Fundamentals of Cell Biology
Introduction to the extracellular matrix (ECM)
Image Credit: Riccardo Cassiani-Ingoni / Science Photo Library
Vertebrate body primarily consists of extracellular space
Connective tissues fill this space, largely composed of ECM
Variability in ECM Amount:
Abundant in cartilage and bone
Sparse in brain and spinal cord
Functions of ECM:
Determines form and shape
Provides mechanical support
Serves as a substrate for cell adhesion and migration
Regulates cell signaling and differentiation
Major components include:
Collagen
Fibronectin
Integrin
Laminin
Proteoglycan
Secreted by cells within it:
Fibroblasts in soft tissues responsible for ECM secretion
Specialized fibroblast-like cells in bone and cartilage, each with differing compositions
Epithelial cells secrete the basal lamina
Description:
A dynamic network of extracellular proteins and polysaccharides
Composition varies based on tissue type
Components:
Fibrous structural proteins (collagens, elastin)
Adhesive proteins (fibronectin, laminin)
Polysaccharides (glycosaminoglycans, proteoglycans)
Function:
Provides tensile strength to ECM
Prevalence:
Most abundant vertebrate protein (~25% by mass)
Extensively characterized multi-gene family (25 specific a-collagens)
Types of Collagen:
Fibrillar (Types I, II, III, V, XI): connective tissues
Fibril-associated (Types IX, XII): link fibrils
Network-forming (Types IV, VII): basement membrane support
Description:
Long, stiff, triple-helical structure
Comprised of three winded alpha chains forming a superhelix
Importance of Proline and Glycine in helix formation
Type I: Found in bones, skin, tendons, ligaments
Deficiency leads to severe bone defects
Type II: In cartilage
Deficiency causes cartilage issues
Type III: Supports skin and blood vessel structure
Results in fragile skin if mutated
Type IV: In basal lamina
Forms a sheet-like network
Unique Characteristics of Other Types:
Mutations lead to various diseases including myopia and fragile skin.
Collagen synthesized as procollagen with extra N- and C- terminal pro-peptides
Processes in ER/Golgi include:
Glycosylation and hydroxylation influencing H-bonding
Formation of a triple-stranded helix in ER
Cleavage of propeptides allows for self-assembly into collagen fibrils
Enhanced by stacking of collagen molecules
Cross-linking occurs at lysine residues in non-helical regions
Generally more flexible with interrupted structures
Characteristics:
Not cleaved post-secretion and bind to ECM components
Connects to other collagen fibrils and additional ECM components
Ehlers-Danlos syndrome: Mutations in type III collagen causing skin/joint issues
Osteogenesis imperfecta: Caused by mutations in type I collagen, leading to bone fragility
Chondrodysplasia: Mutations in cartilage collagens causing deformities
Scurvy: Vitamin C deficiency affecting collagen modification, causing fragility in vessels and bones
An inherited collagen disorder similar to Ehlers-Danlos syndrome
Resulting condition: flexible skin, termed 'winged cat disease'
Contribute to elasticity within the ECM
Key proteins:
Elastin: provides primary elasticity
Fibrillin: glycoprotein assisting in elastic fiber integrity
Properties: Elasticity surpasses that of rubber bands
Mutation in fibrillin gene leading to skeletal and cardiac issues
Associated defects include eye problems and fragile blood vessels
Types of GAGs:
Hyaluronan/hyaluronic acid
Chondroitin sulfate and dermatan sulfate
Heparan sulfate
Keratan sulfate
Proteoglycans: GAGs linked to proteins providing structure and function
GAGs and proteoglycans aggregate and interact to form large complexes
Resist compression by creating large hydration spheres
Regulate ECM activity by interacting with proteins
Serve as co-receptors for signaling molecules
Key Adhesive Proteins:
Fibronectin: Multi-domain protein facilitating cell attachment
Laminin: Key component of basal lamina
Cell Adhesion Molecules (CAMs): Such as NCAM
Composed of two sub-units linked by di-sulfide bonds
Each sub-unit has distinct functional domains including binding sites
Linked to intracellular actin via integrins for structural integrity
Extracellular fibronectin fibrils connect within cellular spaces
Process: Tension stretches fibronectin, activating binding sites for assembly
Ensures appropriate structural response to mechanical needs
Cell Migration: Fibronectin and laminin define pathways for cell movement
Cell Differentiation: ECM influences functional properties of cells (e.g. milk protein secretion)
Video of cells migrating on fibronectin surfaces
Forms flexible and thin ECM layers underlying epithelial cells
Composed of type IV collagen, heparin sulfate proteoglycan, and glycoproteins
Self-assembly properties of laminin and type IV collagen to form functional mesh
Acts as a filter in kidney glomerulus; provides selectivity for macromolecules
Roles in tissue regeneration and cell protection
Serve as primary ECM adhesion receptors
Comprise different subunits with specificity for ECM components
Critical for cell anchorage, signaling pathways, and cytoskeletal connections
Integrins cluster in focal adhesions connecting to actin filaments
Anchoring function in epithelial cells using integrin α6β4
Activation of integrins through binding to ligands, regulating matrix interactions and signaling pathways
Mediated by crosstalk with other pathways, including G-proteins and receptor kinases
Leukocyte Activation: Necessary for inflammation responses
Clot Formation: Role during injury response by aggregating platelets
ECM plays critical roles in determining cell shape and survival
Anchorage dependence observations: ECM level affects cell viability
Degradation of ECM necessary for effective cell movement
Important role in cancer cell migration facilitated by certain proteases
ECM is vital in cellular processes including structure, signaling, and support.
Components essential for various cellular functions, including tissue-specific roles as seen in basal lamina anatomy and interaction with integrins.