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Dr.

Janet Smith Medical Microanatomy


 

Epithelium & Glands

Required reading: Ross & Pawlina, Chapters 4 & 5, & pp. 506-509, 543-551, & 562-567
Wheater, Chapter 5, & pp. 178-180 & 260-262

OBJECTIVES
To understand:
1.   The definition of a tissue, and the characteristics that define the four basic tissue
types: epithelium, connective tissue, muscle, & nerve.
2.   That epithelial cells form either sheets that cover almost all free surfaces of the
body or glands.
3.   That epithelia arise from all three embryonic germ layers (ectoderm, mesoderm
& endoderm).
4.   That an epithelial sheet is classified based on the number of cell layers it
contains plus the shape of the cells in the surface layer. Be able to identify the
different types of epithelia and give examples of where they are found in the body
and why.
5.   The differences between metaplasia and dysplasia.
6.   The numerous functions that different epithelia can serve including secretion,
absorption, protection, transport along the epithelial surface, transport across the
epithelial sheet, and sensory reception. Consider which type(s) of epithelium
would be well suited for each function.
7.   That most epithelial cells are morphologically polarized, with distinctive basal,
lateral, and apical surfaces, and that these surfaces have structural and functional
differences.
8.   The surface specializations such as cilia, microvilli, and membrane junctions
that are found on some epithelial cells.
9.   The structure and functions of a basement membrane.
10.   The distinctions between exocrine glands and endocrine glands.
11.   The various ways that exocrine glands can be divided into subcategories, e.g.:
•   Merocrine vs. apocrine vs. holocrine
•   Mucous vs. serous vs. mucoserous
•   Simple vs. compound
•   Acinar (AKA alveolar) vs. tubular vs. tubuloacinar (AKA tubuloalveolar)
Be able to identify examples of each type of exocrine gland.

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EPITHELIUM & GLANDS MEDICAL MICROANATOMY
 

I.   TISSUE VS. ORGAN


Tissue:
A tissue is a group of structurally &/or physiologically similar cells plus the
intercellular substance that surrounds them.
All the organs of the body are composed of only 4 basic tissue types:
•   Epithelium
•   Connective tissue
•   Muscle
•   Nerve

Organ:
An organ is a higher order structure made from two or more different tissue types
that work together to perform one or more characteristic specialized functions.

II.  EPITHELIA EXIST IN TWO FORMS


Sheets of cells that cover almost all external surfaces (epidermis, cornea) and internal
surfaces (lumens of GI tract, respiratory tract, urogenital tract, cardiovascular
system, as well as the walls of body cavities (e.g., pleural, pericardial) and the outer
surfaces of organs located in those cavities (e.g., heart, lungs)
Glandular epithelium

III.   CHARACTERISTICS OF AN EPITHELIUM


Closely apposed cells (i.e., very little extracellular matrix)
Most epithelia sit on or are surrounded by CT, but are separated from it by a basement
membrane
Many types of membrane junctions hold the cells together (tight junctions, zonulae
adherentes, desmosomes), allow them to communicate with one another (gap
junctions), or bind them to a basement membrane (hemidesmosomes and focal
adhesions)
Not specialized for contraction (the characteristic function of muscle) or conduction of
an action potential (characteristic of nerve)
Serve a variety of other functions (e.g., secretion, absorption, transport, protection,
receptor functions
Most cells are morphologically polarized (e.g., with a basal surface, an apical
surface, and several lateral surfaces)
Almost all are avascular, and are nourished by vessels in the adjacent connective
tissue (CT)
Undergo continuous and relatively rapid turnover (high mitotic rate)
May explain why most cancers arise from epithelial cells
New cells differentiate from a stem cell population to replace old, dying cells.
In an epithelium with several layers of cells (a stratified epithelium), the stem cells
are in the deepest layers, & cells differentiate as they move toward the surface
During embryogenesis each of the three germ layers (ectoderm, mesoderm,
endoderm) gives rise to some epithelial tissue
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EPITHELIUM & GLANDS MEDICAL MICROANATOMY
 

IV.  APICAL MEMBRANE SPECIALIZATIONS


Found on some, but not all epithelia
Microvilli
Cylindrical projections of the plasma membrane that serve to increase the
membrane surface area, often for absorption
Have a core of actin filaments
Actin filaments of the microvillus are anchored to the terminal web at the base of
the microvillus
The terminal web is a network of actin filaments and associated proteins anchored
to the zonula adherens and the apical membrane. It includes or rests on a
network of intermediate filaments.
Very numerous in intestine and some kidney tubules (proximal tubules) where they
form the so-called “brush border” or “striated border” that is visible by light
microscopy (LM)
Many cells have much smaller numbers of microvilli

Glycocalyx
By EM the extracellular surface of the plasma membrane of some cells has a fuzzy
layer called the glycocalyx, which is visible by electron microscopy (EM)
Composed of the carbohydrate side chains of membrane glycoproteins and
glycolipids, plus some adsorbed proteins
Function varies with cell type (digestive enzyme activity, hormone receptor site,
cell-cell recognition)
Particularly prominent on the microvilli of intestinal absorptive cells where it
contains active sites of some digestive hormones

Stereocilia
Are related to microvilli, i.e., THEY ARE NOT CILIA
Like microvilli, they have a core of actin filaments, and anchor into a terminal web
Differ from microvilli in that stereocilia:
Are much longer than microvilli
Have a more complex interconnected and branching structure Share
some but not all of the same accessory proteins as microvilli
Quite rare. Found in parts of the male reproductive tract (epididymis and vas
deferens, where they absorb fluid) and in the sensory cells (hair cells) of the
inner ear.

Cilia
Projections of the plasma membrane that contain an axoneme based on
microtubules rather than actin filaments
Each cilium grows from a basal body (9 triplets of microtubules) derived from a
centriole
There are two major kinds of cilia: “ordinary” (motile) cilia and primary cilia
 

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Ordinary cilia:
Are motile
Axoneme has a 9+2 microtubule arrangement
Motor proteins (dynein arms) are associated with each doublet & are required
for motility
Present on only a few epithelia (large airways, oviduct, ependymal cells in the
ventricles of brain)
Very numerous on cells that have them. When we speak of “ciliated cells” we
are talking about these cells that have numerous motile cilia.
By LM, cilia tend to clump together more than microvilli, giving the apical end of
the cell a fringed appearance
The basal bodies may show up in LM as a dark line at the apical end of the cell
Primary cilia: Are
nonmotile
Axoneme has a 9+0 arrangement with no dynein arms Found
on most epithelial cells
Only one cilium per cell (sometimes called a monocilium)
Are sensory structures, especially mechanoreceptors that transmit signals when
bent, e.g., by movement of fluid in kidney tubules. Fluid flow bends the
cilium, which opens Ca++ channels that initiate a signal cascade.
CLINICAL CORRELATION: POLYCYSTIC KIDNEY DISEASE
In humans two mutant genes that code for proteins in primary cilia cause
polycystic kidney disease
Results in formation of numerous cysts that destroy the kidney cortex and
lead to renal failure

V.   BASEMENT MEMBRANES
Are extracellular structures rather than actual membranes (i.e., not lipid bilayers)
Are composed of a basal lamina and a lamina reticularis (reticular lamina).
The basal lamina itself can be divided into a lamina lucida (which may be a fixation
artifact) and a lamina densa.
Epithelial cells make most of the components of the basal lamina
CT cells make most of the components of the lamina reticularis
The cells adhere strongly to the basement membrane via membrane junctions
(hemidesmosomes, focal adhesions)
Basement membranes are generally not visible by LM using H&E-stained sections.
They can be seen by LM if the tissue is stained via the periodic acid-Schiff (PAS)
technique.
Basement membrane functions include: Anchoring
epithelia to CT
Acting as a semipermeable filtration barrier (important in glomerular capillaries of
the kidney)
Regulating the growth of blood vessels (angiogenesis)
 

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EPITHELIUM & GLANDS MEDICAL MICROANATOMY
 

CLINICAL CORRELATION: METASTASIS AND THE BASEMENT MEMBRANE


In order for malignant epithelial cells to spread throughout the body (metastasize),
they must break through their basement membrane. Malignant cells that are still
confined to the epithelium where they originated are known as carcinomas in
situ.
Some types of normal cells are also capable of crossing basement membranes
(e.g., lymphocytes entering an epithelium as part of immune surveillance)
The mechanisms used by normal and abnormal cells to cross a basement
membrane are not clear. Some may involve proteases that break down the
basement membrane (e.g., matrix metalloproteinases), but non-proteolytic
mechanisms may also exist

VI.  EPITHELIAL CLASSIFICATION


Epithelia are classified according to:
1.  The number of cell layers present
Simple epithelium = one cell layer
All cells rest on the basement membrane, and all reach the free surface
Stratified epithelium = more than one cell layer
Not all cells rest on the basement membrane
Those that do rest on the basement membrane do not reach the free surface
2.  The shape of the cells in the surface layer
Squamous = wide, flat surface cells (shaped like a fried egg)
Cuboidal = surface cells that are about equal in height & width
Columnar = surface cells that are significantly taller than they are wide

NOTE: To correctly classify an epithelium you must specify both the number of cell
layers and the shape of the surface cells. You should be able to look at an
epithelium and classify it, and give examples of where a particular type of
epithelium is found in the body.

Exceptions to the classification rules:


Transitional epithelium
A type of stratified epithelium where the shape of the surfaces cells changes
Found only in parts of the urinary tract
In the relaxed state the surface cells are large and dome-shaped (“umbrella cells”)
In the stretched state the surface cells are flatter and more rectangular
Some surface cells are binucleate
Pseudostratified epithelium appears stratified but is actually not,
because: All cells sit on the basement membrane (like a simple
epithelium), but Not all the cells reach the free surface (the stem cells
tend to be short)
 

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EPITHELIUM & GLANDS MEDICAL MICROANATOMY
 

Two types of stratified squamous epithelium:


Minimally keratinized stratified squamous
An older term is “nonkeratinized”
Surface cells are alive (you know this because they contain visible nuclei_
Found on some of the moist body surfaces (e.g., lining of the esophagus)
Maximally keratinized stratified squamous epithelium
Surface cells are dead (no nuclei)
Found on dry body surfaces (skin)

Two special names for simple squamous epithelia based on their location:
Endothelium:
The simple squamous epithelium the lines the lumen of all blood vessels,
lymphatic vessels, and the heart chambers.
Mesothelium:
The simple squamous epithelium that lines the walls of body cavities (pleural,
pericardial, peritoneal) and the outer surfaces of organs located in those
cavities (e.g., lungs, heart, stomach).

Examples of locations where the different types of epithelia are found: Simple
squamous:
Endothelium
Mesothelium
Wall of renal corpuscles Simple
cuboidal:
Some types of kidney tubules (proximal tubules, distal tubules)
Smaller ducts in some exocrine glands Simple
columnar:
Lumen of the stomach and intestines
Lumen of the gall bladder
Minimally keratinized stratified squamous: Lumen
of the esophagus
Parts of the oral cavity (e.g., inner surface of cheeks)
Maximally keratinized stratified squamous:
Epidermis of the skin
Stratified cuboidal:
A rare type of epithelium (usually only 2 cell layers thick)
Ducts of sweat glands
Stratified columnar:
A rare type of epithelium (usually only 2 cell layers thick) Parts
of larger ducts in some exocrine glands
Pseudostratified columnar:
Parts of the respiratory system (trachea, bronchi), where it includes ciliated cells
Parts of the male reproductive tract (epididymis, vas deferens) where it includes
cells with stereocilia
Transitional:
Found only in parts of the urinary system (ureters, urinary bladder, the proximal
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EPITHELIUM & GLANDS MEDICAL MICROANATOMY
 
part of the urethra)

VII.  EPITHELIAL FUNCTIONS:


Secretion
By glands & by some epithelial sheets (e.g., stomach lining secretes mucus)
Absorption, e.g., of:
Nutrients from the GI tract by intestinal epithelium
Protein from urinary filtrate by kidney tubules (prevents proteinuria)
Transport (across the epithelial layer or along its free surface) Mucus
towards the larynx by tracheal epithelium
Na+ from sweat by sweat gland ducts (conserves Na+)
Protection, e.g., against:
Wear & tear by epidermis, esophageal epithelium, vaginal epithelium Desiccation
by epidermis
UV irradiation by melanin in the epidermis Sensory
receptor function
Taste buds, olfactory epithelium
Permeability barrier
By many epithelia including urinary bladder

Different types of epithelia are better suited for some functions than for others
Secretion or absorption
Usually simple epithelia, and some pseudostratified (e.g., the pseudostratified
epithelium of the trachea secretes mucus)
NOTE: The height of the epithelium may vary with the level of secretory or
absorptive activity of the cells, e.g., thyroid follicular cells
Rapid transport
Usually simple squamous (e.g., endothelium, lung alveoli)
Protection against wear and tear
Stratified squamous epithelium (minimally keratinized on moist surfaces;
maximally keratinized on dry surfaces)
Protection against desiccation
Maximally keratinized stratified squamous
Permeability barrier
Stratified epithelium or a simple epithelium with tight junctions

VIII.  METAPLASIA AND DYSPLASIA


Epithelial types can change over time via the processes of metaplasia or dysplasia
With reference to epithelia, metaplasia and dysplasia can be defined as follows:
Metaplasia: Conversion of one type of normal epithelium into another normal type of
epithelium, often in response to stresses
At least initially, the conversion may be reversible
The most common metaplasias involve conversion of a simple or pseudostratified
epithelium into a stratified squamous epithelium that is less fragile than the
original form
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EPITHELIUM & GLANDS MEDICAL MICROANATOMY
 
Example:
Smoking can cause conversion of the pseudostratified epithelium of large
airways to stratified squamous epithelium
Dysplasia: Conversion of a normal type of epithelium into a morphologically
abnormal one. Dysplastic changes can include:
A variety of abnormal cell shapes and sizes (pleomorphism)
Abnormal arrangement or location of cells (e.g., rounded basal cells near the
surface of a stratified squamous epithelium)
More frequent mitoses
Mitoses in abnormal locations within the epithelium (e.g., throughout a squamous
epithelium rather than restricted to the basal layers)

IX.   GLANDS
Embryological Development
During embryogenesis glands are usually formed by epithelial cells that grow
downward from an epithelial sheet into underlying CT
Exocrine glands retain their connection to the surface and secrete onto that surface
Endocrine glands lose their connection to the surface, and secrete into the
surrounding CT

The morphology of secretory cells is influenced by the type of secretion they produce
Chemical classes of secretory products include:
Polypeptides/proteins Pituitary
(endocrine)
Islets of Langerhans in the pancreas (endocrine)
Pancreatic acinar cells (exocrine)
Steroid hormones (all endocrine) Adrenal
cortex
Ovarian follicles
Leydig cells of the testis
Mucins (the highly viscous, glycosylated proteins in mucus; all exocrine) Goblet
cells (intestine & respiratory tract)
Surface mucous cells of the stomach
Brunner’s gland of the duodenum (a pure mucous gland)
Sebum (composed mainly of waxes, triglycerides, and other lipid derivatives)
Sebaceous glands of the skin (exocrine)
Tyrosine analogs
Thyroid follicular cells secrete the thyroid hormone, T3 & T4 (endocrine)

Exocrine glands vs. endocrine glands


Exocrine glands
Secrete onto a free surface either directly or more commonly via a duct
Goblet cells and the surface mucous cells of the stomach secrete directly into the
lumen of the intestines or stomach, respectively, without any duct
May be unicellular or, more commonly, multicellular Goblet
cells are unicellular exocrine glands
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EPITHELIUM & GLANDS MEDICAL MICROANATOMY
 
Further classified using many different systems including:
Whether their duct branches or not (simple vs. compound glands)
The shape of their secretory unit (tubular, acinar/alveolar, tubuloalveolar) Their
method of releasing secretory product (merocrine, apocrine, holocrine) The
morphology of their secretory cells (serous, mucous)

Endocrine glands
Have no ducts
Release their products (hormones) into the surrounding CT where it can be picked
up by nearby blood vessels
Can be unicellular or, more commonly, multicellular
Cells of the diffuse neuroendocrine system (DNES cells) are unicellular
endocrine glands
Are organized either as cords of cells or as follicles
Follicles are spherical structures that are generally composed of a single layer
of cells surrounding a central lumen
NOTE: Exocrine and endocrine cells can be mixed together in the same epithelium
(e.g., intestinal epithelium). The exocrine cells secrete into the lumen; the endocrine
cells secrete across the basement membrane into the CT.

X.   CLASSIFICATION SCHEMES FOR EXOCRINE GLANDS


Classification based on whether or not the duct branches:
Glands with unbranched ducts = simple glands
Glands with branched ducts = compound glands

Classification based on the shape of the secretory portion:


Tubular
Coiled
tubular
Branched tubular
Acinar, also called alveolar (spherical or shaped like an Erlenmeyer flask)
Branched alveolar
Tubuloalveolar/tubuloacinar (a mixture of tubular and acinar secretory units)

NOTE: If the secretory portion branches, the term “branched” is added


- e.g., “simple branched tubular” means that the duct does not branch, but the
secretory portion does

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EPITHELIUM & GLANDS MEDICAL MICROANATOMY
 

    Gland Classification Example  


  Simple glands Simple tubular Intestinal gland (crypt of Lieberkühn  
Simple coiled tubular Eccrine sweat gland  
Simple branched tubular Pyloric glands (stomach)  
Simple acinar Urethra & small sebaceous  
Simple branched acinar Most sebaceous glands  
  Compound glands Compound tubular Brunner’s glands (duodenum)  
Compound acinar Pancreatic acini  
Compound tubuloacinar Submandibular salivary gland  
NOTE: The 6th edition Ross textbook has the drawings of simple coiled tubular and
simple branched tubular glands reversed in Table 5.6 on p. 149. The 7th edition has
corrected this in Table 5.5 on page 145.

Classification based on method of secretion:

Merocrine secretion:
Only the secretory material is released from the cell; no other portion of the cell
is lost with the secretion
Typically involves secretory material that is contained within a vacuole in the
cell cytoplasm
Vacuolar membrane fuses with the plasma membrane to release the secretion A
very common method of secretion; also found in endocrine glands that
secrete proteins

Apocrine secretion:
Some other part of the cell is lost along with the secretory material A
rare form of secretion
The lipid portion of milk is secreted in an apocrine fashion by the lactating
mammary gland
The lipid droplets are not contained within vacuoles in the cell cytoplasm
The droplet buds through the plasma membrane, taking a portion of the
membrane and a thin rim of cytoplasm with it when it is secreted

Holocrine secretion
The entire cell is shed and usually breaks down to becomes the secretion Rare
Example: Sebaceous glands
NOTE: This system of classification is not usually applied to endocrine glands for
two reasons:
1.   There are no apocrine or holocrine endocrine glands in humans
2.   Some endocrine glands secrete by direct transport of their product across the
plasma membrane (e.g., steroid and thyroid hormones), so they are not really
merocrine in nature either.

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EPITHELIUM & GLANDS MEDICAL MICROANATOMY
 

Classification based on secretory cell morphology

Serous cells
Generally have a relatively round nucleus
The contents of their secretory vacuoles are usually not extracted during
tissue preparation; therefore the apical end of their cytoplasm is fairly
dark staining
The high concentration of proteins in their secretory granules may make their
apical end more eosinophilic than their basal end (rich in RER)
They secrete a watery fluid rich in ions and glycoproteins, which often include
enzymes (e.g., in salivary glands)

Mucous cells
Usually contain so many secretory vacuoles that they flatten the nucleus at the
basal end of the cell
Secrete glycoproteins called mucinogens, which combine with water after
secretion to become highly viscous mucins, which are the main protein
components of mucus
Mucinogens are highly water-soluble and are therefore often extracted during
tissue preparation, leaving the cells with very pale cytoplasm
NOTE: The word “mucous” is an adjective describing the cells that produce
“mucus”

Mucous, serous and mixed mucoserous glands


An individual gland can be:
Pure serous (e.g., parotid salivary gland)
Pure mucous (e.g., Brunner’s glands of the duodenum)
Mixed mucoserous (e.g., submandibular salivary gland)
In mixed glands, an individual secretory unit may contain only mucous cells,
only serous cells, or a combination of both
In a secretory acinus that contains both cell types, the serous cells are
sometimes arranged as serous demilunes
Demilunes are groups of serous cells shaped like a half-moon (“demilune”)
Are attached like a cap to the free end of a mucous secretory unit Common
in glands where mucous cells greatly outnumber serous cells

The three major salivary glands can be distinguished from one another based on
their relative content of serous vs. mucous cells

The parotid glands


Are considered pure serous

The submandibular glands


Are mixed mucoserous, with serous cells outnumbering mucous
The serous cells are organized as pure serous demilunes acini as well as
occasional serous demilunes on a mucous secretory unit
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EPITHELIUM & GLANDS MEDICAL MICROANATOMY
 

The sublingual glands


Are mixed mucoserous, with mucous cells greatly predominating
The serous cells are organized mainly as serous demilunes rather than
pure serous acini because there are so few of them

XI.  LOBES VS. LOBULES


Lobes:
A lobe is a clear anatomical subdivision of an organ that is visible to the naked eye,
i.e., without the use of a microscope
Not all glands have lobes
Lobes are found in some endocrine glands (thyroid) and some exocrine (liver)
Lobules:
A lobule is only clearly visible at the microscopic level
Lobules are separated from one another by sheets (septa) of CT
In compound exocrine glands each lobule is drained by a branch of the duct system
Simple glands (e.g., sweat glands) have no lobules

XII.  MORPHOLOGY OF DUCTS All


ducts DO NOT look the same
Some stain lighter than the secretory cells of the gland; some stain darker
In most simple glands, the ducts generally have the same morphology all along their
length, e.g., sweat glands
In large compound glands (e.g., salivary glands, pancreas), duct morphology
changes as the ducts merge & increase in size

General plan of a compound gland duct system

The smallest ducts are called intercalated ducts


Receive the secretory product directly from the secretory unit
Have a simple low cuboidal epithelium (i.e., cells are intermediate in height between
simple squamous and simple cuboidal)
Are located within a lobule and are therefore a type of intralobular duct

Intercalated ducts merge to form larger intralobular ducts that have a simple cuboidal
to columnar epithelium

These larger intralobular ducts merge into a single duct that leaves the lobule and
becomes an interlobular duct
Interlobular ducts run in the CT septa between lobules
As they merge to form larger interlobular ducts, the epithelium changes
The types of epithelium that may be present at different points along the duct
include simple cuboidal, simple columnar, stratified cuboidal, stratified
columnar, and minimally keratinized stratified squamous

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By definition:
Intralobular ducts (of all kinds) are directly surrounded by the secretory units of the
lobule,
Interlobular ducts are located in the CT septa between lobules, and are thus directly
surrounded by the CT rather than by secretory units
The septa also contain the larger blood vessels that supply the gland

Striated ducts
Some ducts modify the composition of the secretion as it passes through them by
actively transporting materials (e.g., ions) into or out of the duct lumen
The epithelial cells of such ducts may have basal striations caused by mitochondria
that line up in rows within folds of the basal plasma membrane
Such ducts are called striated ducts
The membrane folding increases the surface area available for active transport. The
mitochondria provide ATP for active transport
The rows of mitochondria appear as eosinophilic cytoplasmic stripes (striations)
oriented perpendicular to the basal plasma membrane
All three major salivary glands have striated ducts; pancreas does not
Striated ducts are usually found within lobules rather than between them, i.e., are
usually intralobular ducts

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Bruce Elliot Hirsch, Ph.D Medical Microanatomy
 

CONNECTIVE TISSUE
Required Reading: Ross and Pawlina, Chapters 6 and 9
Wheater, Chapter 4
Recommended Reading: Alberts, pp. 1164-1195

OBJECTIVES
1.   Understand the basic composition of connective tissues and their different roles.
2.   Know the cells and structures responsible for the production, maintenance, nutrition, and
regeneration of connective tissues.
3.   Know the composition of the extracellular matrix of connective tissues.
4.   Know the major forms of collagen and where they are found in the body.
5.   Understand how connective tissue responds in inflammation.

I.   DEFINITIONS AND GENERAL DESCRIPTION


A.   Connective tissue (abbreviated as CT) is one of the four tissue types
B.   Connective tissue has relatively few cells in an extracellular matrix (ECM) formed of
fluid, ground substance, and fibers of various types.
C.   There are two types of connective tissues found in embryos
1.   Mesenchyme is a pluripotential precursor to the various adult connective tissues,
giving rise to connective tissue proper and specialized connective tissue.
a.   It is derived mainly from mesoderm, but some develops from neural crest tissue
b.   Mesenchyme consists of stellate pluripotential cells, reticular fibers, and ground
substance.
2.   Mucous connective tissue is found only in the umbilical cord (Wharton’s jelly) and
parts of the embryo in humans.
a.   It contains few fibers (collagen Types I and III) in a soft jelly-like matrix.
b.   The fibroblasts are large and stellate.
D.   There are several varieties of adult connective tissue proper, discussed in detail later:
1.   Loose connective tissue.
2.   Dense irregular connective tissue.
3.   Dense regular connective tissue.
4.   Dense elastic connective tissue.
E.   There are several types of specialized connective tissues (covered later in this course):
1.   Adipose tissue
a.   Often considered a type of loose CT, rather than a specialized form
2.   Blood
3.   Bone
4.   Cartilage
5.   Hematopoietic tissue
6.   Lymphatic tiss
CONNECTIVE TISSUE MEDICAL MICROANATOMY
   

7.   These tissues are considered to be connective tissues because:


a.   The proportion of matrix to cells is very high (except in adipose tissue).
b.   Some of their cells are derived from or are related to the cells of connective
tissue proper, or move in and out of the blood into forms of connective tissue.
F.   The connective tissue proper serves a number of functions, including:
1.   Structural support
2.   Medium for exchange of nutrients, metabolic wastes, gases, ions, hormones, and
other substances.
3.   Defense and protection. CT is a major site of immune and inflammatory reactions.
4.   Storage of energy reserves in adipose cells.
5.   Store potential energy during motion.
6.   Thermal regulation through subcutaneous fat.
7.   Controlling motion among body parts.
8.   It forms the pathways through which nerves and blood vessels travel.

II.   EXTRACELLULAR MATRIX


A.   The extracellular matrix (ECM) has two types of components: fibers and ground
substance.
1.   The most common form of fiber is collagen.
a.   Collagen provides a tissue with high tensile strength.
b.   Collagen is present in at least 29 known types.
(1)   Each type of collagen has a particular distribution.
(2)   The basic collagen molecule is called tropocollagen.
(3)   Each type of tropocollagen molecule consists of three polypeptide chains,
known as á-chains, wrapped together in a helix.
(4)   The á-chains are encoded by more than 30 different genes.
(5)   The types of á-chains forming the tropocollagen molecule determine the
type of collagen formed.
(6)   Every third amino acid is glycine, and the rest are mainly proline,
hydroxyproline, and hydroxylysine.
c.   Collagen molecules (tropocollagen) aggregate into long fibrils.
(1)   When properly stained and examined by electron microscopy, the fibril in
most types of collagen has a repeated, ~ 68 nm periodic banding pattern.
(a)   The banding pattern results from the way the tropocollagen molecules
are linked end-to-end and side-by-side to form the fibrils.
(b)   An exception is Type IV collagen, which forms a mat of procollagen
molecules rather than banded fibrils.
(2)   The fibrils may further aggregate into larger structures called fibers and
bundles.
(a)   These bundles are often visible by light microscopy.
d.   Certain types of collagen are the most common.
(1)   Type I collagen is the major collagen of dermis, ligament, tendon, organ
capsules, bone, cornea, fibrocartilage, and teeth.

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CONNECTIVE TISSUE MEDICAL MICROANATOMY
   
(a)   In connective tissue proper it is produced by fibroblasts.
(b)   It makes up about 90% of the collagen and about 30% of the protein in
the body.
(c)   It stains pink with H&E (acidophilic), but blue to green in most
connective tissue (trichrome or Azan) stains.
(d)   It occurs in banded fibrils 20–100 nm in diameter, which combine into
much larger fibers.
(2)   Type II collagen is found in hyaline and elastic cartilage, in the nucleus
pulposus of intervertebral disks and in the vitreous body of the eye.
(a)   In cartilage, it is produced by chondrocytes.
(b)   It is present mainly as thin banded fibrils rather than as fibers.
(3)   Type III collagen makes up reticular fibers.
(a)   The 50 nm banded fibrils form thin fibers only 0.5–2nm in diameter,
which form a delicate network.
(b)   Because the fibers are so thin they do not stain like collagen with most
stains, and in the past were thought to be an entirely different material.
(c)   It is highly glycosylated, and therefore it is PAS positive and adsorbs
metallic silver when treated with certain procedures (argyrophilic).
(d)   It is produced by fibroblasts in loose connective tissue, and in other
locations by reticular cells, smooth muscle cells, hepatocytes, or
Schwann cells.
(e)   Reticular fibers make up the stroma of many soft organs such as liver.
(4)   Type IV collagen makes up the lamina densa of the basal lamina.
(a)   The propeptides are not removed from the procollagen molecules,
preventing their aggregation into fibrils.
(b)   The procollagen molecules form a mat.
(5)   Type VII collagen is located in the lamina reticularis, which marks the
connection between the basal lamina of an epithelium & the underlying CT.
(a)   It forms anchoring fibrils, bound to the lamina densa and forming
loops that wrap around the Type I and Type III fibrils of the CT.
2.   Elastic fibers can be stretched to about 150% of their resting length without
breaking, and return to their original length when released.
a.   Their form varies in different locations.
(1)   In loose CT they are long and slender, forming branching networks.
(2)   In elastic ligaments (ligamenta flava) they form coarse bundles 4–5 microns
in diameter.
(3)   In the tunica media of large arteries the elastic fibers form fenestrated
(having holes) sheets.
b.   Elastic fibers contain a core of the protein elastin, surrounded by microfibrils of
the glycoprotein fibrillin.
(1)   Most of the same cells that produce collagen also produce elastic fibers.
c.   Elastic fibers do not take ordinary histological stains well.
(1)   Unstained elastic fibers and sheets, if thick enough, are refractile (i.e., they
look light and shiny).
(2)   Special stains, such as resorcin-fuchsin, aldehyde-fuchsin, and Verhoeff’s

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CONNECTIVE TISSUE MEDICAL MICROANATOMY
   
picro-ponceau color elastin.
3.   Ground substance is a hydrated mixture of glycosaminoglycans (GAGs),
proteoglycans, and glycoproteins.
a.   Most GAGs are linked to proteins to form proteoglycans.
(1)   GAGs are long, unbranched polysaccharides composed of a disaccharide
repeat unit.
(2)   Except for hyaluronic acid (hyaluronan), GAGs consist of fewer than 300
repeating disaccharide units (hyaluronic acid may have as many as 25,000)
(3)   Except for hyaluronic acid, GAGs are usually covalently bound to a core
protein, to form a proteoglycan.
(a)   Depending on the particular proteoglycan, anywhere from one to
several hundred GAGs may be bound to the core protein.
(b)   In proteoglycans with many GAG side chains, the resulting
proteoglycan resembles a test tube brush.
(c)   Because of their carboxyl and sulfate groups, proteoglycans are highly
negatively charged. Tissues rich in proteoglycans (e.g., cartilage
matrix) are therefore highly basophilic if the proteoglycans have been
adequately preserved during fixation.
b.   Proteoglycans perform many roles.
(1)   They act as filters to control the passage of macromolecules.
(2)   Their high negative charge attracts water, making the ECM viscous & gel-like
(3)   They bind to collagen thus cross-linking components of the ECM
(4)   They bind signaling molecules, thus controlling their availability for other
functions.
(5)   The core protein of some proteoglycans is a transmembrane protein in the
plasma membrane. The proteoglycans help anchor the cell to the matrix.
c.   In some tissues such as cartilage, proteoglycans may attach to hyaluronic acid,
forming a very large complex called a proteoglycan aggregate.

Hyaluronic acid (hyaluranon)

GAG side chain


Core protein

A PROTEOGLYCAN
AGGREGATE

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CONNECTIVE TISSUE MEDICAL MICROANATOMY
   
(1)   The noncovalent attachment of the proteoglycans to the hyaluronic acid
backbone is reinforced by small link proteins.
(2)   These aggregates are intermeshed, making a gel of the ground substance.
(a)   A gel, where the flow of water is restricted, resists compressive forces.
d.   Adhesive glycoproteins bind components of connective tissues to one another
(e.g., cell membranes to components of the ECM, or components of the ECM to
one another).
(1)   Each molecule has several binding domains, which are bound to:
(a)   Integrins, transmembrane proteins linked intracellularly to the
cytoskeleton
(b)   Collagen fibers
(c)   Proteoglycans
(2)   Adhesive glycoproteins include:
(a)   Fibronectin is produced mainly by fibroblasts.
i)   It is also present in blood as plasma fibronectin.
ii)   One function is to mark the path for cell migration in embryos.
(b)   Laminin is localized mainly to the lamina lucida of the basal lamina.
(c)   Chondronectin and osteonectin, whose names indicate where they are
found.

III.   CELLS
A.   The cells of connective tissue fall into two groups:
1.   Fixed cells, which either arise in situ or migrate to the CT, and are resident there for
long periods of time. These include fibroblasts, myofibroblasts, macrophages,
adipocytes, mast cells, and adult stem cells
a.   Fibroblasts are the most common of the CT cells.
(1)   They are responsible for the synthesis of almost all of the components of
the extracellular matrix
(a)   Exception: In the smooth muscle layer of blood vessels, smooth muscle
cells rather than fibroblasts produce many of these same products.
(2)   Active fibroblasts are spindle shaped (long, tapering at both ends), have
slightly basophilic cytoplasm, and have an ovoid nucleus.
(a)   Electron microscopy shows much RER and a large Golgi apparatus.
(3)   Inactive fibroblasts (sometimes called fibrocytes) have less RER and are
therefore less basophilic than active fibroblasts.
(a)   With H&E staining the cytoplasm is pink, and may be hard to
differentiate from surrounding collagen fibers
b.   Myofibroblasts appear very similar to fibroblasts in light microscopy.
(1)   EM reveals both fibroblast- like and smooth muscle-like features.
(a)   The cells have RER and Golgi apparatus like a fibroblast.
(b)   They lack a basement membrane, like a fibroblast.
(c)   They contain actin filaments & dense bodies, like smooth muscle cells.
(d)   These cells become more prominent in wound healing.
(e)   They produce substances involved in tissue development and the
inflammatory response, as well as the usual products of fibroblasts.

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CONNECTIVE TISSUE MEDICAL MICROANATOMY
   
c.   Adipose cells store fat.
(1)   They vary in size, depending on the amount of fat stored at any given time.
(2)   They are located in loose connective tissue.
(3)   They can occur singly, in clumps of varying size, or in large quantities (in a
form of loose CT called adipose tissue).
(4)   Fat is usually not visible in standard light microscope slides, because it is
dissolved out of the tissue during preparation.
(5)   Most fat cells are unilocular adipocytes.
(a)   They are present in white adipose tissue (actually yellowish in color).
(b)   Each cell contains one major lipid droplet, located centrally.
(c)   The cytoplasm and nuclei are pushed to the periphery of the cell.
(d)   In sections that include the nucleus, the fat cell has a “signet ring”
appearance.
(e)   Immature unilocular adipocytes initially have several small lipid
droplets, which gradually fuse into a single large droplet.
(6)   Multilocular adipocytes contain many small lipid droplets even when mature.
(a)   Aggregates of multilocular adipose cells form brown fat.
i)   Brown fat is organized into lobules, which gives it a more
glandular appearance than white fat.
ii)   Brown fat is more vascular than white fat, with many capillaries.
iii)   The name “brown fat” comes from the tan color of fresh tissue,
caused by the blood in the capillaries and the cytochromes in the
mitochondria.
(b)   The predominant feature of multilocular adipocytes is an abundance of
mitochondria.
i)   In these mitochondria, uncoupling protein-1 (UCP-1, also called
thermogenin) uncouples the electron transport chain from
phosphorylation, releasing energy as heat rather than as ATP.
ii)   Recent research indicates that brown fat is more active in people
with low BMI, and under cold conditions.
(7)   White fat and brown fat are both derived from mesenchyme, but
surprisingly, brown fat is more closely related to skeletal muscle (also
derived from mesenchyme) than to white fat.
d.   Macrophages, which are related to monocytes, may be either fixed (resident) or
transient (elicited).
(1)   The mononuclear phagocyte system (MPS) consists of blood monocytes and
phagocytic cells derived from them, which can be found in CT and in
various other organs. These phagocytic cells include:
(a)   Histiocytes in ordinary connective tissue
(b)   Kupffer cells in the liver
(c)   Dust cells, or alveolar macrophages in the lungs
(d)   Osteoclasts in bone
(e)   Langerhans cells of the epidermis
(f)   Microglia in the brain
(g)   These various cells are all considered to represent different forms
derived from the same precursor cell, depending on location.
 

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CONNECTIVE TISSUE MEDICAL MICROANATOMY
   
(2)   Macrophages are large, irregularly shaped cells.
(3)   They have a number of functions, many of which will be discussed further,
later in the course.
(a)   Their primary function is phagocytosis of debris and foreign invaders,
and their intracellular breakdown.
(b)   Macrophages are also involved in the immune response, for example,
by presenting antigens to lymphocytes to help activate them.
(c)   They produce many of the cytokines that enhance inflammatory and
immune responses.
(d)   They phagocytize old red blood cells, primarily in the spleen, and
recycle components such as iron.
(e)   They play a role in the development of red blood cells, as part of cell
clusters in the marrow called erythroblastic islets.
(f)   They produce enzymes (collagenase, elastase) important in the turnover
of extracellular matrix components.
(4)   When the amount of foreign debris to be eliminated is large, macrophages
may fuse to form multinuclear foreign body giant cells.
e.   Mast cells contain secretory granules of histamine, heparin, and other substances
involved in the inflammatory response.
(a)   Mast cell granules exhibit metachromasia with toluidine blue and
related stains.
(b)   Although mast cells resemble basophils, a type of white blood cell, and
produce similar products they are different cells; however, they both
are derived from hematopoietic stem cells.
(c)   Sensitized mast cells become “activated” when exposed a second time
to the sensitizing antigen.
i)   Upon first exposure to an antigen, IgE is bound to receptors on the
mast cell plasmalemma, sensitizing the cell.
ii)   A second exposure to the same antigen results in:
a)   The secretion of the mast cell granule content.
b)   Synthesis and release of compounds such as leukotrienes.
iii)   The effects of activation include increased vascular permeability,
bronchial smooth muscle contraction, increased secretion of
mucus, attraction of eosinophils and neutrophils, and other
inflammatory responses.
iv)   Reactions mediated by activated mast cells and basophils include:
a)   Hay fever (allergic rhinitis) is a local response to activation in
the nasal mucosa, which causes increased vascular
permeability (edema and stuffiness) and secretion of the nasal
mucous glands.
b)   Asthma is bronchospasm caused by the contraction of airway
smooth muscle.
c)   Anaphylaxis is the sometimes fatal result of a generalized
systemic degranulation of mast cells and basophils, which
causes airway edema, bronchospasm, and hypovolemic shock.

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CONNECTIVE TISSUE MEDICAL MICROANATOMY
   
2.   Transient cells migrate into and out of the connective tissue.
a.   Plasma cells are large ovoid cells derived from B lymphocytes, and manufacture
antibodies.
(1)   They have basophilic cytoplasm, except for a pale area near the
eccentrically placed nucleus.
(2)   The basophilia represents regions of well developed RER, and the clear
area is the site of the large Golgi apparatus.
b.   Leukocytes pass through the capillary walls by migrating between endothelial
cells (diapedesis) into the connective tissue.
(1)   They include neutrophils, eosinophils, basophils, lymphocytes, and
monocytes.
c.   The number of macrophages can fluctuate widely due to migration of
monocytes from the blood in response to specific stimuli. These monocytes
differentiate into transient macrophages, whose numbers decrease as the
intensity of stimulus wanes.

IV.   TYPES OF CONNECTIVE TISSUE


A.   Loose connective tissue (areolar connective tissue) has abundant ground substance,
relatively few fibers, and a variety of scattered cell types.
a.   Locations of loose connective tissue include the more superficial layer of the
dermis (papillary layer), the superficial fascia, underlying the mesothelial cells
of body cavities, in mucous membranes (which line moist internal surfaces), and
surrounding blood vessels and peripheral nerves.
b.   There are a number of specialized forms of loose connective tissue.
(1)   Lamina propria is located just deep to the epithelium and basement
membrane of a mucous membrane (e.g., in intestine, trachea)
(a)   In many organs the lamina propria is so highly cellular that it is difficult
to see any components of the ECM between the cells. Such a lamina
propria is said to be composed of loose cellular CT.
(2)   Adipose tissue is composed predominantly of fat cells.
(a)   White adipose tissue is located in many different places, where it has
many functions including serving as:
i)   Insulation (superficial fascia)
ii)   A storage site for reserve energy sources
iii)   A deformable packing material (synovial joints, orbit)
iv)   A cushion (heel, buttock)
v)   A compliant support for an organ (perirenal fat)
(b)   The amount of fat in storage changes with nutritional status and activity.
i)   Some fat, such as the subepicardial fat pads, remain even in
starvation.
(c)   White adipose tissue has been shown to actively produce hormones and
other substances involved with appetite and the regulation of body
weight, and also other metabolic pathways.

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CONNECTIVE TISSUE MEDICAL MICROANATOMY
   
(d)   In humans, brown fat is more abundant in the fetus and young children.
i)   It persists in adults, but is typically found in a few places such as
the neck, interscapular region, and adjacent to the heart and major
blood vessels such as the aorta.
(3)   Reticular tissue.
(a)   The main form of collagen is reticular fibers (composed of collagen
type III)
(b)   The collagen forms slender fibers that can be easily seen by light
microscopy only with special stains (e.g., silver stains, PAS).
(c)   It makes up most of the stroma in lymphoid organs (except the
thymus), liver, adipose tissue, and islets of Langerhans.
(4)   Mucous connective tissue.
(a)   In humans it is found only in the umbilical cord (Wharton’s jelly) and
parts of the embryo.
(b)   It contains few fibers (collagen Types I and III) in a soft jelly-like
matrix that is rich in proteoglycans.
(c)   The fibroblasts are large and stellate.
2.   Dense irregular connective tissue has many collagen bundles running in different
unpredictable directions.
a.   There is proportionately less ground substance and more fibrous collagen than
in loose connective tissue, and fewer cells.
b.   Fibers are arranged irregularly so that the tissue can respond to stresses acting
on it from many different directions.
c.   Locations of dense irregular CT include the deeper layer of the dermis (reticular
layer), the capsules of organs, and the sheaths of tendons and nerves.
3.   Dense regular connective tissue is characterized by groups of parallel bundles of
collagen fibers, as in tendons and ligaments.
a.   It is similar in composition to dense irregular connective tissue but the fibers are
more regularly oriented.
b.   While bundles are parallel to each other within a given layer, the bundles in
different layers or regions may take different directions.
(1)   In some tissues (e.g., cornea) the fibers are in layers and are parallel within
each layer, although in different layers they run in different directions
c.   Dense regular connective tissue forms tendons, ligaments, aponeuroses, and the
stroma of the cornea.
4.   Dense regular elastic tissue has relatively little collagen and large amounts of
elastin. The elastic fibers can be arranged in:
a.   Coarse bundles as in the ligamenta flava, stylohyoid ligament, suspensory
ligament of the penis.
b.   Fenestrated sheets of elastic tissue as in the tunica media of large arteries.

V.   CLINICAL ASPECTS
A.   Inflammation is the response to damage or to invasion by foreign substances or cells. It
often occurs in connective tissue.
1.   It is characterized by pain, heat, redness, and swelling.

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CONNECTIVE TISSUE MEDICAL MICROANATOMY
   
a.   In the classical Latin description, the four signs are: dolor, calor, rubor, tumor.
b.   these signs are all due to increased vascular permeability resulting from the
release of histamine and other mediators from mast cells and basophils.
c.   Neutrophils, followed in a day or so by monocytes, are attracted to the area,
where they phagocytose bacteria and debris.
B.   Wound healing involves the interaction of many types of connective tissue cells
including:
1.   Neutrophils, monocytes and macrophages in the early inflammatory stages.
2.   Myofibroblasts, which contract to draw the edges of the wound closer together.
3.   Fibroblasts, which lay down scar tissue.
C.   Scurvy is vitamin C deficiency.
1.   Vitamin C is needed for the conversion of proline and lysine to their hydroxylated
forms, which are important for the formation of stable collagen.
2.   It is characterized by poor wound healing, tooth loss, and reopening of old wounds.
3.   Scurvy can be prevented and cured by fruits and vegetables that contain vitamin C,
such as citrus fruits and cabbage.
D.   Ehlers-Danlos syndrome refers to a group of heritable connective tissue disorders.
1.   One form results from a mutation in lysyl hydroxylase, which results in decreased
numbers of tropocollagen crosslinks that normally contribute to tensile strength.
2.   Symptoms include joint laxity, skin extensibility, and tissue fragility.
3.   The most clinically important form (vascular EDS or type IV EDS) is due to mutations
affecting the amino acid sequence of collagen type III. It results in weak blood
vessels that are prone to rupture.
E.   Marfan’s syndrome results from a defect in the gene coding for fibrillin.
1.   Elastic fibers are abnormal.
2.   The major systems affected are the musculoskeletal, ocular, and cardiovascular.
3.   The most serious consequence results from abnormalities in the heart and large
vessels, sometimes leading to death from heart failure or aneurysm.

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