TISSUE REPAIR
REGENERATION /
HEALING
DEFINITIONS:
REPAIR: Restoration of normal structure
and function of tissues.
• For parenchymal and connective tissue.
HEALING:
For surface epithelium.
REPAIR
• Repair of damaged tissue occurs by
• 1- regeneration by proliferation of
uninjured cells and maturation of
stem cells.
• 2-deposition of connective tissue to
form scar.
REGENERATION
• Replacement of lost structures
• Is dependent on the type of
normal turnover the original
tissue has, skin, intestine.
• Mammals have limited ability to
regenerate.
Scar/ CT deposit
• If the tissue damage is severe:
Connective tissue(fibrous) is laid down to
end in scar formation.
• Fibrosis, as one of the 3 possible outcomes
of inflammation, follows “healing”
• Fibrosis + inflammation= organization.
Both regeneration and Fibrosis occur
simultaneously.
Cell Population Fates
• PROLIFERATION
– Hormonal, especially steroid hormones
– eg., EPO, CSF
*
• DIFFERENTIATION
– UNIDIRECTIONAL, GAIN (specialization)
and LOSS (versatility)
• APOPTOSIS
*One of the most KEY concepts in neoplasia
CELL TYPES
• Labile/dividing: eg.,
marrow, GI
• Stable/Quiescent: liver,
kidney
• NON-mitotic/permanant:
neuron, striated muscle
ADULT
STEM CELLS
• MARROW
(HEMOCYTOBLAST)
(hematopoetic stem cells)
• NON-MARROW
(RESERVE)
MARROW STROMAL CELL
Growth Factors (GFs)
• Polypeptides
• Cytokines
• LOCOMOTION
• CONTRACTILITY
• DIFFERENTIATION
• ANGIOGENESIS
Growth Factors (GFs)
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Epidermal
Transforming (alpha, beta)
Hepatocyte
Vascular Endothelial
Platelet Derived
Fibroblast
Keratinocyte
Cytokines (TNF, IL-1, Interferons)
CELL PLAYERS
(source AND targets)
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Lymphocytes, especially T-cells
Macrophages
Platelets
Endothelial cells
Fibroblasts
Keratinocytes
“Mesenchymal” cells
Smooth muscle cells
E (Epidermal) GF
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•
•
•
Made in platelets, macrophages
Present in saliva, milk, urine, plasma
Acts on keratinocytes to migrate, divide
Acts on fibroblasts to produce
“granulation” tissue
T (Transforming) GF-alpha
• Made in macrophages, T-cells,
keratinocytes
• Similar to EGF, also effect on
hepatocytes
H (Hepatocyte) GF
• Made in “mesenchymal” cells
• Proliferation of epithelium,
endothelium, hepatocytes
• Effect on cell “motility”
VE (Vascular Endothelial) GF
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•
•
•
•
Made in mesenchymal cells
Triggered by HYPOXIA
Increases vascular permeability
Mitogenic for endothelial cells
KEY substance in promoting
“granulation” tissue
PD (Platelet Derived) GF
• Made in platelets, but also MANY
other cell types
• Chemotactic for MANY cells
• Mitogen for fibroblasts
• Angiogenesis
• Another KEY player in granulation
tissue
F (Fibroblast) GF
• Made in MANY cells
• Chemotactic and mitogenic, for
fibroblasts and keratinocytes
• Re-epithelialization
• Angiogenesis, wound contraction
• Hematopoesis
• Cardiac/Skeletal (striated) muscle
T (Transforming) GF-beta
• Made in MANY CELLS
• Chemotactic for PMNs and MANY
other types of cells
• Inhibits epithelial cells
• Fibrogenic
• Anti-Inflammatory
K (Keratinocyte) GF
• Made in fibroblasts
• Stimulates
keratinocytes:
–Migration
–Proliferation
–Differentiation
I (Insulin-like) GF-1
• Made in macrophages, fibroblasts
• Stimulates:
– Sulfated proteoglycans
– Collagen
– Keratinocyte migration
– Fibroblast proliferation
• Action similar to GH (Pituitary
Growth Hormone)
TNF (Tumor Necrosis Factor)
• Made in macrophages, mast cells,
T-cells
• Activates macrophages (cachexin)
• KEY influence on other cytokines
• The MAJOR TNF is TNF-alpha
Interleukins
• Made in macrophages, mast cells,
T-cells, but also MANY other cells
• MANY functions:
– Chemotaxis
– Angiogenesis
– REGULATION of other cytokines
INTERFERONS
• Made by lymphocytes,
fibroblasts
• Activates MACROPHAGES
• Inhibits FIBROBLASTS
• REGULATES other cytokines
SIGNALING
• Autocrine (same cell)
• Paracrine (next door neighbor)
(many GFs)
• Endocrine (far away, delivered
by blood, steroid hormones)
ExtraCellular Matrix (ECM)
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•
•
•
Collagen(s) I-XXVII
Elastin
Fibrillin
CAMs (Cell Adhesion Molecules)
– Immunoglobulins, cadherins, integrins,
selectins
• Proteoglycans
• Hyaluronic Acid
ECM
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•
•
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Maintain cell differentiation
“Scaffolding”
Establish microenvironment
Storage of GF’s
Collagen One - bONE (main component of bone)
Collagen Two - car
TWOlage (main component of cartilage)
Collagen Three - reTHREEculate (main component of reticular fibers)
Collagen Four - FLOOR - forms the basement membrane
DEFINITIONS:
•REGENERATION:
Growth of cells to replace lost tissues
•HEALING: A reparative tissue
response to a wound, inflammation or
necrosis
Tissue regeneration
• Labile tissues contain stem cells that
differentiate to replenish lost cells and
maintain homeostasis.
• Cell proliferation is controlled by cell cycle
and is stimulated by growth factors and
interaction of cells with ECM.
• Regeneration of liver is classic example of
regeneration.
Prometheus, Zeus.
Liver regeneration.
• After resection, IL-6 primes hepatocytes to
receive new cells.
• Growth factors and cytokines push
hepatocytes into cell cycle and later divide
kupffer cells, endothelial and stellate cells.
• In last termination phase, hepatocytes
return to quiescent phase.
TRANSCRIPTION FACTORS
HEPATIC
REGENERATION
TNF
IL6
HGF
HEALING/REPAIR
• FOLLOWS INFLAMMATION
• PROLIFERATION and MIGRATION of
connective tissue cells
• ANGIOGENESIS (Neovascularization)
• Collagen, other ECM protein synthesis
• Tissue Remodeling
• Wound contraction
• Increase in wound strength (scar = fibrosis)
ANGIOGENESIS
(NEOVASCULARIZATION)
• From endothelial precursor cells
• From PRE-existing vessels
• Stimulated/Regulated by GF’s,
especially VEGF
• Also regulated by ECM proteins
• aka, “GRANULATION”, “GRANULATION
TISSUE”, “ORGANIZATION”,
“ORGANIZING INFLAMMATION”
ANGIOGENESIS
GRANULATION TISSUE,
TRICHROME STAIN.
WOUND HEALING
• 1st INTENTION • 2nd INTENTION
• Edges lined up
• Edges NOT lined up
• More granulation
• More
epithelialization
• MORE FIBROSIS
TWO TYPES OF WOUND
Difference
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FIRST INTENTION
Wound contraction
Inflammation
Scar
Healing rapid
Function loss
Oedema
Granulation tissue
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SECOND INTENTION
Present
More
More
Slow
More
More
More
“HEALTHY” Granulation Tissue
FIBROSIS/SCARRING
• DEPOSITION OF COLLAGEN
by FIBROBLASTS
• With time (weeks, months,
years?) the collagen becomes
more dense and the tissue
becomes “STRONGER”.
However function and
appendages might be lost.
COLLAGEN DEPOSITION
• TGF-Beta is most important cytokine for
CT deposition.
• Produced by GT and macrophages
• Changes fibroblasts to myofibroblasts.
• Remodelling/degradation of collagen is
done by MMP.
• ADAM (a disintegrin and MP) is also
related to MMP.
Wound RETARDING factors
(LOCAL)
• DECREASED Blood supply
• Denervation
• Local Infection
• FB
• Hematoma
• Mechanical stress(Cough)
• Necrotic tissue
Wound RETARDING factors
(SYSTEMIC)
• DECREASED Blood supply
• Age(Arteriosclerosis)
• Anemia
• Malignancy
• Malnutrition
• Obesity
• Infection
• Steroids inhibit TGF exception cornea.
Abnormalities of repair
• Inadequate / less GT or scar: wound
dehiscence or rupture (cough/vomiting)
• Excessive GT: Protrudes above the
surrounding skin and blocks
approximation of edges (proud flesh).
• Excessive Collagen: Hypertrophic scar/
Keloid.
• Excessive contraction: Contractures.
THANK YOU