1. Tissue repair (3&4 of 4) Ali Al Khader, M.D. Faculty of Medicine
Al-Balqa’ Applied University

2. What will we discuss today:
Regeneration in tissue repair
Scar formation
Cutaneous wound healing
Pathologic aspects of repair

3. Regeneration in tissue repair
Labile tissues…rapid replacement
…basement membrane needs to be intact
…by proliferation of residual cells and differentiation of tissue stem cells
…for blood cells: proliferation of hematopoietic progenitors, driven by CSFs
(colony-stimulating factors)
Stable tissues…usually limited except in the liver
…nephrectomy…contralateral compensatory hypertrophy and hyperplasia of
proximal duct cells
…the residual connective tissue framework needs to be structurally intact
examples: pancreas, adrenal, thyroid, lung…etc.
modified

4. Robbins basic pathology 9th edition. Courtesy of R
Robbins basic pathology 9th edition..Courtesy of R. Troisi, MD, Ghent University, Flanders, Belgium

5. Steps in scar formation
1- Tissue defect/inflammation
2- Angiogenesis
3- Migration and proliferation of fibroblasts
+ abundant vessels + WBCs = granulation tissue (pink granular
appearance)
4- Extracellular matrix deposition
5- Reorganization of the fibrous tissue (remodeling) to produce the
stable fibrous scar

6. Robbins basic pathology 9th edition

7. Angiogenesis Occurs in: -tissue repair
-development of collateral circulations at sites of ischemia
-tumors
Primarily from existing venules
There are therapies that are being developed to either augment or inhibit the process

8. Angiogenesis steps Vasodilation and permeability NO VEGF VEGF
Recruitment of periendothelial cells (pericytes for small capillaries and smooth muscle cells for larger vessels) to form the mature vessel
Induced by VEGF
Robbins basic pathology 9th edition
Suppression of endothelial proliferation and migration and deposition of the basement membrane
Proliferation of endothelial cells just behind the leading front of migrating cells
VEGF

9. Growth factors involved in angiogenesis
The most important are VEGF & FGF-2
Among VEGF family, VEGF-A is the most important
PlGF = placental growth factor…also a member of the VEGF family
For vessel development in the embryo: VEGF-B & PlGF
Also important for lymphangiogenesis: VEGF-C & -D

10. Growth factors involved in angiogenesis, cont’d
The most important receptor for angiogenesis is: VEGFR-2 on
endothelial cells…a tyrosine kinase receptor
*Of VEGF inducers: -hypoxia the most important
-PDGF
-TGF-alpha
-TGF-beta

11. Growth factors involved in angiogenesis, cont’d
FGF:
…can bind to heparan sulphate and be stored in the ECM
… proliferation & migration of: -endothelial cells
-fibroblasts
-macrophages
-epithelial cells
Angiopoietins (Ang1 & Ang2):
…for the structural maturation (stabilization) of new blood vessels
by recruitment of pericytes & SM cells
deposition of connective tissue

12. Growth factors involved in angiogenesis, cont’d
Ang1…its receptor: Tie2 (a tyrosine kinase receptor)
Also involved in stabilization process: -PDGF
-TGF-beta
Recruits SM cells
endothelial cell proliferation & migration
Production of ECM proteins

13. ECM enzymes Matrix metalloproteinases (MMPs): -Zinc-dependent
-produced by many cell types
-initially as inactive precursors…activated by proteases (e.g., plasmin)
-They degrade ECM and permit remodeling & extension of the vascular tube
-of them: -interstitial collagenases
-gelatinases
-stromelysins

14. ECM deposition FGF, TGF-beta & PDGF are the most important
TGF-beta: -mainly TGF-beta 1
-its receptor has serine-threonine kinase activity
-transcription factors: Smads
-functions: -production of collagen, fibronectin & proteoglycans
- proteinase activity & activity of TIMP

15. ECM deposition, cont’d PDGF:
-Migration and proliferation of -fibroblasts
-SM cells
-Migration of macrophages
IL-1 & IL-13:
-collagen synthesis by fibroblasts
-proliferation and migration of fibroblasts

16. Cutaneous wound healing
Occurs by 1st or 2nd intention according to wound nature and size

17. Healing by 1st intention, cont’d
Epithelial regeneration is the principal mechanism of repair
Steps:
-within 24 hours: neutrophils & fibrin clot
-within hours: migration and proliferation of epithelial cells to form thin continuous epithelial layer beneath the scab
-by day 3: -less neutrophils and more macrophages
-granulation tissue in the incision space
-thicker epithelial layer
-collagen fibers present but still not bridging the incision
-by day 5: -peak neovascularization
-more abundant collagen beginning to bridge the incision
-normal epidermal thickness is retained
-with time: -less inflammation, edema, and vascularity
-more collagen

19. Healing by 2nd intention
More tissue defect
Large wounds
Abscesses
Ulcers
Infarctions
Larger clot/scab
More inflammation
More abundant granulation tissue and larger scar
Wound contraction will follow…very important here in reducing defect size

20. Wound strength By 1 week: 10% of original strength
By 3 months: 70% to 80%
…then: mostly no further improvement
This increase is due to: -more collagen synthesis than degradation in
the first 3 months
-gradual increase in cross-linking and fiber size of
collagen

21. Pathologic aspects of repair
Name this condition ……
Robbins basic pathology 9th edition

22. Pathologic aspects of repair, cont’d
Excessive collagen and other ECM components deposition in parenchymal tissues in chronic diseases = Fibrosis
…due to persistent tissue injury
…can lead to organ dysfunction
…examples: -lung (pulmonary) fibrosis
-liver (hepatic) fibrosis…its end stage is called: ……

23. Thank You