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Mechanism of tissue repair

Dr Walidad

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General concept

Damage to parenchymal cell, non dividingcells or stromal network repair occurs by

fibrosis.

Begins in 24 hours of injury by emigration offibroblasts and induction of endothelial cells.

In 3 to 5 days granulation tissue is formed

which is soft, pink and granular in appearance.

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It contains fibrobroblasts and capillaries in

loose extracellular matrix(ECM).

Granulation tissue then accumulates

connective tissue matrix and results in scar

formation.

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Processes

Repair by connective tissue deposition

consists of four processes:

1. Angiogenesis

2. Migration and proliferation of fibroblasts.

3. Deposition of ECM(scar formation)

4. Remodeling

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Angiogenesis

Blood vessels are produced in two ways:

1. Vasculogenesis, in which primitive vascular

network is assembled from angioblasts

(endothelial cell precursors).

Endothelial precursor cells(EPC) present in

bone marrow may contribute in angiogenesis

by moving towards the injured tissue.

They may replace the lost endothelial cells.

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2. Neovascularization, in which pre-existing

vessels send out capillary sprouts to produce

new vessels. It occurs in 5 steps:

1. Vasodilation due to nitric oxide and increased

capillary permeability of pre-existing vesselsinduced by vascular endothelial growth

factor(VEGF)

2. Migration of endothelial cells toward area oftissue injury.

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3. Proliferation of endothelial cells just behindthe leading front of migrating cells.

4. Inhibition of endothelial cell proliferation andremodelling into capillary tubes.

5. Recruitment of periendothelial cells(pericytesor smooth muscle cells) to form mature

vessels.

New vessels are leaky due to incompletelyformed interendothelial junctions and

increased transcytosis. For this reason granulation tissue is

edematous.

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Growth factors in angiogenesis:

Several factors induce angiogenesis, but mostimportant are:

1. Vascular endothelial growth factor(VEGF)

2. Basic fibroblast growth factor(FGF).

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VEGFs are expressed in low levels in tissue

can be induced by various factors like PDGF,TGF-, TGF- and hypoxia.

Stimulate proliferation and motility ofendothelial cells resulting in capillarysprouting.

FGFs consists of 20 members including FGF-1and FGF-2.

FGF-2 stimulates proliferation of endothelial

cells. Also promotes migration of macrophages and

fibroblasts to damaged area

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Newly formed vessels need stabilization.

Angiopoietins 1 and 2 initiate stabilization

process by recruiting pericytes

PGDF recruits smooth muscle cells.

TGF- enhances production of ECM proteins

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Migration of fibroblasts and ECM

deposition(scar formation)

Scar formation builds on granulation tissueframework.

Occurs in 2 steps:

1. Migration and proliferation of fibroblasts intothe site of injury.

2. Deposition of ECM by these cells.

The recruitment and proliferation offibroblasts is driven by many growth factorslike PDGF, FGF-2, and TGF-.

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These factors are derived from activated

endothelium and inflammatory cells especially

macrophages.

Mast cells and lymphocytes may also

contribute in fibroblast proliferation.

Later, number of proliferating fibroblasts andnew vessels decreases and ECM deposition is

increased.

Collagen is synthesized by fibroblasts. Same growth factors stimulate ECM synthesis.

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Ultimately scar is evolved in the granulation

tissue.

Scar consists of inactive fibroblasts, dense

collagen, fragments of elastic tissue and other

ECM components.

As scar matures, vascular regression occurs in

scar which becomes pale and largely

avascular.

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Growth factors involved in scar

formation

Factors involved in scar formation include TGF-

, PDGF, FGF and cytokines.

TGF- is a polypeptide and a potent

fibrogenic agent.

It stimulates production of collagen,

fibronectin, and proteoglycans.

Inhibits collagen degradation by decreasing

proteinase activity.

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It also inhibits lymphocyte proliferation and

can have strong anti-inflammatory effect.

PDGF is stored in platelets and released onplatelet activation.

Produced by endothelial cells, activated

macrophages and smooth muscle cells. It causes migration and proliferation of

fibroblasts, smooth muscle cells and

macrophages.

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Cytokines like IL-1 and TNF- may also

function as growth factors and participate in

scar formation.

They induce fibroblast proliferation and can

have fibrogenic effect.

They stimulate synthesis of collagen as well.

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ECM and tissue Remodeling

Scar ECM continues to be modified and

remodeled even after deposition.

The outcome of repair process is a balance

between ECM synthesis and degradation.

The degradation of collagens and other ECM

components is done by matrix

metalloproteinases(MMPs).

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MMPs include:

1. Interstitial collagenases, which cleave fibrillar

collagen.2. Gelatinases which degrade amorphous

collagen and fibronectin.

3. Stromelysins which degrade ECMconstituents like proteoglycans, laminin,

fibronectin and amorphous collagen.

MMPs are produced by various cells likefibroblasts, macrophages, neutrophils and

epithelial cells.

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Their synthesis is regulated by growth factors,

cytokines and some other factors.

TGF- inhibits MMPs synthesis. The activity of MMPs is tightly controlled due

to their potential to produce havoc in tissues.

They are activated only at site of tissue injury.

Activated collagenases can be rapidly inhibited

by tissue inhibitors of metalloproteinases

(TIMPs), produced by mesenchymal cells.

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Thank you