1. Dr. Hiba Wazeer Al Zou’bi
Tissue Repair 1
Dr. Hiba Wazeer Al Zou’bi

3. Tissue repair
Repair (Healing): Restoration of tissue architecture and function after an injury
1- Regeneration:
Replacement of damaged cells by similar parenchymal cells and return to a normal state
Proliferation of residual (uninjured) cells that retain the capacity to divide, and by replacement from tissue stem cells
Typical response to injury in the rapidly dividing epithelia of the skin and intestines, and some parenchymal organs ( liver)
Requires intact connective tissue

4. 2- Scar formation
- The injured tissues are incapable of regeneration, or the supporting structures of the tissue are severely damaged
- Occurs by the laying down of connective (fibrous) tissue
- The fibrous scar cannot perform the function of lost parenchymal cells, but it provides enough structural stability .
- If fibrosis develops in a tissue space occupied by an inflammatory exudate, it is called organization (as in organizing pneumonia ).

5. The Proliferative Potential of Different Cell Types
Labile cells (continuously dividing):
Hematopoietic cells in the BM
Majority of surface epithelia:
Stratified squamous surface in skin, oral cavity, vagina and cervix
Cuboidal epithelium of ducts: salivary gland, pancreas, biliary tract
Columnar: GIT epithelium, uterus and fallopian tube
Transitional epithelium: Urinary tract
Stable cells (quiescent): Minimal replicative activity in normal state, but capable of proliferation in response to injury or loss of tissue mass:
Parenchyma of most solid tissue: Liver, Kidney, and Pancreas
Smooth muscles.
Permanent (nondividing): Injury is irreversible and results in Scar formation:
Cardiac muscle
Skeletal muscle
Neurones

6. Stem Cells Two important features:
Self renewal capacity (maintain a functional population of precursors for long periods of time)
Asymmetric replication (when a stem cell divides, one daughter cell enters a differentiation pathway and gives rise to mature cells, while the other remains an undifferentiated stem cell that retains its self-renewal capacity).
Two Types:
Embryonic stem cells: the most undifferentiated stem cells, and have extensive cell renewal capacity.
- Adult stem cells (tissue stem cells): less undifferentiated cells and are found among differentiated cells within an organ or tissue, the self-renewal capacity much more limited.

7. Examples of Adult Stem Cells Locations

8. Examples of Adult Stem Cells
Bone marrow
Liver
Skeletal muscle
Intestine
Skin
Hematopoietic stem cells Hering canal Satellite cells Crypt cells Hair follicle bulge

9. Growth Factor
Proteins that stimulate the survival and proliferation of particular cells.
Induce cell proliferation by binding to specific receptors and affecting the expression of genes whose products typically have several functions:
They promote entry of cells into the cell cycle, relieve blocks on cell cycle progression, prevent apoptosis, and enhance the synthesis of cellular proteins in preparation for mitosis.
A major activity of growth factors is to stimulate the function of growth control genes, many of which are called proto-oncogenes.

10. Growth Factors EGF (epidermal growth factor)
Mitogenic for keratinocytes and fibroblasts
Stimulates keratinocytes migration
Stimulates proliferation of granulation tissue
TGF-a(Transforming Growth factor –alfa):
Stimulates proliferation of hepatocytes, many other epithelia
HGF/scatter factor (hepatocyte growth factor)
Enhance proliferation of hepatocytes and other epithelial cells
Increase cell motility
VEGF (vascular endothelial growth factor)
Stimulates proliferation of endothelial cells
Increased vascular permeability

11. Growth Factor PDGF (platelet-derived growth factor)
Chemotactic for neutrophils, macrophage, fibroblast, smooth muscle cell
Activates and stimulates proliferation of fibroblasts, endothelial cells and other cells
Stimulates ECM protien synthesis
FGFs (fibroblast growth factors)
Chemotactic and mitogenic for fibroblast
Stimulates angiogenesis and ECM protien synthesis
KGF (Keratinocytes growth factors)(FGF7)
Stimulates keratinocyte migration, proliferation, and differentiation
TGF-b(Transforming Growth Factor Beta)
Chemotactic for leukocytes and fibroblasts
Supress acute inflammation

12. Patterns of Intercellular Signaling

13. Receptors for Growth Factors
1- Receptors with intrinsic tyrosine kinase activity:
- Once phosphorylated, the receptors can bind and activate other intracellular proteins (e.g., RAS, phosphatidylinositol 3[PI3]-kinase, phospholipase Cγ [PLC-γ]) and stimulate downstream signals that lead to cell proliferation.
2- Seven transmembrane G-protein coupled receptors:
- Contain seven-transmembrane α-helix segments
- After ligand binding, the receptors associate with intracellular guanosine triphosphate (GTP)-binding proteins (G proteins) that contain guanosine diphosphate (GDP).
- Binding of the G proteins causes the exchange of GDP with GTP, resulting in activation of the proteins.
- Several signaling pathways activated: cyclic AMP (cAMP)

14. 3- Receptors lacking intrinsic tyrosine kinase activity that recruit kinases:
- Ligand interaction induces an intracellular conformational change that allows association with intracellular protein kinases called Janus kinases (JAKs).
- Phosphorylation of JAKs activates cytoplasmic transcription factors called STATs (signal transducers and activators of transcription), which shuttle into the nucleus and induce transcription of target genes.

15. Examples of Signal Transduction Systems

16. Extracellular Matrix
1- Interstitial matrix: present in the spaces between cells in connective tissue, between epithelium and supportive vascular and smooth muscle structures. It is synthesized by mesenchymal cells (e.g., fibroblasts) and tends to form a three-dimensional, amorphous gel.
Fibrillary and nonfibrillar collagens
Elastin
Proteoglycans and hyaluronate
Fibronectin
2- Basement membrane: lies beneath the epithelium and is synthesized by overlying epithelium and underlying mesenchymal cells
Type IV collagen
Laminin

17. Major Components of the ECM

18. Three basic components of ECM:
(1) Fibrous structural proteins: collagens and elastins, confer tensile strength and recoil
(2) Water-hydrated gels: proteoglycans and hyaluronan, permit resilience and lubrication
(3) Adhesive glycoproteins that connect the matrix elements to one another and to cells: Fibronectin and laminin.

19. Components of the Extracellular Matrix
Collagen
Fibrillar collagens form major proportion of CT in healing wounds & scars
Hydroxylation, mediated by vit C, provides strength
Non-fibrillar (type IV) :main component of BM
Elastin
- The ability of tissues to recoil and return to a baseline structure. This is especially important in the walls of large vessels (which must accommodate recurrent pulsatile flow).
- Consists of a central core of elastin surrounded by a meshlike network of fibrillin glycoprotein.
- Defects in fibrillin synthesis lead to skeletal abnormalities and weakened aortic walls as in Marfan syndrome.

20. Components of the Extracellular Matrix
Proteoglycans and Hyaluronan:
Proteoglycans consist of long polysaccharides, called glycosaminoglycans or mucopolysaccharides ( dermatan sulfate and heparan sulfate), linked to a protein backbone.
- Serve as reservoirs for growth factors secreted into the ECM (e.g., fibroblast growth factor [FGF], HGF).
- Integral cell membrane proteins that have roles in cell proliferation, migration, and adhesion.
- Hyaluronan (also called hyaluronic acid), a huge mucopolysaccharide without a protein core binds water, and forms a viscous, gelatin-like matrix.

21. Proteoglycan

22. Adhesive glycoproteins:
Fibronectin (a major component of the interstitial ECM):
Have specific domains that bind to collagen, fibrin, heparan, and proteoglycans and can also attach to cell integrins via a tripeptide arginine–glycine–aspartic acid (abbreviated RGD) motif.
Tissue fibronectin forms fibrillar aggregates at wound healing sites
Plasma fibronectin binds to fibrin within the blood clot that forms in a wound.
Laminin (Most abundant glycoprotein in basement membrane)
Connects cells to underlying ECM components such as type IV collagen and heparan sulfate.
Can also modulate cell proliferation, differentiation, and motility.

23. Fibronectin

24. Laminin

25. Adhesion receptors (Cell adhesion molecules (CAMs))
1- Immunoglobulins
2- Cadherins
3- Selectins
4- Integrins

26. Integrins: - leukocyte adhesion to endothelium.
The main cellular receptors for ECM components, such as fibronectins and laminins.
Present in the plasma membrane of most cells, with the exception of red blood cells. They bind to many ECM components through RGD motifs, initiating signaling cascades that can affect cell locomotion, proliferation, and differentiation.
Their intracellular domains link to actin filaments, thereby affecting cell shape and mobility.

27. Functions of the Extracellular Matrix
Mechanical support for cell anchorage and cell migration, and maintenance of cell polarity
Control of cell proliferation by binding and displaying growth factors and by signaling through cellular receptors of the integrin family.
Scaffolding for tissue renewal: integrity of the basement membrane or the stroma of parenchymal cells is critical for the organized regeneration of tissues.
Establishment of tissue microenvironments: Basement membrane acts as a boundary between epithelium and underlying connective tissue.