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The Extracellular Space

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Presentation on theme: "The Extracellular Space"— Presentation transcript:

1 The Extracellular Space
Epithelial tissues closely packed cells lining spaces in the body (e.g. skin, intestine, etc) Connective tissues Largely composed of non-living extracellular material (e.g. cartilage, tendon, dermis)

2 The Extracellular Matrix (ECM)
An organized network of materials located beyond the plasma membrane

3 Basement membranes Thick regions of ECM Surround muscle/fat
Underlie the basal surface of epithelial tissues

4 Basement membranes Separate different tissues
Provide mechanical support Barrier to macromolecule and cellular movement Substrate for cell migration Generate signals that maintain cell survival

5 ECM: Collagens 27 different types
High tensile strength (resistant to pulling forces) Alpha-helical trimers bundle together into fibrils Types I, II, III (fibrillar) form rigid cables Adjacent collagens are strengthened by covalent cross-links Hydroxylysine - lysine Type IV (nonfibrillar) can form an interconnected lattice

6 ECM: Collagens 27 different types
Type IV (nonfibrillar) can form an interconnected lattice Composed of helical and non-helical segments (flexibility) Globular domains at each end (lattice contact points) Collagens bind: Fibronectins Integrins (cell surface)

7 ECM and disease Diseases caused by defects in collagen genes
Osteogenesis imperfecta Fragile bones Ehlers-Danlos syndrome Hyperflexible joints, highly extensible skin

8 ECM: Proteoglycans Protein core + glycosaminoglycan (GAG) polysaccharide complex High amount of negative charge binds cations and H2O Hydrated gel resists compressive forces Hyaluronic acid links many proteoglycans to form large molecules Fill the scaffold created by collagens

9 ECM: Fibronectins Modular domains for interactions
Bind collagens, proteoglycans, integrins at cell surface NC cells

10 ECM: Laminins 3 polypeptides linked by disulfide bonds
Form a second lattice interwoven with Collagen IV lattice Bind to proteoglycans, integrins at cell surface PGC on laminin

11 ECM Remodeling Matrix metalloproteinases (MMPs)
Degrade ECM proteins to enable: Tissue remodeling Cell migration Wound healing

12 Steps leading to metastatic spread
MMP activity

13 Cell - ECM Interactions
Plasma membrane talin Integrins Only found in animals Heterodimer of alpha and beta subunits 18 alpha and 8 beta subunits known 12 different alpha/beta combinations known Transmembrane proteins Extracellular domain, transmembrane domain, intracellular domain Inside-out signaling Post-translational alterations to cytoplasmic tail regulate conformation changes in extracellular domain Talin separates beta from alpha to open receptor to active state

14 Inactive

15 Active


17 Cell – ECM: Integrins Ligand binding
RGD loop of Fibronectin binds to integrin receptor extracellular domain Isolated RGD Loop can be exploited to block platelet aggregation / blood clotting

18 Cell – ECM: Integrins Adhesion to substrate
Receptors cluster increasing overall strength Signal transmission Binding of ligand (collagen) can change cytoplasmic domain Cytoplasmic domain can activate kinases such as FAK and Src Activated kinases can transmit signals to nucleus and change gene expression

19 Cell – ECM: Integrins Structures important for adhesion to substrate
Focal adhesions: Scattered, discrete, transient, dynamic, rapidly form and break Clusters of integrins bound to collagen / Fibronectin Cytoplasmic domains attach to cytoskeleton connecting exterior forces to internal signals Actin filaments Focal adhesion kinase (FAK)

20 Forces exerted by focal adhesions

21 Cell – ECM: Integrins Structures important for adhesion to substrate
Hemidesmosome more permanent anchor to basement membrane Integrins bound to laminin to dense collection of intermediate filaments

22 ECM and disease Disease: epidermolysis bullosa
Epidermis poorly connected to basement membrane / dermis Fluid accumulates in between = blister (keratins)

23 Cell - ECM Interactions

24 Cell - Cell Interactions
Cadherins: Ca2+ dependent adhesion Homophilic interactions allow self-sorting of mixed cell populations Disease role: metastasis of cancer Lose adhesion by downregulating cadherin expression Penetrate / invade barriers by upregulating MMP expression

25 Cell - Cell Interactions
Structures important for cell-cell adhesion Adherens junctions (30nm gap between cells) Cadherin-cadherin interactions in belt-like strips holding two cells together Cytoplasmic domains link to the cytoskeleton

26 Cell - Cell Interactions
Structures important for cell-cell adhesion Desmosomes (1 um diameter disc) Resist mechanical stress Cadherin-cadherin interactions linked to cytoskeleton (intermediate filaments)

27 Cell - Cell Interactions
Tight junctions Seal two membranes together Block paracellular movement Occludin and claudins (24 genes) Important for maintaining blood-brain barrier

28 Cell - Cell Interactions
Gap junctions Join cytoplasmic spaces between adjacent cells via a narrow pore 1.5nm diameter 1kD cutoff, small molecules freely pass (ATP, cAMP, Ca2+, etc) Subunits are connexins Open / close regulated by phosphorylation Integrates cells of a tissue into a functional unit


30 Cell - Cell Interactions

31 Plant cell-cell interactions
Plasmodesmata Join adjacent plant cytoplasmic spaces Capable of dilation, 1kD cutoff can open to a 50kD cutoff Exploited by some plant viruses

32 Roles of the plant cell wall
Structural role supporting and protecting plant cells Cellulose microfibrils confer tensile strength Signaling roles Cell wall-associated transmembrane protein kinases Dynamic not static, undergoes significant remodeling

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