1. Lecture # 31 TISSUE REPAIR: REGNERATION, HEALING & FIBROSIS - 3 Dr. Iram Sohail Assistant Professor Pathology College Of Medicine Majmaah University

2. OBJECTIVES Describe cell & tissue regeneration Explain the process of repair by connective tissue Discuss angiogenesis Discuss the migration of fibroblast & extracellular deposition (scar formation) Explain extracellular matrix & tissue remodeling

3. CELL & TISSUE REGENERATION In labile cells (continuously dividing cells), cell renewal occurs continuously Examples Bone marrow Gut epithelium Skin

4. Whenever there is a damage to gut epithelium or increased loss of blood cells, the stem cells will go into differentiation & proliferation and lost or damaged cells will be replaced by new cells. In bone marrow, this renewal occurs because of growth factors & colony stimulating factors.

5. Tissue regeneration can occur in stable cells (parenchymal organs) like liver, pancreas, adrenal gland, thyroid, lung. Best example is live regeneration in liver transplantation, in which the donor liver & recipient liver both go into regeneration and acquire almost the same size & weight in both.

6. This regeneration of liver is possible because of growth factors like, – HGF (hepatocytes growth factor) – TGF – alpha (transforming growth factor – alpha)

8. REPAIR BY CONNECTIVE TISSUE If the tissue injury is severe or chronic (long standing)and causing damage of parenchymal cells and epithelia & as well as stroma, or if the non-dividing cells are injured, then repair occurs by scar formation (not regeneration).

9. Repair starts within 24 hours of injury by the help of fibroblast & endothelial cells.

10. By 3 to 5 days, granulation tissue (pink, soft tissue, composed of fibroblast and newly formed blood vessels) is formed. Eventually the granulation tissue accumulates connective tissue and scar formed.

11. Repair by connective tissue is composed of 4 processes. 1.Angiogenesis (Formation of new blood vessels) Angiogenesis or neovascularization is an important step in the process of healing, in which preexisting vessels send out small capillaries to form new vessels.

12. The main steps in angiogenesis are Vasodilation due to nitric oxide Increased vascular permeability due to VEGF (vascular endothelial growth factor) Migration of endothelial cells towards the area of injury

13. Proliferation of endothelial cells Recruitment of peri-endothelial cells Formation of mature blood vessels Growth factors involved in angiogenesis are VEGF, FGF, and TGF-beta

15. 2 & 3. Migration of fibroblast & ECM deposition It occurs in 2 steps Migration & proliferation of fibroblast into the site of injury Deposition of ECM by these cells

16. Growth factors responsible for this are – PDGF – FGF-2 – TGF- beta (most potent fibrogenic growth factor) Secreted by macrophages, lymphocytes & mast cells.

17. Collagen synthesis occurs by fibroblast and collagen accumulates & eventually it transform into a pale, avascular scar is formed.

18. 4.ECM & tissue remodeling Transformation of granulation tissue into scar formation involves shifts in the composition of ECM. The outcome of tissue repair is a balance between ECM synthesis & degradation.

19. The degradation of collagen and other ECM are caused by MMPs (matrix metalloproteinases).

20. MMPs include – Interstitial collagenases – Gelatinases MMPs are produced by – Neutrophils – Macrophages – Epithelial cells – Fibroblasts

21. MMPS are tightly regulated/inhibited by – TIMPs (tissue inhibitors of metalloproteinase) – Growth factors