Tissue repair (2 of 4)

What will we discuss today?

• Growth factors

• Role of the extracellular matrix in tissue repair

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

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

Selected growth factors

Not only from platelets

Autocrine VS Paracrine VS Endocrine signaling…

Robbins basic pathology 9th edition…modified

Signaling Mechanisms of Growth Factor Receptors

*Intracellular receptors: …their ligands are hydrophobic vitamin D steroid thyroid hormones hormones

These are for plasma membrane receptors

Usually monomeric

Robbins basic pathology 9th edition…modified

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

Phosphatidylinositol 3[PI3]-kinase

phospholipase Cγ *PLC-γ])

Transcription

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

cyclic AMP (cAMP)

inositol 1,4,5-triphosphate (IP3) Release of calcium from the ER

This is the largest family of plasma membrane receptors

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

Extracellular matrix Amorphous & non-lamellar

Also: non-fibrillary collagens and fibronectin

Robbins basic pathology 9th edition…modified

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

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

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 …….

Proteoglycans and hyaluronan

• Proteoglycans:

…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

Proteoglycans and hyaluronan, cont’d

• Hyaluronan

… = 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

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

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

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

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

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