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Dr. Emad I H Shaqoura M.D, M.Sc. Anatomy Faculty of Medicine, Islamic University-Gaza October, 2015 Connective Tissue

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Page 1: Connective Tissue - الصفحات الشخصية | الجامعة الإسلامية ...site.iugaza.edu.ps/eshaqoura/files/Connective-Tissue...Functions of the Connective Tissue 1

Dr. Emad I H Shaqoura

M.D, M.Sc. Anatomy

Faculty of Medicine, Islamic University-Gaza

October, 2015

Connective Tissue

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Functions of the Connective Tissue

1. Maintains the form of organs throughout the body.

2. Provides a matrix that supports and binds other tissues and

cells together in organs.

3. The interstitial fluid of connective tissue gives metabolic

support to cells as the medium for diffusion of nutrients

and waste products.

4. Aiding in the defense and protection of the body.

5. Storage of fat.

Connective Tissue, Dr. Emad I Shaqoura, IUG 2

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Structure of the Connective Tissue

It is the most abundant of the four basic tissue types.

Connective Tissue

Extracellular Matrix

Fibers Ground

Substance

Cells

Connective Tissue, Dr. Emad I Shaqoura, IUG 3

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Structure of the Connective Tissue

The connective tissue is composed of:

1. Cells.

2. Extracellular matrix.

It is the major constituent of the connective tissue.

It is composed of:

1. Protein fibers: (collagen, reticular, and elastic)

2. Ground substance: anionic hydrophilic mixture of

proteoglycans, GAGs and multiadhesive glycoproteins.

Connective Tissue, Dr. Emad I Shaqoura, IUG 4

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Copyright © McGraw-Hill Companies

Figure 5-2

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Embryonic Origin of C.T

Connective tissues originate from embryonic mesenchyme ,

a tissue developing mainly from the mesoderm.

Mesenchyme consists largely of viscous ground substance

with few collagen fibers and cells.

Mesenchymal cells are undifferentiated, spindle-shaped cells.

They have:

1. large nuclei, with prominent nucleoli and fine chromatin.

2. Scant cytoplasm extended as two or more thin cytoplasmic

processes.

Connective Tissue, Dr. Emad I Shaqoura, IUG 6

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Copyright © McGraw-Hill Companies

Figure 5-1

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Embryonic Origin of C.T (cont’d)

Mesodermal cells migrate from their origin, surround and

penetrate developing organs.

Embryonic mesenchyme:

1. Produces all types of connective tissue proper and the

specialized connective tissues.

2. Includes stem cells for other tissues such as blood, the

vascular endothelium, and muscle.

Connective Tissue, Dr. Emad I Shaqoura, IUG 8

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Cells of Connective Tissue

© Elsevier. Gartner & Hiatt: Color Textbook of Histology 3E. Connective Tissue, Dr. Emad I Shaqoura, IUG 9

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Cells of Connective Tissue (cont’d) The cells in connective tissues are grouped into two

categories: fixed cells and transient cells.

I. Fixed cells are a resident population of cells that have developed and remain in place within the connective tissue, where they perform their functions. The fixed cells are a stable and long-lived population that includes:

1. Fibroblasts

2. Adipose cells

3. Pericytes

4. Mast cells

5. Macrophages

Connective Tissue, Dr. Emad I Shaqoura, IUG 10

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Cells of Connective Tissue (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 11

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Cells of Connective Tissue (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 12

II. Transient cells (free or wandering cells) originate mainly in the bone marrow and circulate in the bloodstream. Upon receiving the proper stimulus or signal, these cells leave the bloodstream and migrate into the connective tissue to perform their specific functions. Because most of these motile cells are usually short-lived, they must be replaced continually from a large population of stem cells.

1. Plasma cells

2. Lymphocytes

3. Neutrophils

4. Eosinophils

5. Basophils

6. Monocytes

7. Macrophages

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13

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Fibroblasts

Connective Tissue, Dr. Emad I Shaqoura, IUG 14

Fibroblasts, the most common cells in connective tissue,

produce and maintain most of the tissue’s extracellular

components e.g., collagen, elastin, proteoglycans, GAGs,…..

Two levels of fibroblast activity can be observed

histologically:

1. Fibroblasts (active cells).

2. Fibrocytes (quiescent cells).

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Active Fibroblast

Connective Tissue, Dr. Emad I Shaqoura, IUG 15

Has more abundant and irregularly branched cytoplasm.

Its nucleus is large, ovoid, euchromatic, and has a prominent nucleolus.

The cytoplasm has much rough endoplasmic reticulum (RER) and a well-developed Golgi apparatus.

Junqueira's Basic Histology Text and Atlas 13th Ed

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Active Fibroblast (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 16

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Quiescent Fibroblast

Connective Tissue, Dr. Emad I Shaqoura, IUG 17

Smaller than the active

fibroblast.

Is usually spindle-shaped

with fewer processes.

Much less RER.

Contains a darker, more

heterochromatic nucleus.

Junqueira's Basic Histology Text and Atlas 13th ed.

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Fibroblasts (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 18

Fibroblasts are targets of growth factors that influence cell growth and differentiation.

In adults, connective tissue fibroblasts rarely undergo division. However, stimulated by locally released growth factors, cell cycling and mitotic activity resume when the tissue requires additional fibroblasts, for example, to repair a damaged organ.

Fibroblasts involved in wound healing, sometimes called myofibroblasts, have a well-developed contractile function and are enriched with a form of actin also found in smooth muscle cells.

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Medical Application

Connective Tissue, Dr. Emad I Shaqoura, IUG 19

The regenerative capacity of connective tissue is clearly observed in organs

damaged by ischemia, inflammation, or traumatic injury.

Spaces left after such injuries, especially in tissues whose cells divide poorly or

not at all (e.g., cardiac muscle), are filled by connective tissue, forming dense

irregular scar tissue.

The healing of surgical incisions and other wounds depends on the reparative

capacity of connective tissue, particularly on activity and growth of fibroblasts.

in some rapidly closing wounds, a cell called the myofibroblast, with features of

both fibroblasts and smooth muscle cells, is also observed.

These cells have most of the morphologic characteristics of fibroblasts but

contain increased amounts of actin microfilaments and myosin and behave

much like smooth muscle cells.

Their activity is important for the phase of tissue repair called wound

contraction.

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Adipocytes (Fat Cells)

Connective Tissue, Dr. Emad I Shaqoura, IUG 20

They are C.T cells

specialized for cytoplasmic

storage of lipid as neutral

fats, or less commonly for

the production of heat.

The large deposits of fat in

the cells of adipose

connective tissue also serve

to cushion and insulate the

skin and other organs.

Junqueira's Basic Histology Text and Atlas 13th ed.

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Macrophages & the Mononuclear

Phagocyte System

Connective Tissue, Dr. Emad I Shaqoura, IUG 21

Macrophages are phagocytic cells specialized in turnover of protein fibers and removal of dead cells, tissue debris, or other particulate material.

Their morphology varies according to their functional activity and to the tissue they inhabit.

A typical macrophage measures between 10 and 30 μm in diameter and has an eccentrically located, oval or kidney-shaped nucleus.

Macrophages are present in the connective tissue of most organs and are often referred to by pathologists as “histiocytes.”

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Macrophages & the Mononuclear

Phagocyte System (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 22

In the TEM, macrophages have a characteristic irregular

surface with pleats, protrusions, and indentations, a

morphologic expression of their active pinocytotic

and phagocytic activities.

They generally have a well-developed Golgi apparatus and

many lysosomes.

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Copyright © McGraw-Hill Companies

Figure 5-4

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Macrophages & the Mononuclear

Phagocyte System (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 24

Macrophages derive from bone marrow precursor cells that

divide, producing monocytes that circulate in the blood.

These cells cross the wall of venules to penetrate connective

tissue, where they differentiate further, mature, and acquire

the morphologic features of phagocytic cells.

Therefore, monocytes and macrophages are the same cell at

different stages of maturation.

Precursor Cells (bone marrow)

Monocytes (blood)

Macrophages (C.T)

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Macrophages & the Mononuclear

Phagocyte System (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 25

Macrophages play an important role in the early stages of

repair after tissue damage, where they accumulate in

connective tissue by local proliferation and monocyte

recruitment from the blood.

Macrophages are distributed throughout the body.

Along with other monocyte-derived cells, they comprise a

family of cells called the mononuclear phagocyte

system.

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Macrophages & the Mononuclear

Phagocyte System (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 26

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Macrophages & the Mononuclear

Phagocyte System (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 27

All monocyte-derived cells are long-living cells and may

survive for months in the tissues.

The transformation from monocytes to macrophages in

connective tissue involves:

1. increases in cell size,

2. increased protein synthesis,

3. increases in the number of Golgi complexes

4. and increases in the number of lysosomes.

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Medical Application

Connective Tissue, Dr. Emad I Shaqoura, IUG 28

Macrophages are key components of the innate immunity, removing cell debris, neoplastic cells, bacteria, and other invaders.

Macrophages are also important antigen-presenting cells required for the activation and specification of lymphocytes.

When macrophages are stimulated (by injection of foreign substances or by infection), they become activated macrophages, showing:

1. An increase in their capacity for phagocytosis and intracellular digestion.

2. Enhanced metabolic and lysosomal enzyme activity.

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Medical Application (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 29

Macrophages are also secretory cells producing enzymes for

ECM breakdown and various growth factors or cytokines

that help regulate immune cells and reparative functions.

When adequately stimulated, macrophages may increase in

size and fuse to form multinuclear giant cells, usually

found only in pathologic conditions.

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Medical Application (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 30

www.ebi.edu.au

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Mast Cells

Connective Tissue, Dr. Emad I Shaqoura, IUG 31

Mast cells are oval or

irregularly shaped

connective tissue cells.

The cytoplasm is filled

with basophilic secretory

granules.

The nucleus is centrally

situated and often obscured

by abundant secretory

granules. Junqueira's Basic Histology Text and Atlas 13th ed.

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Mast Cells (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 32

These granules are electron-dense and heterogeneous

(ranging from 0.3 to 2.0 μm in diameter).

Junqueira's Basic Histology Text and Atlas 13th ed.

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Mast Cells (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 33

Because of their high content of acidic radicals in their

sulfated GAGs, mast cell granules display metachromasia,

which means that they can change the color of some basic

dyes (e.g., toluidine blue) from blue to purple or red.

The granules are poorly preserved by common fixatives, so

that mast cells are frequently difficult to identify.

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Mast Cells (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 34

Wheater's Functional Histology - A Text and Color Atlas 6th ed.

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Connective Tissue, Dr. Emad I Shaqoura, IUG 35

Wheater's Functional Histology - A Text and Color Atlas 6th ed.

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Mast Cells (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 36

Progenitor cell (Bone marrow)

Progenitor cell

(Blood)

Connective tissue

Differentiate into mast cells

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Mast Cells (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 37

Mast cells have roles in the local inflammatory response, innate immunity, and tissue repair through releasing important molecules such as:

1. Heparin: acts locally as an anticoagulant.

2. Histamine: which promotes increased vascular permeability and smooth muscle contraction.

3. Serine proteases: which activate various mediators of inflammation.

4. Eosinophil and neutrophil chemotactic factors: which attract those leukocytes.

5. Cytokines: polypeptides directing activities of leukocytes and other cells of the immune system.

6. Phospholipid precursors: for conversion to prostaglandins, leukotrienes, and other important lipid mediators of the inflammatory response.

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Copyright © McGraw-Hill Companies

Figure 5-6

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Plasma Cells

Connective Tissue, Dr. Emad I Shaqoura, IUG 39

Plasma cells are B-lymphocyte–derived, antibody-producing cells.

They are large, ovoid cells having basophilic cytoplasm due to their

richness in RER.

Next to the nucleus, the Golgi apparatus and centrioles occupy a region

that may appear pale in routine histologic preparations.

The nucleus of the plasma cell is generally spherical but eccentrically

placed.

Many of these nuclei contain compact, peripheral regions of

heterochromatin alternating with lighter areas of euchromatin, a

configuration that can give the nucleus of a plasma cell the appearance of

a clock face.

There are at least a few plasma cells in most connective tissues.

Their average lifespan is only 10-20 days.

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Copyright © McGraw-Hill Companies

Figure 5-7

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Medical Application Plasma cells are derived from B lymphocytes and are

responsible for the synthesis of immunoglobulin antibodies.

Each antibody is specific for the one antigen that stimulated the clone of B cells and reacts only with that antigen or molecules resembling it.

The results of the antibody-antigen reaction are variable, but they usually neutralize harmful effects caused by antigens.

An antigen that is a toxin (e.g., tetanus, diphtheria) may lose its capacity to do harm when it binds to its specific antibody.

Bound antigen-antibody complexes are quickly removed from tissues by phagocytosis.

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Leukocytes

Connective Tissue, Dr. Emad I Shaqoura, IUG 42

Leukocytes, or white blood cells, make up a population of

wandering cells in connective tissue.

They leave blood by migrating between the endothelial cells

lining venules to enter connective tissue by a process called

diapedesis.

This process increases greatly during inflammation.

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Fibers

Connective Tissue, Dr. Emad I Shaqoura, IUG 43

The fibrous components of connective tissue are elongated

structures formed from proteins that polymerize after

secretion from fibroblasts.

Types of fibers:

1. Collagen fibers.

2. Reticular fibers.

3. Elastic fibers: formed by elastin protein.

These fibers are distributed unequally among the different

types of connective tissue.

formed by collagen protein family

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Collagen

Connective Tissue, Dr. Emad I Shaqoura, IUG 44

Collagen is the most abundant protein in the human body,

representing 30% of its dry weight.

Collagen is a key element of all connective tissues, as well as

epithelial basement membranes and the external laminae of

muscle and nerve cells.

Collagens are secreted by fibroblasts and several other cell

types.

A family of 28 collagens exists in vertebrates that can be

grouped into different categories according to the structures

formed by their interacting subunits.

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Collagen Types

Connective Tissue, Dr. Emad I Shaqoura, IUG 45

1. Fibrillar collagens:

Notably collagen types I, II, and III, have subunits that

aggregate to form large fibrils clearly visible in the electron or

light microscope.

Collagen type I, the most abundant and widely distributed

collagen, forms large, eosinophilic bundles usually called

collagen fibers.

These often densely fill the connective tissue, forming

structures such as tendons, organ capsules, and dermis.

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Copyright © McGraw-Hill Companies

Figure 5-8

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Copyright © McGraw-Hill Companies

Figure 5-8

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Collagen Types (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 48

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Collagen Types (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 49

2. Sheet-forming collagens:

Such as type IV collagen.

They have subunits produced by epithelial cells.

They are the major structural proteins of external

laminae and the basal lamina in all epithelia.

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Collagen Types (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 50

3. Linking/anchoring collagens:

They are short collagens that link fibrillar collagens to

one another (forming larger fibers) and to other

components of the ECM.

Type VII collagen binds type IV collagen and anchors

the basal lamina to the underlying reticular lamina in

basement membranes.

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Collagen Types (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 51

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Collagen Synthesis

Connective Tissue, Dr. Emad I Shaqoura, IUG 52

Collagen synthesis occurs in many cell types especially

fibroblasts.

The initial procollagen α chains are made in the RER.

Many different α chains have been identified, varying in

length and sequence.

In the ER three α chains are selected, aligned, and folded as a

triple helix, which is the defining feature of collagens.

The triple helix (procollagen) undergoes exocytosis and is

cleaved to a rod-like collagen molecule that is the basic

subunit from which the fibers or sheets are assembled.

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Collagen Synthesis (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 53

These subunits may be homotrimeric, with all three chains

identical, or heterotrimeric, with two or all three chains

having different sequences.

Different combinations of procollagen α chains produce the

various types of collagen with different structures and

functional properties.

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Copyright © McGraw-Hill Companies

Figure 5-10

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Collagen Synthesis (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 55

Because there are so many steps in collagen biosynthesis,

there are many points at which the process can be

interrupted or changed by defective enzymes or by disease

processes.

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Collagen Synthesis (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 56

Type I collagen fibrils have diameters ranging from 20 to 90 nm and can be several micrometers in length.

Adjacent rod-like collagen subunits of the fibrils are staggered by 67 nm, with small gaps (lacunar regions) between their ends.

This structure produces a characteristic feature of type I collagen visible by EM: transverse striations with a regular periodicity.

Type I collagen fibrils assemble further to form large, extremely strong collagen fibers that are bundled by linking collagens and proteoglycans.

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Copyright © McGraw-Hill Companies

Figure 5-11

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Collagen Synthesis (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 58

Collagen type II (present in cartilage) occurs as fibrils but

does not form fibers or bundles.

Sheet-forming collagen type IV subunits assemble as a

lattice-like network in epithelial basal laminae.

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Collagen (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 59

In the light microscope, collagen fibers are acidophilic;

they stain:

pink with eosin.

blue with Mallory trichrome stain.

red with Sirius red.

Because of the long and tortuous course of collagen bundles,

their length and diameter are better studied in spread

preparations than in histologic sections e.g., mesentery.

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Connective Tissue, Dr. Emad I Shaqoura, IUG 60

Collagen fibers, H & E stain

Collagen fibers, Sirius red stain

Collagen fibers, Mallory trichrome stain

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Collagen (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 61

Collagen turnover and renewal in normal connective tissue is generally a very slow but ongoing process.

In some organs, such as tendons and ligaments, the collagen is very stable, whereas in others, as in the periodontal ligament surrounding teeth, the collagen turnover rate is high.

To be renewed, the collagen must fist be degraded.

Degradation is initiated by specific enzymes called collagenases.

Collagenases clip collagen fibrils or sheets in such a way that they are then susceptible to further degradation by nonspecific proteases.

Various MMPs are secreted by macrophages and play an important role in remodeling the ECM during tissue repair.

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Medical Application

Connective Tissue, Dr. Emad I Shaqoura, IUG 62

A keloid is a local swelling caused by abnormally large amounts of collagen that form in scars of the skin.

Keloids occur most often in individuals of African descent and can be a troublesome clinical problem to manage.

Not only can they be disfiguring, but excision is almost always followed by recurrence.

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Reticular Fibers

Connective Tissue, Dr. Emad I Shaqoura, IUG 63

Consist mainly of collagen type III that forms an extensive

network (reticulum) of extremely thin heavily glycosylated

fibers (10% of the fiber content).

Staining properties:

Reticular fibers are seldom visible in H&E preparations.

They are characteristically stained black by impregnation with

silver salts (argyrophilic).

Reticular fibers are also periodic acid-Schif (PAS) positive.

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Figure 5-12

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Reticular Fibers (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 65

Reticular fibers are present in the following sites:

1. The reticular lamina of basement membrane.

2. Surrounding adipocytes, smooth muscle and nerve fibers, and

small blood vessels.

3. The supportive stroma for the parenchymal secretory cells of

the liver and endocrine glands.

4. The stroma of hemopoietic tissue (bone marrow) and some

lymphoid organs (e.g., spleen and lymph nodes).

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Elastic Fibers

Connective Tissue, Dr. Emad I Shaqoura, IUG 66

They are thinner than the type I collagen fibers.

They form sparse networks interspersed with collagen

bundles in many organs, particularly those subject to much

bending or stretching.

They form fenestrated sheets called elastic lamellae in the

wall of large blood vessels, especially arteries.

Staining properties:

They are not strongly acidophilic and stain poorly with H&E.

They are stained more darkly than collagen in other

stains such as orcein and aldehyde fuchsin.

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Figure 5-13

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Elastic Fibers (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 68

Elastic fibers (and lamellae) are a composite of firillin

microfibrils embedded in a larger mass of cross-linked

elastin.

Both components are secreted from fibroblasts (and

smooth muscle cells in vascular walls) and produce elastic

fibers in a stepwise manner.

The properties of elastic fibers and lamellae result from

the structure of the elastin subunits and the unique

cross-links holding them together.

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Figure 5-14

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Medical Application

Connective Tissue, Dr. Emad I Shaqoura, IUG 70

Fibrillins comprise a family of proteins involved in making the scaffolding necessary for the deposition of elastin.

Mutations in the fibrillin genes result in Marfan syndrome, a disease characterized by a lack of resistance in tissues rich in elastic fibers.

Because the walls of large arteries are rich in elastic components and because the blood pressure is high in the aorta, patients with this disease often experience aortic swellings called aneurysms, which are life-threatening conditions.

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Ground Substance

Connective Tissue, Dr. Emad I Shaqoura, IUG 71

The ground substance of the ECM is a highly hydrated, transparent, complex mixture of macromolecules, principally of three classes:

1. Glycosaminoglycans (GAGs),

2. proteoglycans,

3. and multiadhesive glycoproteins.

It fills the space between cells and fibers in connective tissue.

Because it is viscous, acts as both a lubricant and a barrier to the penetration of invaders.

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Figure 5-16

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Glycosaminoglycans

Connective Tissue, Dr. Emad I Shaqoura, IUG 73

Also called mucopolysaccharides.

They are long polysaccharides consisting of repeating

disaccharide units, usually a uronic acid and a hexosamine.

The hexosamine can be glucosamine or galactosamine, and

the uronic acid can be glucuronic or iduronic acid.

The largest, almost unique, and most ubiquitous GAG is

hyaluronic acid (HA or hyaluronan).

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Glycosaminoglycans (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 74

Hyaluronic acid is a long polymer of the disaccharide

glucosamine-glucuronate.

It is synthesized directly into the ECM by an enzyme

complex, hyaluronate synthase, located in the cell membrane

of many cells.

Hyaluronic acid forms a dense, viscous network of polymers,

which binds a considerable amount of water, giving it an

important role in allowing diffusion of molecules in

connective tissue and in lubricating various organs and joints.

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Glycosaminoglycans (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 75

All other GAGs are much smaller, sulfated, covalently attached

to proteins (as parts of proteoglycans), and are synthesized in

Golgi complexes.

The four major GAGs found in proteoglycans are: dermatan

sulfate, chondroitin sulfates, keratan sulfate, and heparan sulfate.

All of which have different disaccharide units and tissue

distributions.

Like hyaluronic acid, these GAGs are intensely hydrophilic,

contributing to the viscosity of ground substance, and are

polyanions, binding a great number of cations (usually sodium) by

electrostatic (ionic) bonds.

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Connective Tissue, Dr. Emad I Shaqoura, IUG 76

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Proteoglycans

Connective Tissue, Dr. Emad I Shaqoura, IUG 77

They are composed of a core protein to which are covalently

attached various sulfated GAGs.

They are synthesized on RER, mature in the Golgi, where the

GAG side chains are added, and secreted from cells by exocytosis.

Some proteoglycans, such as the major cartilage constituent

aggrecan, contain a greater mass of polysaccharide chains than

polypeptide.

In cartilage, aggrecan-hyaluronate complexes fill the space

between collagen fibers and cells and contribute greatly to the

physical properties of this tissue.

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Figure 5-17

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Proteoglycans (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 79

Both matrix-linked and cell surface proteoglycans also bind

and sequester certain signaling proteins, for example

fibroblast growth factor (FGF).

Degradation of proteoglycans during the early phase of tissue

repair releases these stored growth factors that then stimulate

new cell growth and ECM synthesis.

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Medical Application

Connective Tissue, Dr. Emad I Shaqoura, IUG 80

Because of their high viscosity, HA and proteoglycans

tend to form a barrier against bacterial penetration of

tissues.

Bacteria that produce hyaluronidase, an enzyme that

hydrolyzes hyaluronic acid and disassembles proteoglycans

complexes, reduce the viscosity of the connective

tissue ground substance and have greater invasive power.

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Multiadhesive Glycoproteins

Connective Tissue, Dr. Emad I Shaqoura, IUG 81

They are very large molecules with branched oligosaccharide

chains.

All have multiple binding sites for cell surface receptors

(integrins) and for other matrix macromolecules.

They have important roles in the adhesion of cells to their

substrate.

Laminin provides adhesion for epithelial and other cells, with

binding sites for integrins, type IV collagen, and specific

proteoglycans.

All basal and external laminae are rich in laminin, which is

essential for the assembly and maintenance of these structures.

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Figure 5-18

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Multiadhesive Glycoproteins (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 83

Fibronectin: synthesized largely by fibroblasts, has binding

sites for collagens and certain GAGs, and forms insoluble

fibrillar networks throughout connective tissue.

The fibronectin substrate provides specific binding sites for

integrins and is important both for cell adhesion and cellular

migration through the ECM.

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Figure 5-18

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Multiadhesive Glycoproteins (cont’d)

Connective Tissue, Dr. Emad I Shaqoura, IUG 85

The integrin family of integral membrane proteins act as matrix receptors for laminin, fironectin, some collagens, and certain other ECM proteins.

Integrins bind their ligands in the ECM with relatively low affinity, allowing cells to explore their environment without losing attachment to it or becoming glued to it.

Integrins are heterodimers of two transmembrane polypeptides: the α and β chains.

Great diversity in the α and β chains allows the cells to have different specific ligands preferentially.

Cytoplasmic portions of integrins associate with peripheral membrane proteins that bind actin filaments.

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Figure 5-19

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Interstitial Fluid

Connective Tissue, Dr. Emad I Shaqoura, IUG 87

A small quantity of free interstitial fluid, with ion

composition similar to that of blood plasma, is also present in

the C.T matrix.

Interstitial fluid contains plasma proteins of low molecular

weight that pass through the thin walls of capillaries.

Although only a small proportion of connective tissue

proteins are plasma proteins, it is estimated that as much as

one-third of the body’s plasma proteins are stored in the

matrix of connective tissue because of its volume and wide

distribution.

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Medical Application

Connective Tissue, Dr. Emad I Shaqoura, IUG 88

Edema is the excessive accumulation of water in the

extracellular spaces of connective tissue.

This water comes from the blood, passing through the

capillary walls that become more permeable during

inflammation and normally producing slight swelling.

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Figure 5-20

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Types of Connective Tissue

Connective Tissue, Dr. Emad I Shaqoura, IUG 90

Connective Tissue Proper

Embryonic Connective Tissue

Specialized Connective Tissue

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Connective Tissue, Dr. Emad I Shaqoura, IUG 91

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Connective Tissue Proper

Connective Tissue, Dr. Emad I Shaqoura, IUG 92

C.T Proper

Dense C.T

Regular Irregular

Loose C.T

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Loose Connective Tissue

Connective Tissue, Dr. Emad I Shaqoura, IUG 93

Also called areolar tissue.

Is very common and generally supports epithelial tissue.

It comprises the lamina propria of the digestive system and fills the spaces between muscle and nerve fibers.

Usually well-vascularized whatever their location, thin layers of loose connective tissue surround most small blood vessels of the body.

The loose connective tissue typically contains cells, fibers, and ground substance in roughly equal parts, with predominance of fibroblasts and collagen fibers.

It has a delicate consistency; it is flexible and not very resistant to stress.

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Figure 5-21

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Dense Connective Tissue

Connective Tissue, Dr. Emad I Shaqoura, IUG 95

It has the same components found in loose connective tissue,

but with fewer cells and a clear predominance of collagen

fibers over ground substance.

It is less flexible and far more resistant to stress than loose

connective tissue.

It has two types; irregular and regular.

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Dense Irregular Connective

Connective Tissue, Dr. Emad I Shaqoura, IUG 96

In dense irregular connective tissue, bundles of collagen

fibers appear randomly interwoven, with no definite

orientation.

The collagen fibers form a tough three-dimensional network,

providing resistance to stress from all directions.

Dense irregular connective tissue is often found closely

associated with loose connective tissue, with the two types

frequently grading into each other and making distinctions

between them somewhat arbitrary.

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Figure 5-21

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Dense Regular Connective Tissue

Connective Tissue, Dr. Emad I Shaqoura, IUG 98

The type I collagen bundles of dense regular connective

tissue are arranged according to a definite pattern, with

fibers and fibroblasts aligned in parallel for resistance to

prolonged or repeated stresses exerted in the same direction.

Common examples of dense regular connective tissue, are

tendons and ligaments.

Consisting almost entirely of densely packed collagen fibers,

they are white in the fresh state and almost inextensible.

The parallel, closely packed bundles of collagen are separated

by very little ground substance.

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Dense Regular Connective Tissue

Connective Tissue, Dr. Emad I Shaqoura, IUG 99

The fibrocytes have elongated nuclei lying parallel to the fibers and sparse cytoplasmic folds that envelop portions of the collagen bundles.

The cytoplasm of these “tendinocytes” is rarely revealed in H&E stains.

Tendons are poorly vascularized and repair of damaged tendons is very slow.

In some tendons, the dense irregular connective tissue sheath is covered by flattened synovial cells of mesenchymal origin, which produce lubricant fluid (similar to the fluid of synovial joints) containing water, proteins, hyaluronate, and other GAGs.

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Figure 5-22

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Medical Application

Connective Tissue, Dr. Emad I Shaqoura, IUG 101

Overuse of tendon-muscle units can result in tendonitis, characterized by inflammation of the tendons and their attachments to muscle.

Common locations are the elbow, the Achilles tendon of the heel, and the shoulder rotator cuff.

The swelling and pain produced by the localized inflammation restricts the affected area’s normal range of motion and can be relieved by injections of anti-inflammatory agents such as cortisone.

Fibroblasts eventually repair damaged collagen bundles of the area.

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Mucoid Tissue

Connective Tissue, Dr. Emad I Shaqoura, IUG 102

Mucoid (or mucous) connective tissue is another embryonic type of connective tissue, found mainly in the umbilical cord and fetal organs.

With abundant ground substance composed chiefly of hyaluronic acid, mucoid tissue is jellylike with sparse collagen fibers and scattered fibroblasts.

Mucoid tissue is the principal component of the umbilical cord, where it is referred to as Wharton’s jelly.

A similar form of connective tissue is also found in the pulp cavities of young teeth, which remain as a postnatal source of mesenchymal stem cells.

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Figure 5-24

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Reticular Tissue

Connective Tissue, Dr. Emad I Shaqoura, IUG 104

In reticular tissue, fibers of type III collagen form a delicate

3D network that supports various types of cells.

The fibrous network of this specialized connective tissue

is produced by modified fibroblasts called reticular cells

that remain associated with and partially covering the fibers.

It provides a framework with specialized microenvironments

for cells in hemopoietic tissue and some lymphoid organs

(bone marrow, lymph nodes, and spleen).

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Figure 5-23

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Connective Tissue, Dr. Emad I Shaqoura, IUG 106