Introduction to Connective Tissue
Steve Schettler, PhD
Elena Stark MD, PhD
Department of Pathology & Laboratory Medicine
David Geffen School of Medicine at UCLA
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Non-graphic content and organization Copyright 2012 S.P. Schettler.
1
Connective Tissue
• Terms: collagen, ground substance,
dense regular connective tissue, areolar
tissue, reticular fibers, elastic fibers,
stroma, parenchyma
• Cells: fibroblast
• Disorders: Scurvy, Ehlers-Danlos
Types of Connective Tissue
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Much of the tissue mass that we will encounter in histology is connective tissue.
While we might have a passing familiarity with what is known as fibrous connective tissue,
other types of tissues in the body are also considered connective tissue such as blood, bone,
cartilage and fat (or adipose) tissue.
The common element of connective tissue is that they tend to have a low cell:matrix ratio
relative to other tissues.
Broadly, connective tissue consists of cells that reside in a matrix (the non-cellular
materials that surround cells).
blood
bone
cartilage
adipose
Connective Tissue: Dermis
In this module we will focus on fibrous connective
tissue and its appearance, functions, and composition.
So far we have only examined
epithelial tissues. If we look at an
example of an epithelium such as
skin, we know that deep to the
epithelium lies the basement
membrane (which is a connective
tissue structure), and a
compartment under the epidermis
known as the dermis.
The dermis is a connective tissue
layer, and we will begin our
discussion of this tissue type here.
Epidermis
Dermis
Skin, stained with H&E. The location of the
basement membrane is indicated by the
blue line.
Connective Tissue: Dermis
The epidermis has a high density of
cells and a low abundance of
extracellular matrix (ECM) as is
typical of an epithelium. By contrast,
the dermis has a lower density of
cells but a higher abundance of
ECM. This is typical of most
connective tissues.
Within the dermis are scattered cells;
many of these are the cells that
secrete the ECM: these cells are
called fibroblasts.
The ECM is comprised of collagen
fibers and something called ground
substance.
Epidermis
Epidermis image
Dermis
Dermis, stained with H&E.
Connective Tissue: Fibroblasts
Fibroblasts.
We can appreciate fibroblasts by the
fusiform appearance (shaped like a
spindle or a football) of their soma
and especially their nucleus.
A few fibroblasts have been
indicated in the image with green
circles, and the small image inset
shows several fibroblasts at high
power.
Epidermis
Epidermis image
Dermis
Dermis, stained with H&E.
Fibroblasts that are in a resting state
tend to have a flattened appearance,
while those that are actively
secreting collagen will assume more
of an elliptical shape.
Connective Tissue: ECM:
Collagen
The ECM.
The eosinophilic, fibrous material that
occupies much of the dermis is a
fibrillar protein known as collagen.
Collagen is the most abundant protein
in the body (up to 30% of the dry
weight of a human), and adopts fibrillar
or sheet-like arrangements. Indeed,
collagen provides strength, rigidity, and
elasticity for connective tissues across
the body.
Epidermis
Epidermis image
Dermis
Dermis, stained with H&E.
In the case of the dermis, most of the
collagen fibers will be of the type I
variety. Present to a lesser degree in
the dermis is type III collagen (see
Ehler’s-Danlos later in this module).
Connective Tissue: ECM:
Collagen
Collagen Types mentioned in this
course:
•Type I collagen – most common
(skin, bone, tendon)
Epidermis
Epidermis image
•Type II collagen – provides
compression resistance to cartilage
•Type III collagen – associated with
type I fibrils, forms reticular fibers
(See Ehler’s – Danlos discussion in
the section: Collagen Disorders)
•Type IV collagen – basement
membrane (forms networks or
sheets instead of fibrils)
Dermis
Dermis, stained with H&E.
Connective Tissue: ECM:
Ground Substance
Besides collagen, the other primary
constituent of the ECM is something
called ground substance.
Epidermis
For our purposes, we can assume
that the white spaces between
collagen fibers are filled with ground
substance.
Ground substance has three primary
components: the first two are
proteoglycans and
glycosaminoglycans (or GAGs).
These molecules absorb a large
amount of water and form a gel,
which serves as a reservoir for
nutrients and for cell waste products.
Epidermis image
Dermis
Dermis, stained with H&E.
Connective Tissue: ECM:
Ground Substance
The third component of ground
substance is a class of molecules
known as multiadhesive
glycoproteins. These provide
binding sites for cells and collagen,
and serve as a substrate for cell
migration and adhesion to the ECM.
Examples of these molecules include
fibronectin and laminin.
Epidermis
Epidermis image
Dermis
In addition functioning as an
extracellular reservoir, ground
substance provides turgidity and
mechanical shock absorption.
Dermis, stained with H&E.
Extracellular Matrix: Collagen:
Reticular fibers
Type III collagen forms tiny branched
structures known as reticular fibers.
Some organs have an architecture
that is predominantly composed of
reticular fibers. This type of
arrangement results in an organ with
an open-type of circulation;
examples of this include the liver,
spleen and lymph nodes, and also
bone marrow.
Organs like these tend to be highly
cellular and have a spongy
consistency.
Lymph node prepared with a silver stain. Notice the black
branched-like appearance of the reticular fibers that are
stained in this image. The cells in the lymph node have
not been stained and are not visible as a result.
Extracellular Matrix: Collagen:
Reticular fibers
Note that reticular fibers are also
commonly encountered alongside
type I collagen fibers, and even
elastic fibers, which we will describe
next.
We will briefly revisit reticular fibers
in Block II when we examine the
liver.
Lymph node prepared with a silver stain. Notice the black
branched-like appearance of the reticular fibers that are
stained in this image. The cells in the lymph node have
not been stained and are not visible as a result.
Extracellular Matrix: Elastic fibers
In addition to fibrillar collagen, some
tissues will have elastic fibers that
are comprised of a protein called
elastin.
Like the name suggests, elastic
fibers are able to stretch and they
can withstand a stretch of
approximately 1.5x their normal
length without breaking.
Elastic fibers are encountered in
skin, arteries, veins, lung tissue, and
some types of cartilage, to name a
few examples.
Skin stained for elastic fibers using Verhoeff’s preparation.
The fine horizontal black lines are the elastic fibers.
Collagen Disorders
Scurvy
– Vitamin C (ascorbic acid) is an essential nutrient for efficient assembly of
collagen fibrils. Humans are on a rather short list of animals that are unable to
synthesize this nutrient, and so must obtain it from dietary sources. A deficiency
in vitamin C impairs collagen formation by at least two mechanisms: First,
vitamin C is required for efficient hydroxylation of procollagen, the precursor
molecule for collagen. In the absence of normal hydroxylation, the procollagen is
inhibited from adopting its final helical shape, as a result, it is more easily
degraded by enzymes and is inefficiently secreted by fibroblasts. Secondly, the
rate at which procollagen is synthesized is inhibited. As a result, wounds heal
very poorly and the skin and gums bleed readily.
Ehlers-Danlos
– A range of genetic disorders that result from various mutations affecting one or
more aspects of transcription, assembly, or modification of collagen, particularly
type III collagen. Patients will commonly have very stretchable skin,
hypermobile joints, poorly healing wounds with abnormal scarring, and a greatly
increased risk of aneurism or rupture of the colon. One experimental mouse
model of this disorder provides evidence that disruption of normal type III
collagen function disrupts the formation and assembly of type I collagen fibrils.
Liu et al. 1997. PNAS. Type III collagen is crucial for collagen I
fibrillogenesis and for normal cardiovascular development.
Connective Tissue: Adipose
Deep to the dermis is another layer
of connective tissue that is
composed of adipose (or fat) tissue;
we know this layer as the
hypodermis or subcutis.
Dermis
Adipose tissue serves several
functions that include the storage of
energy in the form of lipid, providing
insulation, providing shape to the
body, and as a space-filling tissue
and shock absorber.
Hypodermis
In addition to these properties,
adipose tissue is an endocrine organ
that plays a role in regulating the
body’s metabolism.
Hypodermis image
Hypodermis, stained with H&E.
Connective Tissue: Adipose
The appearance of white adipose
Dermis
tissue, as that pictured here, features
few apparent nuclei, and abundant
‘open space’. The open spaces
correspond to lipid droplets that
Hypodermis image
occupy much of the volume of a
Hypodermis
single adipocyte.
The reason that the adipocytes
appear ‘empty’ is that during
histological preparation, sections
undergo a defatting step that
removes most of the lipids from the
tissue. This step is necessary to
perform since H&E are water soluble
stains.
Hypodermis, stained with H&E.
Describing Connective Tissue
Classifying connective tissue:
Generally speaking, fibrous
connective tissue is described in
terms of its density and its regularity.
Density refers to how tightly packed
the collagen fibers are, while
regularity refers to how well the
fibers are arranged in a single
direction.
The fibers that make up a highly
regular tissue are only arranged in a
single direction, and tend not to be
“wavy”. More irregular connective
tissue will have a “relaxed” or
“messy” appearance.
Tendon, stained with H&E. The elongated nuclei belong
to fibroblasts. Note the tightly packed and high
directional arrangement of this tissue.
Describing Connective Tissue
On one end of the spectrum, we
have tendon (the strong connective
tissue that connects skeletal muscle
to bone). Tendon is described as a
dense, regular connective tissue,
and is indeed the densest and most
regular fibrous connective tissue we
will ever encounter.
As a result of this organization,
tendon is maximally strong and
resistant to deformation in the
direction that the collagen fibers are
arranged. As you might have
guessed, this is also the direction by
which muscular force is applied to
the tendon.
Tendon, stained with H&E. The elongated nuclei belong
to fibroblasts. Note the tightly packed and high
directional arrangement of this tissue.
Describing Connective Tissue
As a general rule, as the density of
connective tissues increases, fewer
vascular and lymphatic structures
will typically be encountered there.
Indeed, the tendon pictured here has
no vascularization visible within its
substance.
However, in order to provide the
fibroblasts the nutrients they require,
vessels are located outside the
tendon, in a connective tissue sheath
that is still highly regular, but is less
dense than the tendon.
Tendon, stained with H&E. The elongated nuclei belong
to fibroblasts. Note the tightly packed and high
directional arrangement of this tissue.
Describing Connective Tissue
On the other end of the spectrum is
loose irregular connective tissue,
(also known as areolar connective
tissue).
lumen
The low density, or looseness, and
irregularity means that this tissue is
not particularly strong or resistant to
deformation in one particular
direction.
The looseness quality means that a
great deal of water can be present in
this tissue and as such, this tissue
can be compressed and expanded
without suffering permanent
structural damage.
Areolar connective tissue stained with H&E. This
section was taken from a bronchus. Note the loose
and wavy appearance of the collagen fibers in the
submucosa.
Describing Connective Tissue
Looseness creates a permissive
environment for immune cells to
traverse the tissue compartment,
and also supports abundant vascular
and lymphatic structures.
Note that there is a certain degree of
ambiguity in describing dense
irregular and loose regular
connective tissues as they can look
very similar.
As a result, they are often
adequately referred to simply in
terms of density or looseness, which
implies that the regularity is not
easily described.
lumen
Areolar connective tissue stained with H&E. This
section was taken from a bronchus. Note the loose
and wavy appearance of the collagen fibers in the
submucosa.
Stroma and Parenchyma
These terms will be utilized throughout the histopathology course.
Connective tissue can often be described as making up the stroma of an
organ; the supporting infrastructure. Stroma can be contrasted with
parenchyma: the cells that conduct the ‘specific business’ of an organ.
Here is a crude example: the hepatocytes of the liver (the cells that perform
the liver-specific function of removing toxic chemicals from the blood) are
the parenchyma of the liver, and the collagen fibers plus the veins and
arteries of the liver are the stroma; the structures that support the
parenchyma.
The End