MATRICE EXTRACELLULARE - ECM

E’ un complesso miscuglio di

i) Proteine

ii) Glicoproteine

iii) proteoglicani

strutturali e funzionali, organizzati in un’unica ultrastruttura tri-dimensionale tessuto-specifica.

Diversità di forme e funzioni, adatte

ai requisiti di ciascun tessuto

- variazioni della quantità relativa dei vari tipi di

macromolecole

- modo in cui esse si organizzano

Distinguiamo due tipi di ECM

• La matrice extracellulare (interstiziale) dei tessuti connettivi

• La lamina basale

Nella matrice extracellulare

le molecole dell’ECM

circondano le cellule

riempiendo gli spazi

interstiziali intercellulari

Nelle lamine basali le

molecole di ECM sono

deposte solo sulla superficie

basale su cui sono si

adagiano le cellule

Mentre nella matrice interstiziale le molecole tendono a formare un lattice

tridimensionale, la membrana basale si organizza invece in un piano

Types of ECMs

• Basement membrane (basal lamina)

• Epithelia, endothelia, muscle, fat, nerves

• Elastic fibers

• Skin, lung, large blood vessels

• Stromal or interstitial matrix

• Bone, tooth, and cartilage

• Tendon and ligament

Ruolo strutturale:

• supporto per le cellule

Regolazione

• divisione cellulare

• adesione

• motilità

Sviluppo

• migrazione

• differenziamento

Riserva di fattori di crescita

Trasduzione del segnale

• molecole dell’ECM -> recettori di superficie -> espressione genica

Funzioni dell’ ECM (attive)

Why do all multicellular animals have ECM?

• Act as structural support to maintain cell organization and integrity (epithelial tubes; mucosal lining of gut; skeletal muscle fiber integrity)

• Compartmentalize tissues (pancreas: islets vs. exocrine component; skin: epidermis vs. dermis)

• Provide hardness to bone and teeth (collagen fibrils become mineralized)

• Present information to adjacent cells:

• Inherent signals (e.g., RGD motif in fibronectin)

• Bound signals (BMP7, TGFβ, FGF, SHH)

• Serve as a highway for cell migration during development (neural crest migration), in normal tissue maintenance (intestinal mucosa), and in injury or disease (wound healing; cancer)

Nella maggior parte dei tessuti connettivi le macromolecole della

matrice sono secrete in gran parte dai fibroblasti

Altre proteine della famiglia dei fibroblasti:

• Condroblasti -> formano la cartilagine

• Osteoclasti -> formano l’osso

Types of ECM Components

• Proteoglycans

• Perlecan, aggrecan, agrin, collagen XVIII

• Hyaluronan (no protein core)

• Collagens

• Fibrillins, elastin, LTBPs, MAGPs, fibulins

• Large Glycoproteins

• Laminins, nidogens, fibronectin, vitronectin

• “Matricellular” Proteins

• SPARC, Thrombospondins, Osteopontin, tenascins

GLYCOSAMINOGLYCANs - GAGs

Glycosaminoglycans (GAGs) are unbranched polysaccharide chains composed of

repeating disaccharide units.

One of the two sugars in the repeating disaccharide is always an amino sugar (N-

acetylglucosamine or N-acetylgalactosamine), which in most cases is sulfated (----).

The second sugar is usually a uronic acid (glucuronic or iduronic).

Hyaluronan (also called hyaluronic acid or hyaluronate)is the simplest of the GAGs.

It consists of a regular repeating sequence of up to 25,000 disaccharide units, is found in variable amounts in all

tissues and fluids in adult

Funzioni:• Resistenza a forze di compressione (tessuti/cartilagini)

• Riempitore (sviluppo embrionale)

• Presente nel fluido articolare (lubrificante)

FDA approved HA for cosmetic use

in humans – 2003:

The role of HA in atrioventricular canal

morphogenesis:

Role of HA in morphogenesis:

• Acts as space filler and facilitator of cell migration

– If synthesized on the basal side of an

epithelium, creates a cell-free space into

which other cells can migrate

Functions of hyaluronan:

• Resists compressive forces in joints and tissues

– Important constituent of joint fluid

• In osteoarthritis, decreased concentration and decreased

molecular weight of intra-articular HA

Classified by sugar composition

– Keratan sulfate, chondroitin sulfate, dermatan sulfate, heparan sulfate

• Modification of sugar residues allows for enormous diversity

• Associate with each other and with other ECM components to make complex meshworks

Proteoglycans are composed of GAG chains covalently

linked to a core protein

Are Composed of GAG Chains Covalently Linked to a Core Protein

proteoglycans can contain as much as 95% carbohydrate by weight, mostly in the form

of long, unbranched GAG chains, each typically about 80 sugars long

Proteoglycans

Intrappolamento dell’acqua • Resistenza alla compressione

• Ritorno alla forma originale

Creazione di spazi

Legame alle fibre di collagene • Formano una rete

• Nell’osso, si combinano con l’idrossiapatite di calcio e carbonato di calcio.

Adesione cellulare • Migrazione cellulare durante lo sviluppo embrionale

Possono regolare l’attività di fattori di crescita (quali FGF)

Funzione dei proteoglicani

Aggrecan is the major glycoprotein of articular cartilage:

• Provides hydrated gel structure that endows cartilage with load-bearing properties

• Chondroskeletal morphogenesis during development

Signaling roles of proteoglycans:

• Proteoglycans can regulate the activities of secreted proteins– Gels formed by GAG chains act as “sieves” that regulate passage of molecules by size and charge

– Bind secreted signaling molecules

• Control diffusion, range of action, lifetime, modify signaling activity– e.g.,heparan sulfate immobilizes chemokines on the endothelial surface of a blood vessel at a site of

inflammation

• Cell-surface proteoglycans act as co-receptors