compound tubular Compound acinar Compound tubuloacinar
Figure 5.10 Classification of multicellular exocrine glands. (From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed.
Philadelphia, Saunders, 2007, p 107.)
Intercalated Striated
duct cell duct cell
Mixed salivary gland
Myoepithelial
Intercalated duct cell
Striated duct
Serous cell
Figure 5.11 Salivary gland: its organization,

secretory units, and system of ducts. (From
Serous acinus Gartner LP, Hiatt JL: Color Textbook of Histology,
3rd ed. Philadelphia, Saunders, 2007, p 108.)
Mucous acinus
Main duct
Serous demilunes
Lobar duct Mucous cell
Intralobular
duct
Intralobular
duct
Intercalated
duct
Acinus
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Multicellular gland
Lobule
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6 Connective Tissue
Connective tissue, one of the four basic tissues of the supersedes the functions of cells and fibers because
body, is derived mostly from mesoderm, and serves the defense of the body depends on the characteris-
to connect those tissues and different types of con- tics of the ground substance.
nective tissues to each other. During Extracellular matrix, the nonliv-
embryonic development, multipoten- Key Words ing component of connective tissue,
tial mesenchymal cells of the primitive composed of ground substance and
• Extracellular matrix
embryonic connective tissue known fibers, is described in Chapter 4, but
as mesenchyme migrate throughout • Cells of connective its salient features are reviewed here.
the body to differentiate into mature tissue Ground substance is composed of:
cells of specialized connective tissue, • Lipid storage by fat
• Glycosaminoglycans, either
such as tissues of cartilage, bone, and cells
sulfated (e.g., keratan sulfate,
blood. Mesenchymal cells also give • Inflammatory heparin, chondroitin sulfates,
rise to cells of connective tissues that response dermatan sulfate, and heparan
are not specialized—connective tissue
• Connective tissue sulfate) or nonsulfated (e.g.,
proper, including fibroblasts, adipo-
cytes, and mast cells.
types hyaluronic acid).
• Proteoglycans, which, by being
The various types of connective
covalently bound to hyaluronic
tissues have diverse and far-ranging
acid, form macromolecules of aggrecan
functions:
aggregates, producing the gel state of the
• Cartilage, bone, tendons, ligaments, and capsules extracellular matrix.
of organs provide structural support. • Some adhesive glycoproteins, such as
• Blood, lymph, and connective tissue proper act fibronectin, which is dispersed throughout the
as a medium for exchange by delivering extracellular matrices, and laminin, which is also
nutrients, waste products, and signaling widespread as it is localized in the basal lamina.
molecules to and from cells of the body. Others, such as chondronectin, are located in
• Certain cells that travel in the bloodstream leave cartilage, and osteonectin is located in bone.
the blood and enter connective tissue proper to Fibers, also nonliving substances, are of two types:
defend and protect the body from potentially
deleterious agents. • Collagen fibers are of 25 different types
• Adipose cells store lipids and congregate to form depending on the amino acid sequence of their
adipose tissue serving as local storage depots three alpha chains, but only 6 are of major
of fat. importance for the purpose of this textbook
(Table 6.1). Most collagen fibers have great
Connective tissue proper is composed of extracel- tensile strength. Glycine, proline, hydroxyproline,
lular matrix and cells, some of which function in and hydroxylysine are the most common amino
manufacturing the matrix in which they and other acids of collagen.
cells are embedded. Depending on the function of a • Elastin and microfibrils compose elastic fibers.
particular connective tissue, cells or the extracellular The amorphous protein elastin, composed
matrix predominates and forms the essential compo- mostly of glycine and proline, is responsible
nent. Fibers are more important than their cells, the for their elasticity (e.g., elastic fibers may be
fibroblasts, for the function of tendons and liga- stretched 150% of their length), whereas
ments, whereas in loose connective tissue, fibroblasts microfibrils are responsible for their stability.
serve a more important function than do the fibers. Elastin also contains a high concentration
In other instances, such as during immunological of lysine, responsible for the formation of
responses, the function of the ground substance desmosine bonds that are elastic and deformable.
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Table 6.1 MAJOR TYPES AND CHARACTERISTICS OF COLLAGEN
Molecular
63
Molecular Type Formula Synthesizing Cells Function Location in Body
I (fibril-forming); most [α(I)]2α2(I) Fibroblasts, osteoblasts, Resists tension Dermis, tendon,

common of all odontoblasts, ligaments,
collagens cementoblasts capsules of
Chapter
organs, bone,
dentin,
cementum
II (fibril-forming) [α1(II)]3 Chondroblasts Resists pressure Hyaline cartilage,
elastic cartilage
III (fibril-forming); also [α1(III)]3 Fibroblasts, reticular Forms structural Lymphatic system,
known as reticular
fibers; highly
cells, smooth muscle
cells, hepatocytes
framework of spleen,
liver, lymph nodes,
spleen, liver,
cardiovascular
6
glycosylated smooth muscle, adipose system, lung, skin
tissue
Connective Tissue
IV (network-forming); [α1(IV)]2α2(IV) Epithelial cells, muscle Forms meshwork of Basal lamina
do not display 67-nm cells, Schwann cells lamina densa of basal
periodicity, and alpha lamina to provide
chains retain support and filtration
propeptides
V (fibril-forming) [α1(V)]2α2(V) Fibroblasts, Associated with type I Dermis, tendon,
mesenchymal cells collagen, also with ligaments,
placental ground capsules of
substance organs, bone,
cementum,
placenta
VII (network-forming); [α1(VII)]3 Epidermal cells Forms anchoring fibrils Junction of
form dimers that that fasten lamina densa epidermis and
assemble into to underlying lamina dermis
anchoring fibrils reticularis
From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 76.
Ehlers-Danlos syndrome is a group of rare Marfan syndrome is an autosomal dominant
genetic disorders affecting humans caused by disorder in which the elastic tissue is weakened
defective collagen synthesis. Symptoms vary because of a mutation in the fibrillin gene. This
widely based on the type of Ehlers-Danlos disorder affects the elastic fibers of the
syndrome the patient has. In each case, the cardiovascular, ocular, and skeletal systems.
symptoms are ultimately due to faulty or reduced Individuals with Marfan syndrome are unusually
amounts of collagen, the most common of which tall, with very long arms, fingers, legs, feet, and
include unstable joints that are easily dislocated toes. Cardiovascular problems are life-threatening
and hypermobile because of overstretchable and include valvular problems and dilation of the
ligaments that are composed of defective ascending aorta. Ocular disorders include myopia
collagen. Some forms affect the skin, and others and detached lens. Skeletal disorders include
affect the walls of blood vessels. The severity of abnormally weak periosteum because of defects
the syndromes of this incurable disease can vary in the elastic fibers being unable to provide an
from mild to life-threatening. appositional force in bone development.
copyright law.
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Connective Tissue Cells Pericytes
64
Pericytes, derived from mesenchymal cells, partially
The cells of connective tissue proper are classified
surround endothelial cells of capillaries and small
into two categories: fixed (resident), referring to cells

venules (see Fig. 6.2). They possess their own basal
that do not migrate, and transient, referring to cells
lamina, which may fuse with that of adjacent endo-
that use the blood and lymph vascular system(s) to
thelial cells. Pericytes share some of the characteris-
Chapter
relocate to regions of connective tissue proper where

tics of smooth muscle and endothelial cells, and they
they have a particular function to perform, and then
may give rise to fibroblasts, endothelial cells, or vas-
they either die there or leave to go to a different loca-
cular smooth muscle cells in response to injury.
tion (Table 6.2).
6 Fixed Cells of Connective Tissue

Adipose Cells
Fat cells (adipocytes) are amitotic and function in
Fibroblasts the synthesis and storage of triglycerides (see Fig.
Connective Tissue
Fibroblasts (Figs. 6.1 and 6.2), the most abundant 6.2). There are two types of adipose cells—unilocu-
cells of connective tissue, are derived from mesen- lar and multilocular.
chymal cells and are responsible for synthesizing the • Unilocular fat cells, large round cells (≤120 µm
extracellular matrix. Fibroblasts are either active or in diameter) filled with a single drop of lipid,
quiescent; myofibroblasts are a subcategory of fibro constitute the principal population of white
blasts: adipose tissue. Electron microscopy shows a thin
• Active fibroblasts lie parallel to the long axis of peripheral cytoplasm rich in ribosomes with a
collagen bundles as elongated, fusiform cells small Golgi complex, few mitochondria, RER,
with pale-staining cytoplasm and a dark, large and numerous pinocytotic vesicles along the
ovoid nucleus. During matrix production, the cytoplasmic aspect of the cell membrane.
Golgi apparatus and rough endoplasmic • Multilocular fat cells are polygonal in shape, are
reticulum (RER) are well developed. Myosin is smaller than white fat cells, and store fat in small
located throughout the cytoplasm, and actin and droplets throughout the cytoplasm. Electron
α-actinin are localized at the cell periphery. micrographs show abundant mitochondria,
• Inactive fibroblasts are smaller, display which are responsible for the cell’s darker
acidophilic cytoplasm, and have a denser, deeply coloration—hence their being called brown fat
stained nucleus. RER and the Golgi apparatus cells, the principal component of brown adipose
are reduced in these cells, but ribosomes are tissue.
abundant.
• Fibroblasts may be modified to become
myofibroblasts in regions of wound healing.
They possess characteristics of fibroblasts and
smooth muscle cells, but in contrast to smooth CLINICAL CONSIDERATIONS
muscle, they do not have an external lamina.
Myofibroblasts function in wound contraction, Although fibroblasts are considered to be fixed
and as resident cells of the periodontal ligament cells, they are able to display some limited
movement. These cells may undergo cell
they may assist in tooth eruption.
division under special conditions, such as in
wound healing. Additionally, when tendons are
stressed because of overuse, fibroblasts may
be stimulated to become chondrocytes and
form cartilage matrix around themselves and
Table 6.2 FIXED AND TRANSIENT CELLS
transform the tendon into fibrocartilage.
Fixed Cells Transient Cells Additionally, fibroblasts may differentiate into
Fibroblasts Plasma cells adipose cells; under pathological conditions,
Adipose cells Lymphocytes fibroblasts may even differentiate into
Pericytes Neutrophils osteoblasts.
Mast cells Eosinophils
Macrophages Basophils
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Monocytes
Macrophages
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Undifferentiated
mesenchymal cell 65
Chapter
Endothelial
Chondroblast Adipocyte cell Osteoblast
Fibroblast Mesothelial
cell
6
Chondrocytes Osteocyte
Connective Tissue
Figure 6.1 Origins of connective tissue
cells. (From Gartner LP, Hiatt JL: Color
Hematopoietic Textbook of Histology, 3rd ed. Phila
stem cell delphia, Saunders, 2007, p 112.)
Red blood
Lymphocyte cell
precursor
T lymphocyte
Neutrophil
B lymphocyte
Monocyte
Mast cell
Plasma cell
Eosinophil
Macrophage
Basophil
Osteoclast Megakaryocyte
Collagen
Endothelial
cell Fat cells
Pericyte
Fibroblast
Macrophages Figure 6.2 Cell types and fiber types in loose connective tissue. (From Gartner
LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007,
p 113.)
Plasma
cells
Elastic
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fiber
Mast
cell
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Storage and Release of Fat by Adipose Cells alimentary canal), neutral proteases (tryptase,
66 chymase, and carboxypeptidases), aryl sulfatase,
During digestion, fats in the lumen of the small intes-
β-glucuronidase, kininogenase, peroxidase,
tine are catabolized by pancreatic lipase into fatty
superoxide dismutase, eosinophil chemotactic

acids and glycerol, substances that are absorbed by
factor, and neutrophil chemotactic factor.
surface absorptive cells of the epithelial lining. When
• Secondary mediators, synthesized from
in the cytoplasm of these cells, the fatty acids and
Chapter
membrane arachidonic acid precursors, include

glycerol enter the smooth endoplasmic reticulum,
leukotrienes (C4, D4, and E4), thromboxanes
where they are re-esterified and conveyed to the
(thromboxane A2 and thromboxane B2), and
Golgi apparatus, where they are invested with a pro
prostaglandins (prostaglandin D2).
tein coat. These proteinated triglycerides, called chy-
• Secondary mediators that are not derived from
6 lomicrons, are released into the lamina propria of
the small intestine to enter lymph channels, known
arachidonic acid precursors include platelet-
activating factor, bradykinins, interleukins (IL-4,
as lacteals, and eventually are released into the blood
IL-5, and IL-6), and tumor necrosis factor-α. (See
Connective Tissue
stream.
Table 6.3 for a list of the major primary and
Capillaries that vascularize adipose tissue have an
secondary mediators released by mast cells.)
enzyme, lipoprotein lipase, manufactured by adipo-
cytes, on the luminal surface of their endothelial cells
Mast Cell Activation and Degranulation
(Fig. 6.3). This enzyme catabolizes chylomicrons and
other blood-borne lipids, such as very-low-density The plasma membranes of mast cells possess high-
lipoproteins (VLDL), into glycerol and fatty acids. affinity cell surface Fc receptors (FcεRI) for IgE mol-
The fatty acids leave the capillaries; penetrate the ecules that project into the extracellular space. These
adipocyte plasmalemma; and within the cytoplasm cells have the ability to release pharmacologic agents
of fat cells are formed into triglycerides, which are that set off a localized response known as immedi-
stored in the pool of lipid droplets, an efficient and ate hypersensitivity reaction or, in extreme cases, a
low weight method of energy storage. When norepi- widespread, possibly fatal response known as an ana-
nephrine and epinephrine bind to their respective phylactic reaction. Certain drugs, venoms of some
receptor sites on the fat cell membrane, the adipo- insects, various pollens, and other antigens may elicit
cyte’s adenylate cyclase system is activated to form these responses in the following manner (see Fig.
cyclic adenosine monophosphate (AMP), which 6.4):
induces the cytoplasmic enzyme hormone-sensitive
lipase to degrade triglycerides of the lipid droplet. 1. Mast cells become sensitized when they bind
The fatty acids and glycerol leave the adipocyte to IgE antibodies against a particular antigen to
enter the surrounding capillaries (see Fig. 6.3). their FcεRI receptors, but the mast cells do not
respond to the first exposure to the antigen.
Mast Cells 2. If the same antigens enter the connective tissue
Mast cells (20 to 30 µm in diameter) are derived for a second time, the antigens bind to the
from precursors in the bone marrow and enter the IgE on the mast cell surface, causing the
connective tissue compartment where they mature, immunoglobulin molecules to be linked to each
live for a few months, and only seldom enter the other and the receptors to be crowded together,
cell cycle. These ovoid cells with a centrally placed stimulating receptor coupling factors to activate
nucleus have membrane bound granules (Fig. 6.4 adenylate cyclase and phospholipase A2.
and Table 6.3) that are responsible for their meta- 3. Adenylate cyclase is responsible for the
chromasia. Mast cells store some pharmacologic formation and increased concentration of cyclic
agents, known as primary or preformed mediators, AMP within the plasma cell cytosol, inducing
in granules and synthesize others, known as second- the release of Ca++ ions from sequestered storage
ary mediators, as they are required. compartments, which induces the exocytosis of
preformed mediators by degranulation.
• Primary mediators are histamine and heparin 4. Phospholipase A2 induces the synthesis of
(in connective tissue mast cells) or histamine arachidonic acid, which is transformed into
and chondroitin sulfate (in mucosal mast cells secondary mediators that are immediately
of the mucosa of the respiratory tract and released into the extracellular space.
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33

preparation for cell division, is composed of inter-

results in the formation of two identical daughter

G0 (G zero) phase. • M cyclins: Cyclin B binds to CDK1, and this

• Anaphase begins when the cohesion proteins that

(chromosomes) start to be pulled apart. The

disappearance of the nucleolus, the beginning of is beginning to anticipate cytokinesis.

Meiosis I (Reductional Division)

Prophase II Metaphase II Anaphase II Telophase II

frequently in chromosomes 8, 9, 13, 18, and

(Table 4.1). huge domain that is responsible for the gel

Collagen (type II)

Table 4.1 TYPES OF GLYCOSAMINOGLYCANS (GAGs)

Chondroitin 10,000–30,000 d-glucuronic acid-β-1,3-N-acetylgalactosamine-6-SO4 Cartilage, Wharton’s jelly,

Packing of tropocollagen molecules

• In some lymph nodes, the spleen, bone marrow,

include selective glycosylation of some lysine

Figure 4.3 Type I collagen synthesis and assembly. Types III,

Squamous Cuboidal Columnar Pseudostratified

Epithelium and Glands

Table 5.1 CLASSIFICATION OF EPITHELIA

flattened (distended) to urethra

whereas in the ear they assist the hair cells in

and 0.2 µm in diameter), finger-like structures

Epithelium and Glands

Intermediate Actin cortex

bends instead. Terminal bars, as viewed by light microscopy, are

to be junctional complexes that facilitate the adher-

Epithelium and Glands

Strands of Zonulae occludentes

Adjacent plasma membranes

The calcium-sensitive moiety of cadherins is extra-

proteins circumference of the cell.

Epithelium and Glands

Adjacent plasma membranes

Basal Surface Specializations Renewal of Epithelial Cells

proteins circumference of the cell.

Epithelium and Glands

Adjacent plasma membranes

basal lamina that they secrete. The surrounding con-

whereby the cells of the gland release their secretory

scleroderma; it is also associated with the

Epithelium and Glands

itary gland. Endocrine glands of the follicle arrange-

do not store the secretory product, they release it into

within the cell, is released on receiving a neural stim-

Epithelium and Glands

Figure 5.11 Salivary gland: its organization,

I (fibril-forming); most [α(I)]2α2(I) Fibroblasts, osteoblasts, Resists tension Dermis, tendon,

into two categories: fixed (resident), referring to cells

relocate to regions of connective tissue proper where

6 Fixed Cells of Connective Tissue

superoxide dismutase, eosinophil chemotactic

membrane arachidonic acid precursors, include

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