RM

Lecture 09 2024 10 03 ECM

Learning Objectives

  • Define and characterize the extracellular matrix (ECM).

  • Delineate the roles of different ECM components.

  • Identify the roles of Integrins in mammalian cells.

  • Differentiate between models for cellular adhesion.

  • Identify and differentiate between classes of molecules that mediate cell-cell interactions.

The Extracellular Matrix

  • Extra: Means "outside" or "beyond."

  • Matrix: Refers to a foundational structure or substance that other elements form from or develop within.

Major Components of the ECM

  • Proteoglycans: Large molecules that play critical roles in ECM structure.

  • Fibers: Provide mechanical strength.

  • Organizers: Help to arrange matrix components.

  • Examples: Laminin, Perlecan, Type IV Collagen, Fibronectin, Fibrillar collagens (e.g., types I, II), Nidogen/entactin.

Functions of the ECM

  1. Anchoring and surrounding cells to maintain solid-tissue three-dimensional architecture and define tissue boundaries

    2. Determining the biomechanical properties (stiffness/elasticity, porosity, shape) of the extracellular environment

    3. Controlling cellular polarity, survival, proliferation, differentiation, and fate (e.g., asymmetric division of stem cells; see Chapter 22), and thus embryonic and neonatal development and adult function and responses to the environment and to disease

    4. Inhibiting or facilitating cell migration (e.g., serving as either a barrier to movement or, conversely, as a “track” along which cells — or portions of cells — can move)

    5. Binding to and acting as a reservoir of growth factors; in some cases, the ECM (a) helps generate an extracellular concentration gradient of the growth factor, (b) serves as a co-receptor for the growth factor, or (c) aids in proper binding of the growth factor to its receptor (ECM component and growth factor jointly serve as a receptor’s combined ligand)

    6. Activating cell surface signaling receptors

Tissue Variations of ECM

  • The ECM’s composition varies significantly across different tissue types.

  • Ex: Connective tissue vs tightly packed epithelial cells and their associated fibroblasts.

Plant Comparative Matrix

  • Cell walls constitute the supportive matrix in plant tissues. Cell walls = their supportive matrix

  • Cellulose and Pectin are primary components.

  • Arabidopsis thaliana serves as a model organism in these studies.

Cell Adhesions

  • Connections between cells are vital for multicellularity.

  • Different adhesions serve distinctive roles, making multicellularity feasible.

Animal Tissues and Their Functions

  • Epithelial Tissue: Covers and protects; includes squamous, glandular types.

  • Muscular Tissue: Involved in movement, includes striated (skeletal, cardiac) and non-striated types.

  • Connective Tissue: Provides support; includes blood, lymph, adipose, cartilage, and bone.

  • Nervous Tissue: Responsible for communication and coordination.

Epithelial Cell Model

Cellular Structures

  • Models display various cell adhesion molecules (CAMs), including tight junctions, adherens junctions, desmosomes.

  • Features of cell-cell adhesion mechanics visualized through cellular interactions.

Adhesion Receptors

  • Cell surface molecules, known as adhesion receptors, play a critical role in cell communication. 2 types::

    • Cell-Cell Adhesion

    • Cell-Matrix Adhesion

  • CAM is important for communication. No communication is bad for the system.

  • Major CAM families: Cadherins, Immunoglobulin (Ig) superfamily, Integrins, and surgar binding proteins called Lectins

Adherence Molecules

  • Homophilic interactions: CAD molecules interact between the same cell types.

  • Heterophilic interactions: CAD molecules interact with different cell types.

  • Key CAM examples include E-Cadherin and Selectins.

Cis/Trans Interactions

  • Cadherin molecules engage in both cis (within the same cell) and trans (adjacent cells) interactions, promoting cellular cohesion. The ability to mic and match them makes them a versatile family of proteins.

Page 14: Information Relay

  • Cell adhesion molecules connect to signaling pathways, affecting cell behavior based on adhesion status.

Page 15: Engagement Changes

  • Adhesion molecules can transmit mechanical signals through conformational changes, recruiting other proteins for reinforcement.

  • Adhesion molecules can be mechanotransducing. Fibronectin stretching in the ECM form cells nearby can cue recruitment of further proteins for reinforcement by revealing cryptic binding sites

Cell Junctions

Epithelial Cells

  • Function: Line, protect, absorb, secrete, cushion.

  • Classified as simple (one cell layer) or stratified based (2+ layers) on cell layers.

Epithelial Cell Interactions

Cadherin Zippers

  • Adherens junctions utilize cadherin interactions to form zipper-like structures, enhancing cell adhesion. Adherens junctions connect the lateral membranes of adjacent epithelial cells near the apical surface, below tight junctions

  • Cadherin molecules interact with each other in the same cell (cis) or with adjacent cells (trans) to create a zipper

  • Individual interactions = weak, en masse = strong

Desmosomes

  • Act as strong adhesion sites that connect cells through cadherin proteins, adding strength through intermediate filaments.

  • Important in diseases affecting cell-adhesion integrity. Characterized by defects in adhesion: cell - cell and/or cell-substrate

Page 22: Hemidesmosomes

  • Function to anchor epithelial cells to the basal lamina, dancing analogously to traditional desmosomes.

  • Kertain filament = intermediate filaments; spot welding to the basal lamina

Integrins Activated by Binding Target

  • integrin are a large family of alpha/beta heterodimeric cell surface proteins that play a crucial role in cell adhesion and signaling, facilitating the connection between the extracellular matrix and the cytoskeleton.

Dynamics of Integrin Function

  • Integrins modulate both cell-cell/matrix interactions and adapt conformation to engage with varying targets.

  • they exhibit differing conformational states that alter affinity for targets

  • a6b4 is the main laminin binding one in epithelium

Tight Junctions Overview

Characteristics

  • Seal body cavities, restrict the diffusion of membrane components, important in maintaining barrier integrity in epithelial tissues. It keeps the fluids separated between the epithelial cell layer.

  • they form ring structures around the top of the cells. Rings are connected to adjacent cells rings.

Key Proteins

  • Many integral membrane proteins are involved in tight junctions.

  • Occludin, Claudin, and Tricellulin contribute significantly to forming tight junctions across epithelial cells.

    • Occludin and Claudin are highly studied

    • Tricellulin appears where three cells tight junctions meet

    • Junction Adhesion Molecules (JAM) so involved.

Tight Junction Interaction

Adapter Proteins

  • Adapter proteins interact with these proteins in tight junctions including Zona occludens proteins mediate transcellular transport, influencing solute movement between cells.

Gap Junctions

  • Large complexes found in junctions amidst the gaps

  • Facilitate cell communication through connexon channels that allow small molecules and ions to pass between cells.

  • 6 protein TM connexon units form hemichannels that connect to adjacent cells.

Tunneling Nanotubes

  • Connect adjacent cells and facilitate the transfer of organelles and smaller molecules, enhancing intercellular communication.

Basal Lamina Structure

  • Layers of the basal lamina consist mainly of Type IV collagen, laminin, and nidogen, serving as a foundation for epithelial cells.

  • Mat like structure; sheets of epithelia sit on basal lamina

Laminins

  • Laminins are multi-adhesive proteins critical for the structure of the basal lamina and serve as binding sites for integrins.

  • has a cross like trimer (a, B, y)

  • they self assemble into large structures using their globular domains.

  • C terminal domains allow for binding by cell receptors, including some integrins.

Collagen Structure

  • Collagen forms a triple-helix structure formed from left handed helical proteins and is the most abundant protein in animals, playing a vital role in tissue strength.

  • characteristic glycine-x-y repeats. the bundles form right hand helices.

Connective Tissue

Bone Structure

  • Matrix constitutes the majority of bone with collagen fibrils and calcium phosphate contributing to its structure and strength.

  • cells are dark spots

  • bands contain collagen fibrils

  • calcium phosphate also present

Collagen Bundles

  • Formation of collagen fibers (superstructure) occurs via fibroblasts and osteoblasts, crucial for maintaining connective tissue integrity. Built by:

    • fibroblasts - skin

    • osteoblasts -bone

    • exocytosis

  • Cross linked triple helix

Collagen Synthesis

  • Collagen synthesis involves procollagen production (IC), secretory vesicle formed, and self-assembly into functional fibers.