1. Tissue repair (2 of 4) Ali Al Khader, M.D. Faculty of Medicine
Al-Balqa’ Applied University

2. What will we discuss today?
Growth factors
Role of the extracellular matrix in tissue repair

3. Growth factors They promote entry of cells into the cell cycle
They relieve blocks on cell cycle progression
They prevent apoptosis
They enhance the synthesis of cellular proteins in preparation for mitosis

4. Growth factors A major activity is: to stimulate proto-oncogenes
Produced by -macrophages
-lymphocytes
-parenchymal cells
-stromal (connective
tissue) cells
*They are growth control genes
*Mutations in them unrestrained cell proliferation characteristic of cancer (oncogenesis)
recruited to the site of injury or are activated at this site, as part of the inflammatory process
in response to cell injury

5. Selected growth factors
Autocrine VS Paracrine VS Endocrine signaling…
Not only from platelets
Robbins basic pathology 9th edition…modified

6. Signaling Mechanisms of Growth Factor Receptors
These are for plasma membrane receptors
*Intracellular receptors:
…their ligands are hydrophobic
vitamin D steroid thyroid
hormones hormones
Robbins basic pathology 9th edition…modified
Usually monomeric

7. Signaling mechanisms, cont’d
Receptors with intrinsic kinase activity
…binding of ligand dimerization phosphorylation of the
receptor subunits the receptor binds and activates other
intracellular proteins
RAS
Transcription
Phosphatidylinositol 3[PI3]-kinase
phospholipase Cγ [PLC-γ])

8. Signaling mechanisms, cont’d
G protein–coupled receptors
…seven-transmembrane α-helix segments
… = seven-transmembrane receptors
…binding to ligand the receptors associate with intracellular guanosine triphosphate (GTP)-
binding proteins (G proteins) that contain guanosine diphosphate (GDP) exchange of GDP
with GTP activation of the G proteins
inositol 1,4,5-triphosphate (IP3)
Release of calcium from the ER
This is the largest family of plasma membrane receptors
cyclic AMP (cAMP)

9. Role of the Extracellular Matrix in Tissue Repair
Two basic forms:
-interstitial matrix
-basement membrane
Major 3 components:
-fibrous structural proteins such as collagens and elastins
-water-hydrated gels such as proteoglycans and hyaluronan
-adhesive glycoproteins
tensile strength and recoil
resilience and lubrication
connect the matrix elements to one another and to cells

10. Extracellular matrix Also: non-fibrillary collagens and fibronectin
Amorphous & non-lamellar
Also: non-fibrillary collagens and fibronectin
Robbins basic pathology 9th edition…modified

11. Collagen
3 separate polypeptide chains braided into a ropelike triple helix
30 collagen types have been identified
Some collagen types (e.g., types I, II, III, and V) form fibrils by virtue of lateral cross-linking of the triple helices … = fibrillary collagens
…particularly in healing
wounds and in scars
covalent bonds catalyzed by the
enzyme lysyl-oxidase
needs vitamin C

12. Collagen, cont’d Vitamin C deficiency????
Ehlers-Danlos & osteogenesis imperfecta genetic defects in
fibrillary collagens
*Examples of non-fibrillary collagens:
…type IV basement membrane
…type IX intervertebral discs
…type VII dermal-epidermal junctions

13. Elastin The ability to recoil
Walls of large vessels…recurrent pulsatile flow
Uterus, skin, ligaments….etc.
Central core of elastin + surrounding fibrillin glycoprotein
Its defect will cause …….

14. Proteoglycans and hyaluronan
…highly hydrated compressible gels
…e.g., cartilage in joints
…long polysaccharides, called glycosaminoglycans or
mucopolysaccharides (examples are dermatan sulfate and heparan
sulfate), linked to a protein backbone

15. Proteoglycans and hyaluronan, cont’d
… = hyaluronic acid
…huge mucopolysaccharide without a protein core
*Proteoglycans provide reservoirs for growth factors secreted into the
ECM (e.g., fibroblast growth factor [FGF], HGF)
*Some proteoglycans are integral membrane proteins…roles in cell
proliferation, migration and adhesion…by binding growth factors and
chemokines

16. Adhesive Glycoproteins and Adhesion Receptors
Fibronectin…of interstitial ECM
Laminin…of basement membrane
*Adhesion receptors: cell adhesion molecules (CAMs)…4 families:
-Immunoglobulins
-Cadherins
-Selectins
-Integrins

17. Fibronectin Disulfide-linked heterodimer
Produced by different cell types
Tissue and plasma forms
Domains for binding ECM components, e.g., collagen, proteoglycan…etc.
…and for binding cellular integrins (via 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 wound, providing the substratum for ECM deposition and re-epithelialization

18. Laminin The most abundant glycoprotein in basement membrane
Connects cells to underlying ECM components such as type IV collagen and heparan sulfate
Laminin can also modulate cell proliferation, differentiation, and motility

19. Integrins Transmembrane heterodimeric glycoprotein chains
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
Bind to many ECM components through RGD motifs, initiating signaling cascades that can affect cell locomotion, proliferation, and differentiation
Intracellular domains link to actin filaments, thereby affecting cell shape and mobility

20. 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
…by signaling through cellular receptors of
the integrin family
Scaffolding for tissue renewal
…disruption of the ECM results in a failure of the tissues to regenerate
and repair by scar formation
Establishment of tissue microenvironments
…e.g., The basement membrane forms part of the filtration apparatus in the kidney

21. Thank You