Raghda Al-Droubi

Marwa Abo Zour

Tissue repair (2 of 4)

What will we discuss today?

• Growth factors و التحول من مكان آلخر اضافة الى تكون ال migration و ال proliferation بأثروا على الخالا عشان حفزوا ال

extracellular matrix

• Role of the extracellular matrix in tissue repair ECM ه عبارة عن شغلتن اساستن:

1-Basement membrane

) interstitial matrix -2ما بن الخالا(

Growth factors

• They promote entry of cells into the cell cycle

• They relieve blocks on cell cycle progression 53Pرح شل ال GFال 53 ……… P (genome guardian)بدها اش وقفها متل ال cell cycleالنه ال ***

• They prevent apoptosis مو تموت.…و تنقسم و الخ cell cycle النهم بدهم الخلة تفوت ال apoptosis بمنعوا ال

• They enhance the synthesis of cellular proteins in preparation for mitosis

(للخلة او انزمات blocks ال همه عبارة عن )تكون بروتنات transcription\translation احنا بنحتاج

Protein synthesis :1- structural component ( blocks)

2-functional proteins ( enzymes)

عن حفزوا انقسام الخالا و proliferation of cells رح حفزوا ال

خلوهم دخلوا ال cell cycle ال هه عبارة عن تضاعف الDNA و ما تبعه من

mitosis

cell cycleعن ال blocks رح شلوا ال

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 injuryهدول هدفهم تعوض ال

proto-oncogenesبحفزوا جنات موجودة ف كروموسومات الخلة هاي الجنات اسمها GFبشكل عام ال ** oncogenesف الخالا السرطانة اسمهم ** Growth mostly stimulateبتصنع بروتنات تتحكم ف ال (proto-oncogenes)هدول الجنات **

Proto-oncogenes ** مهمن جدا ف ال cancer

oncogenes و بتحولوا ل mutationانه بصر لهم و بصر عندي تكاثر للخالا بشكل غر مسطر عله و

غر متوقف

Tumor suppressor genes P53** رح صنعول اشاء تعاكس عملة ال

oncogenesis (cancer)

Selected growth factors

Not only from platelets

Autocrine VS Paracrine VS Endocrine signaling…

Robbins basic pathology 9th edition…modified

• Autocrine : الخلة تفرز اش شتغل على نفس الخلة

• Paracrine : الخلة تفرز اش شتغل على خلة مجاورة

• Endocrine: الخلة تفرز اش مش ف الدم و بأثر على خلة بعدة

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

membraneارتبطت ب اشاء قدرت تمرق من ال **

• Receptor with intrinsic kinase activity dimerبصر فها تكون ل -1

pathwayجزء منه بتحفز و بحفزل 2-

• GPCRs

• Receptor without intrinsic kinase activity

cytokinesتذكروا عالقته بال 1-

tyrosine kinaseاالنزم ما فه جواته -2

GPCPف ال chemokinesبالعاده اما ال cytokinesلل receptorsبكون فه -3

JAKبكون اسمهم ال نفسه receptorمو من داخل ال tyrosine kinasesبحفزل ligand bindingبعد ال -4 STATال هوه ال transcription factorبحفز kinase phosphorylationبعملوا

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

Proto oncogene cancerمهم جدا ف ال

Kinase activity جواته بعمل

phosphorylation وجزء بفسر جزء <ل جزء منه<

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

ؤدي الى استبدال ligand لما رتبط ف ال

ACTIVEو بصر GTP بال GDPال

GDP >> inactive GTP >> active

Role of the Extracellular Matrix in Tissue Repair

repairالذراع االخز لعملية ال

• 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

1-Collagen ( fibrillary –non fibrillary) 2-Elastin 3-proteoglycan 4-hyaloronane 5-Fibronectin

:بتكون من بروتنن مهمن جدا

1- type four collagen (non fibrillary and non lamellar) 2-Lamin or proteoglycan

Extracellular matrix Amorphous & non-lamellar

Also: non-fibrillary collagens and fibronectin

Robbins basic pathology 9th edition…modified

لس على

شكل طبقات

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 >> مهم ف عملة الcross-linking ألنه مهم لالنزم المسؤول عن

هذه العملة

Collagen, cont’d

•Vitamin C deficiency???? Scurvy wound healing , gum , eyes: ؤدي الى مشاكل ف VC نقص : االسقربوط •

• 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

الناس ال جلدهم بكون

مرخ كتر

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 …….Marfan syndrome Normal trunk with very long arms and legs , problems in aorta

Proteoglycans and hyaluronan

• Proteoglycans: جزء كربوهيدات وجزء بروتين

…highly hydrated compressible gels :

lubricationامتصاص الصدمات باالضافة الى ال

…e.g., cartilage in joints

…long polysaccharides, called glycosaminoglycans or

mucopolysaccharides (examples are dermatan sulfate and heparan

sulfate جزء الكربوهدرات ), linked to a protein backbone جزء البروتن

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)

GF ارتباطه مع ال: من مهماته

*Some proteoglycans are integral membrane proteins…roles in cell

proliferation, migration and adhesion…by binding growth factors and

chemokines

adhesionبعضهم بكونوا موجودن ف غشاء الخلة وساعدوا ف عملة ال

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)

(RGD)من خالل تسلسل حمض امن معن fibrinرتبط بال **

tissue healing: وارتباطه شكل منصة لحدوث تفاعالت عله مثل ال , clot ال داخل ال fibrin مع ال Fibronectinرتبط **

• 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

cytoskeletonبسبب حدوث تغرات ف ال

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 منصة لحدوث التفاعالت

…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

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