Tissue Repair

Davis Massey, D.D.S., M.D.

Department of Pathology
MCV/VCU
 Repair

Reading: Robbins: Pathologic Basis of

Disease, chapter 3, pp 47 - 59
 Repair
Regeneration of injured cells by cells of
same type as with regeneration of
skin/oral mucosa (requires basement
membrane)
Replacement by fibrous tissue
(fibroplasia, scar formation)
Both require cell growth, differentiation,
and cell-matrix interaction
 Tissue Regeneration

Controlled by biochemical factors

released in response to cell injury, cell
death, or mechanical trauma
Most important control: inducing resting
cells to enter cell cycle
Balance of stimulatory or inhibitory factors
Shorten cell cycle
Decrease rate of cell loss
 Varieties of Proliferative
Potential
Labile (always dividing) cells:
Replace dying cells
Epithelia: skin, oral cavity, exocrine ducts,
GI tract, GYN, hematopoietic
Stable (quiescent) cells:
Usually G0 and low rate of division
Driven into G1 and rapid proliferation
Liver, kidney, pancreas, endothelium,
fibroblasts
 Varieties (Contd)

Permanent (non-dividing ) cells:

Permanently removed from cell cycle
Irreversible injury leads only to scar
Nerve cells, myocardium
 Intercellular Signaling

3 pathways
Autocrine: cells have receptors for their
own secreted factors (liver regeneration)
Paracrine: cells respond to secretion of
nearby cells (healing wounds)
Endocrine: cells respond to factors
(hormones) produced by distant cells
 Growth Factors and Molecular
Events
Polypeptide growth factors (e.G., PDGF,
FGF, TGF-) with many (pleiotropic)
effects
Proliferation, migration, differentiation,
remodeling (all part of wound healing)
Gene expression (protooncogenes)
Sequence of events in factor signaling
Receptor binding (ligation)
 Molecular Events (Contd)

Receptor activation: monomers >

dimerization > autophosphorylation
Signal transduction and second
messengers (e.g., GTP-binding proteins,
phospholipases, MAP kinases)
Induce expression of transcription factor
genes (e.g., myc, fos, jun)
Cell cycle (growth) regulated by cyclins
 Growth Factors

Epidermal growth factor (EGF)

Keratinocytes, fibroblasts
Vascular endothelial growth factor
(VEGF)
Angiogenesis
Transforming growth factor- (TGF-)
Fibrogenesis
 Factors (Contd)

Platelet-derived growth factor (PDGF)

Migration and proliferation of fibroblasts,
smooth muscle, and monocytes
 Extracellular Matrix (ECM)

ECM provides turgor, rigidity, support,

adhesion substrate, reservoir for factors
ECM must remain intact for
parenchymal healing
Three ECM protein components
Collagens: most common; triple helix of
polypeptide chains; extracellular framework
of body
 ECM (Contd)

14 types
I-III: interstitial/fibrillar, most abundant
IV-VI: non-fibrillar, basement membranes
Adhesive glycoproteins: e.g., Laminin,
fibronectin, thrombospondin, integrins
which bind ECM components to each
other, and to other cells
Proteoglycans: sugars linked to proteins;
influence ECM permeability and structure
 Connective Tissue Repair
(Scar Formation)
Loss of parenchyma and ECM
Formation of new blood vessels
(angiogenesis), fibroblast migration and
proliferation (lay down collagen) < 24 hr
Granulation tissue: pink, soft, granular
grossly
Maturation and organization
(remodeling) of fibrous tissue
 Angiogenesis

Vessels derive from endothelial cell

precursors (angioblasts) or from
budding of pre-existing vessels
BM degradation
Endothelial migration
Endothelial proliferation
Endothelial maturation
Periendothelial cell recruitment (pericytes,
smooth muscle)
 Fibrosis (Fibroplasia)
Occurs within the granulation tissue
framework (new blood vessels and
loose ECM)
Proliferation of fibroblasts at site of
injury
Growth factors (TGF-, PDGF, EGF,
FGF)
Cytokines (IL-1, TNF-)
Deposition of ECM (collagen)
 Scar Remodeling

Remodeling to strengthen repair

Metalloproteinases (interstitial
collagenases, gelatinases, stromelysins)
Produced by macrophages, neutrophils,
fibroblasts as inactive precursors
In response to local factors
Debris carried away by phagocytes
(debridement)
 Wound Healing: Primary Union

Clean incision
Line of closure fills with clotted blood
Dehydration at surface creates scab
24 hr: neutrophils, mitoses of basal
epithelium
Wound Healing: Primary Union
1 - 2 days: epithelial basal cells grow
along cut dermis
3 days: neutrophils gone,
macrophages enter, granulation
tissue forms
5 days: space filled with granulation
tissue and collagen fibrils bridge line
of closure, epidermis at pre-incision
thickness
 Primary Union (Contd)

Week 2: accumulation of collagen,

fibroblasts, and blanching begins
(edema and inflammation reduced)
End of first month: connective tissue
devoid of inflammation; epidermis intact
Tensile strength increases to 70 - 80%
of unwounded skin in 3 months
 Wound Healing: Secondary
Union
Large tissue defect
More inflammation
More granulation tissue
Wound contraction - myofibroblasts
 Host Factors Influence
Inflammation and Repair

Nutrition
Steroids
Infection
Mechanical factors
Blood supply
Aberrations of Inflammation and
Repair
Inadequate scar formation
Wound dehiscence
Ulceration
Hypertrophic scar/keloid
Exuberant granulation tissue - proud
flesh
Wound contracture
 Summary

Wound healing as evolving, changing

process
Various mechanisms involved
Various mediators
Orderly movement, proliferation, and
differentiation of cells