Histology Connective tissue

                 Connective tissue

Connective tissue is the most abundant type of tissue in the body. It serves to connect and support other tissues and also has regulatory and immunologic functions. Connective tissue consists of cells, mainly fibroblasts, and an extracellular matrix (ECM). The specific composition of the ECM determines the biochemical properties of the connective tissue. There are many different types of connective tissue, with loose and dense connective tissue being the most common.
Disorders of connective tissue are discussed in detail in the connective tissue diseases learning card.
Connective tissue consists of specialized cells that are embedded in the extracellular matrix (ECM). Connective tissue is classified as loose or dense connective tissue depending on the ratio and structure of its components.
  • Cells
– Resident cells (e.g., fibroblasts, fibrocytes), which synthesize extracellular matrix
– Transient cells (e.g., macrophages, neutrophils)
  • Extracellular matrix (ECM)

Three types of fibers :
  1. Collagen fibers 
  2. Reticular fibers 
  3. Elastic fibers 

– Glycosaminoglycans
– Proteoglycans
– Glycoproteins
– Water 
Cells of the connective tissue

Resident cells
  • Fibroblasts (the most common cell type in connective tissue
– Origin: derived from mesenchymal stem cells
– Function: synthesis and organization of the ECM
– Histological features: spindle-shaped cells arranged in a branching pattern 
  • Fibrocytes: fibroblast with low metabolic activity 
  • Myofibroblasts: contractile hybrid cells with features of both fibroblasts and smooth muscle cells

– Function: synthesize ECM components and are involved in the proliferative phase of wound healing
– Histological features: indistinguishable from fibroblasts under the light microscope without immunohistochemical staining for, e.g., actin or desmin.
Transient immune cells

  • Immune cells: lymphocytes, plasma cells, macrophages, and mast cells 

Extracellular matrix

The extracellular matrix (ECM) is composed of various macromolecules arranged in a three-dimensional structure. Its specific composition determines the biochemical properties of the connective tissue.
Extracellular matrix fibers (connective tissue fibers)

Collagen molecules are the basis of collagen fibers and reticular fibers. They account for the majority of proteins in the ECM, which makes them the most abundant proteins in the human body. Elastic fibers are composed of elastin molecules and can be found together with collagen fibers in tissues that require elasticity in addition to tensile strength, e.g., the lung.


a family of glycoproteins synthesized by fibroblasts and secreted (as triple-stranded procollagen) into the extracellular space. Collagen is the most ubiquitous protein in humans.
Structure: a collagen molecule is a protein with a repeating amino acid sequence (Gly-X-Y)n
The first amino acid of this triplet is glycine (collagen is comprised of ⅓ glycine).
Position X: most commonly proline (second most common: lysine or hydroxylysine)
Position Y: most commonly hydroxyproline (second most common: lysine or hydroxylysine)
Types: Out of about 42 genes coding for collagen chains, about 28 types of collagen triple helices can be assembled. Some collagen types form fibrils, e.g., collagen types I, II, III, V, and XI, while others do not, e.g., collagen types IV, VIII, and X.
Degradation: enzymatic via specific collagenases 
Synthesis: Collagens are synthesized at the rough ER (rER). 

Collagen types
Type 1 collagen :
Tissue distribution
Bone (produced by osteoblasts), skin, tendons, ligaments, fascia, dentin, cornea, internal organs, scar tissue (late stages of wound healing).

Related conditions
Osteogenesis imperfecta type I.

Type 2 collagen:
Tissue distribution
Cartilage (including hyaline), vitreous humor of the eye, intervertebral disc (nucleus pulposus).

Related condition
Achondrogenesis (type II).

Type 3 collagen:

Tissue distribution
Reticular fibres in skin, blood vessels, granulation tissue, uterus, fetal tissue early embryos and throughout embryogenesis.

Related condition
Ehlers-Danlos syndrome (vascular type).

Type 4 collagen:

Tissue distribution
Basement membranes, lens

Related condition
Alport syndrome
Goodpasture syndrome: autoantibodies target type IV collagen

Type 5 collagen:

Tissue distribution
Bone, skin, fetal tissue, placenta

Related condition
Ehlers-Danlos syndrome (classic type).

  • Definition: elastic protein that is a major component of elastic fibers
  • Characteristics

– Rich in the non-hydroxylated amino acids glycine, proline, and lysine 
– Provides tissue with elasticity (via alternating α-helices and hydrophobic domains) 
  • Synthesis: several elastin molecules are cross-linked (polymerization) and form bundles as elastic fibers

– Fibrillin forms the scaffold for laying down tropoelastin
– Cross-linking between tropoelastin takes place extracellularly with the aid of transglutaminase and lysyl oxidase
  • Degradation: enzymatically via elastase (elaastase inhibition by α1-antitrypsin) .

Glycosaminoglycans (GAGs)

  • Definition: a family of unbranched polysaccharide chains of repeating disaccharide units with multiple negative charges that constitute a large volume fraction of the ECM 
  • Structure: polymer of repeating disaccharide units

– First sugar = a derivative of uronic acid (e.g., glucuronic acid), second sugar = a hexosamine (e.g., the amino sugar N-acetylglucosamine) 
  • Four main groups 

– Hyaluronic acid
– Chondroitin sulfate and dermatan sulfate
– Heparan sulfate
– Keratan sulfate
  • Function:

– Bind H2O in connective tissue due to its negative charges → act as a cushion 
– Component of proteoglycans 

  • Definition: proteins with numerous covalently linked GAG side chains 
  • Function:

– Bind H2O → shock absorption and a supportive function (e.g., in cartilage → resistance to compression of articular cartilage)
– Formation of cell-cell or cell-matrix junction 
– Further signaling and regulatory functions (e.g., by binding signaling molecules)
  • Examples

Aggrecan: large proteoglycan found in cartilage as an aggregate with hyaluronic acid → shock absorption withstands compression
Decorin: small proteoglycan that binds collagen fibrils → regulates fibril assembly
Glycoproteins of the ECM
  • Definition: proteins with short carbohydrate side chains that contribute to the organization of the extracellular matrix by offering specific binding sites for cells and other matrix molecules
  • Examples

– Fibronectin: glycoprotein important for cell-matrix interactions
Function: binds to collagen and integrins and plays an important role in embryogenesis (regulates cell migration) and hemostasis (cross-linking of fibrin molecules with thrombocytes and fibroblasts)
– Laminin: major component and organizer of the basal lamina (besides type IV collagen)
Function: binds to collagens, integrins, and proteoglycans

Connective tissue types
Loose connective tissu:

Main components 
  • Collagen fibers (especially types I and III)
  • Elastic fibers
  • Hyaluronic acid
  • Decorin

  • Structural framework for organs (interstitium)
  • Attaches epithelia to underlying tissue
  • Allows for independent movement 

  • Interstitium
  • Most abundant form of connective tissue

Dense connective tissu

Main components 
  • Collagen fibers (especially type I)

  • Provide tensile strength, especially in tissue under mechanical stress

  • Dense regular connective tissue : tendons, ligaments, aponeurosis
  • Dense irregular connective tissue:  dermis (stratum reticulare), fascia  , dura mater, sclera, cornea, and organ and joint capsules

Reticular connective tissue

Main components 
  • Reticular cells and reticular fibers form a network , where stem cells from blood and the immune system mature.

  • Reticular cells and reticular fibers form a network , where stem cells from blood and the immune system mature.

  • Bone marrow and secondary lymphoid organs

Elastic ligaments

Main components 
  • Elastic fibers > collagenous fibers

  • Provides ligaments with a high level of elasticity

  • Yellow ligament (ligamentum flavum), nuchal ligament

Mucous connective tissue

Main components 
  • Fine collagen fibers, hyaluronic acid, and H2O form Wharton jelly 

  • Protects and insulates umbilical cord vessels

  • Umbilical cord

Stroma of ovary

Main components
  • Few reticular fibers
  • Numerous spindle-shaped cells

  • Follicle formation in the ovary (folliculogenesis) 

  • Ovaries

Clinical significance
  • Fibrosis: proliferation of fibroblasts and deposition of collagen in tissues
Can be a result of a reparative process (e.g., following injury, inflammation, and/or necrosis): e.g., cirrhosis, retroperitoneal fibrosis
Or as part of a reaction to chronic irritants (e.g., pneumoconiosis, chronic lymphedema)
  • Marfan syndrome
  • Ehlers-Danlos syndrome
  • Menkes disease
  • Osteogenesis imperfecta
  • Scurvy
  • Connective tissue diseases
  • Wound healing
  • Fibroma

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