🦠Cell Biology Unit 18 – Extracellular Matrix and Cell Adhesion

Key Components of the Extracellular Matrix

• Consists of a complex network of macromolecules secreted by cells into the extracellular space
• Includes fibrous proteins (collagen, elastin), glycoproteins (fibronectin, laminin), and proteoglycans
  • Collagen provides tensile strength and structural support to tissues
  • Elastin imparts elasticity and resilience, allowing tissues to stretch and recoil
• Contains non-fibrous components such as hyaluronic acid, a high molecular weight polysaccharide
• Serves as a reservoir for growth factors, cytokines, and other signaling molecules
• Provides a scaffold for cell attachment, migration, and tissue organization
• Influences cell behavior through mechanical and biochemical cues
• Varies in composition and properties depending on the tissue type and developmental stage

Structure and Function of ECM Molecules

• Collagen is the most abundant ECM protein, forming triple-helical structures that assemble into fibrils and fibers
  • Different types of collagen (I, II, III, IV) have specific tissue distributions and functions
• Fibronectin is a large glycoprotein involved in cell adhesion, migration, and differentiation
  • Contains binding sites for integrins, collagen, and other ECM components
• Laminin is a major component of basement membranes, mediating cell-matrix interactions
• Proteoglycans consist of a core protein with covalently attached glycosaminoglycan (GAG) chains
  • GAGs are highly negatively charged, attracting water and contributing to tissue hydration and compressive resistance
• Hyaluronic acid is a non-sulfated GAG that forms hydrated gels, providing tissue lubrication and space-filling properties
• ECM molecules interact with each other and with cell surface receptors to form a dynamic and organized network
• The specific composition and arrangement of ECM components determine the mechanical and biological properties of tissues

Cell Adhesion Molecules and Their Roles

• Cell adhesion molecules (CAMs) are cell surface proteins that mediate cell-cell and cell-matrix interactions
• Integrins are a major family of transmembrane receptors that bind to ECM proteins and regulate cell adhesion, migration, and signaling
  • Consist of α and β subunits that form heterodimers with specific ligand-binding properties
  • Integrin activation and clustering lead to the formation of focal adhesions, which link the ECM to the cytoskeleton
• Cadherins are calcium-dependent CAMs that mediate homophilic cell-cell adhesion
  • Play crucial roles in tissue morphogenesis, cell sorting, and the maintenance of tissue integrity
• Selectins are a family of CAMs involved in leukocyte trafficking and inflammation
  • Mediate the initial rolling and tethering of leukocytes to the endothelium during the inflammatory response
• Immunoglobulin superfamily CAMs (IgSF-CAMs) are involved in various cell-cell interactions
  • Neural cell adhesion molecule (NCAM) plays a role in neurite outgrowth and synaptic plasticity
• CAMs not only provide mechanical adhesion but also transduce signals that regulate cell behavior and fate

ECM-Cell Interactions and Signaling

• ECM-cell interactions are mediated by cell surface receptors, primarily integrins
• Integrins cluster and form focal adhesions upon binding to ECM ligands
  • Focal adhesions are multiprotein complexes that link the ECM to the actin cytoskeleton
  • Serve as signaling hubs that regulate cell adhesion, migration, and mechanotransduction
• Integrin signaling activates various intracellular pathways, including focal adhesion kinase (FAK) and Rho GTPases
  • FAK phosphorylation triggers downstream signaling cascades that control cell survival, proliferation, and differentiation
  • Rho GTPases (Rho, Rac, Cdc42) regulate actin cytoskeleton dynamics and cell motility
• ECM-bound growth factors (FGF, TGF-β) can be released and activate their respective signaling pathways
• Mechanical properties of the ECM (stiffness, elasticity) can influence cell behavior through mechanotransduction
  • Cells sense and respond to ECM rigidity through integrin-mediated adhesions and actomyosin contractility
• ECM-cell interactions are bidirectional, with cells constantly remodeling the ECM in response to various stimuli

ECM in Tissue Organization and Function

• ECM provides a structural framework for tissue organization and influences cell behavior and fate
• Basement membranes are specialized ECM structures that separate epithelial and endothelial cells from underlying connective tissue
  • Consist primarily of collagen IV, laminin, and proteoglycans
  • Regulate cell polarity, differentiation, and tissue compartmentalization
• Interstitial matrix is the ECM surrounding cells within connective tissues
  • Composition varies depending on the tissue type (bone, cartilage, tendon)
  • Provides mechanical support, facilitates nutrient diffusion, and regulates cell function
• ECM guides tissue morphogenesis during development through its influence on cell migration, adhesion, and differentiation
  • Epithelial-mesenchymal interactions during organogenesis are mediated by ECM components
• ECM contributes to tissue-specific functions
  • Collagen fibers in tendons and ligaments provide tensile strength and resistance to stretching
  • Proteoglycan-rich matrix in cartilage enables load-bearing and shock absorption
• ECM-cell interactions are crucial for maintaining tissue homeostasis and preventing pathological conditions

ECM Remodeling and Dynamics

• ECM undergoes constant remodeling in response to physiological and pathological stimuli
• Matrix metalloproteinases (MMPs) are a family of enzymes that degrade ECM components
  • Secreted as inactive proenzymes and activated by proteolytic cleavage
  • Tightly regulated by tissue inhibitors of metalloproteinases (TIMPs)
• Dysregulation of MMP activity can lead to excessive ECM degradation or accumulation, contributing to various diseases
• ECM synthesis is mediated by cells such as fibroblasts, chondrocytes, and osteoblasts
  • Collagen synthesis involves intracellular processing and extracellular fibril assembly
  • Proteoglycan synthesis occurs in the Golgi apparatus, followed by secretion into the extracellular space
• ECM turnover is a balance between synthesis and degradation, maintaining tissue integrity and function
• ECM remodeling is essential for wound healing, tissue repair, and regeneration
  • Provisional matrix (fibrin clot) forms initially, followed by the deposition of collagen and other ECM components
  • Remodeling of the ECM facilitates cell migration, proliferation, and differentiation during the healing process
• Growth factors (TGF-β, PDGF) and mechanical forces can stimulate ECM synthesis and remodeling

Pathological Alterations of ECM and Cell Adhesion

• Alterations in ECM composition, structure, or cell adhesion can contribute to various pathological conditions
• Fibrosis is characterized by excessive deposition of ECM, particularly collagen, leading to tissue stiffening and dysfunction
  • Occurs in response to chronic inflammation, injury, or metabolic disorders
  • Examples include liver cirrhosis, pulmonary fibrosis, and cardiac fibrosis
• Basement membrane thickening and ECM accumulation are hallmarks of diabetic complications (nephropathy, retinopathy)
• Defects in collagen synthesis or structure can cause connective tissue disorders
  • Ehlers-Danlos syndrome is characterized by hyperextensible skin and joint hypermobility due to collagen abnormalities
  • Osteogenesis imperfecta is caused by mutations in collagen I, leading to brittle bones and frequent fractures
• Impaired cell adhesion can contribute to tumor metastasis and invasion
  • Loss of E-cadherin expression in epithelial tumors enables cell detachment and migration
  • Overexpression of matrix metalloproteinases facilitates ECM degradation and tumor cell invasion
• Chronic inflammation can lead to ECM degradation and tissue damage
  • Rheumatoid arthritis is characterized by synovial inflammation and cartilage destruction mediated by MMPs
• Targeting ECM and cell adhesion molecules is a potential therapeutic strategy for various diseases

Practical Applications and Current Research

• Tissue engineering and regenerative medicine rely on the manipulation of ECM and cell adhesion to create functional tissue constructs
  • Biomaterials that mimic the native ECM composition and structure are used as scaffolds for cell growth and differentiation
  • Decellularized ECM from donor tissues can be used as a natural scaffold for tissue regeneration
• ECM-based therapies are being explored for wound healing and tissue repair
  • Collagen-based dressings and matrices promote wound closure and dermal regeneration
  • Hyaluronic acid-based hydrogels are used for cartilage repair and joint lubrication
• Targeting ECM remodeling enzymes (MMPs, TIMPs) is a potential strategy for treating fibrosis and cancer
  • MMP inhibitors have been investigated for their anti-tumor and anti-metastatic effects
  • TIMP delivery has shown promise in reducing fibrosis and promoting tissue regeneration
• Cell adhesion molecules are being targeted for drug delivery and immunotherapy
  • Antibodies against integrins or selectins can be used to deliver drugs specifically to tumor cells or sites of inflammation
  • CAR T-cell therapy involves genetically modifying T cells to express chimeric antigen receptors that target tumor-specific adhesion molecules
• High-throughput screening and proteomics approaches are being used to identify novel ECM and cell adhesion targets for therapeutic intervention
• Advances in imaging techniques (super-resolution microscopy, atomic force microscopy) are providing new insights into the nanoscale organization and dynamics of ECM and cell adhesion complexes