Chapter 20 - Integrating Cells into Tissues

Integrating Cells into Tissues

20.1 Cell-Cell and Cell-Extracellular Matrix Adhesion: An Overview

• Cell-cell and cell–extracellular matrix (ECM) interactions are critical for:

  • Assembling cells into tissues.

  • Controlling cell shape and function.

  • Determining the developmental fate of cells and tissues.

• Cell-adhesion molecules (CAMs) mediate direct cell-cell adhesions:

  • Homotypic adhesions: adhesion between the same type of cell.

  • Heterotypic adhesions: adhesion between different types of cells.

• Adhesion receptors mediate cell-matrix adhesions.

• Extracellular matrix (ECM) is:

  • A dynamic, complex meshwork of proteins and polysaccharides.

  • Contributes to the structure and function of a tissue.

Overview of Major Cell-Cell and Cell-Matrix Adhesive Interactions

• Cell-Cell Adhesions

  • Tight Junction

  • Gap Junction: Includes a Connexon

  • Adherens Junction: Connected to Actin Filaments

  • Desmosome: Connected to Intermediate Filaments

• Cell-Matrix Adhesions

  • Focal Contact: Connected to Actin Filaments

  • Hemidesmosome: Connected to Intermediate Filaments

• Components

  • Cell-adhesion molecules (CAMs)

  • Adhesion receptors

  • Extracellular matrix (ECM)

  • Adapters (Intracellular)

Major Families of Cell-Adhesion Molecules (CAMs) and Adhesion Receptors

• Cadherins

  • Mediate homophilic interactions

  • Have calcium-binding sites

• Ig-Superfamily CAMs (NCAM)

  • Mediate homophilic interactions through Ig domains

• Integrins

  • Mediate heterophilic interactions

  • Interact with fibronectin via type III fibronectin repeats

• Selectins

  • Mediate heterophilic interactions

  • Bind to sugars on glycoproteins via lectin domains

Model for Generation of Cell-Cell Adhesions

• Cis Interactions: Lateral interactions between molecules on the same cell surface.

• Trans Interactions: Interactions between molecules on opposing cell surfaces.

• Cell-cell adhesions are generated through a combination of cis and trans interactions.

Extracellular Matrix (ECM) Components

• Extracellular Matrix Proteins

  • Collagens

    • Sheet forming (e.g., type IV)

    • Fibrillar collagens (e.g., types I, II, and III)

  • Multi-adhesive matrix proteins

    • Laminin

    • Fibronectin

    • Nidogen/entactin

  • Proteoglycans

    • Perlecan

Variation in Relative Density of Cells and ECM in Different Tissues

• Connective Tissue:

  • Characterized by a high density of ECM and fewer cells (e.g., fibroblasts).

• Tightly Packed Epithelial Cells:

  • Characterized by a high density of cells and less ECM.

Functions of the Extracellular Matrix

• Anchoring and engulfing cells to maintain solid tissue three-dimensional architecture and define tissue boundaries.

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

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

• 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).

• Binding to and acting as a reservoir of growth factors; in some cases, the ECM:

  • Helps generate an extracellular concentration gradient of the growth factor.

  • Serves as a co-receptor for the growth factor.

  • Aids in proper binding of the growth factor to its receptor (ECM component and growth factor jointly serve as a receptor's combined ligand).

ECM and Tissue Development

• Antibodies to fibronectin block branching morphogenesis in developing mouse tissues.

• Disruptions in cell-matrix and cell-cell interactions interfere with tissue development.

• Inactivating the genes for some ECM proteins results in defective skeletal development in mice.

  • Example: Collagen II deficiency.

  • Example: Perlecan deficiency.

Integrin Adhesion Receptor-Mediated Signaling Pathways

• Integrin adhesion receptor-mediated signaling pathways control diverse cell functions

• ECM Ligand binds to Integrin (adhesion receptor)

• Triggers Receptor tyrosine kinase

• Activates Various adapters and signaling kinases:

  • PI3K

  • GRB2

• Classic signaling pathways:

  • Akt/PKB

  • Ras

  • NF-kB

  • Raf

  • JUN

  • MEK

  • ERK/MAPK

• Cellular responses to adhesion receptor signaling:

  • Cell proliferation (cycle)

  • Cell survival

  • Cytoskeletal organization

  • Cell migration

  • Gene transcription

Models of Domains in Mechanosensor Proteins Responding to Mechanical Forces

• (a) Fibronectin type III domain

  • Mechanical force (stretching) causes conformational change

  • Changes in accessibility of binding site

• (b) Talin five-helix bundle domain

  • Mechanical force (stretching) causes conformational change

  • Changes in accessibility of binding site

20.2 Cell-Cell and Cell-Extracellular Junctions and Their Adhesion Molecules

• Anchoring junctions include adherens junctions, focal contacts, desmosomes, and hemidesmosomes.

• Cadherins and integrins mediate cell-cell and cell-ECM junctions.

• Tight junctions define epithelial cell polarity and regulate extracellular (paracellular) flow of water and solutes from one side of the epithelium to the other.

• Gap junctions connect the cytoplasms of adjacent cells for metabolic and electrical coupling.

Principal Types of Epithelia

• (a) Simple columnar epithelia:

  • Elongated cells – including mucus-secreting cells (in the lining of the stomach and cervical tract) and absorptive cells (in the lining of the small intestine).

  • Microvilli – on apical surface.

• (b) Simple squamous epithelia:

  • Thin cells – including cells lining blood vessels (endothelial cells/endothelium) and many body cavities.

• (c) Transitional epithelia:

  • Several layers of cells with different shapes – line certain cavities subject to expansion and contraction (e.g., the urinary bladder).

• (d) Stratified squamous (nonkeratinized) epithelia:

  • Line surfaces such as the mouth and vagina.

  • Resist abrasion.

  • Generally prevent material absorption/secretion into or out of lined cavity.

Principal Types of Cell Junctions Connecting the Columnar Epithelial Cells Lining the Small Intestine

• Apical Surface

  • Microvillus

  • Tight junction

• Lateral Surface

  • Adherens junction

  • Desmosome

  • Gap junction

• Basal Surface

  • Hemidesmosome

Cell Junctions

• Anchoring junctions

  • 1. Adherens junctions

    • Cell-cell

    • Cadherins

    • Actin filaments

    • Catenins, vinculin

    • Shape, tension, signaling, force transmission

  • 2. Desmosomes

    • Cell-cell

    • Desmosomal cadherins

    • Intermediate filaments

    • Plakoglobin, plakophilins, desmoplakins

    • Strength, durability, signaling

  • 3. Hemidesmosomes

    • Cell-matrix

    • Integrin (\alpha6\beta4)

    • Intermediate filaments

    • Plectin, dystonin/BPAG1

    • Shape, rigidity, signaling

  • 4. Focal, fibrillar, and 3-D adhesions

    • Cell-matrix

    • Integrins

    • Actin filaments

    • Talin, kindlin, paxillin, vinculin kinase

    • Shape, signaling, force transmission, cell movement

• Tight junctions

  • Cell-cell

  • Occludin, claudins, JAMS

  • Actin filaments

  • ZO-1,2,3, PAR3, cingulin

  • Controlling solute flow, signaling

• Gap junctions

  • Cell-cell

  • Connexins, innexins, pannexins

  • Via adapters to other junctions

  • ZO-1,2,3

  • Communication, small-molecule transport between cells

• Plasmodesmata (plants only)

  • Cell-cell

  • Undefined

  • Actin filaments

  • NET1A

  • Communication, molecule transport between cells

E-Cadherin Mediated Adhesion

• E-cadherin mediates Ca^{2+}-dependent adhesion of L cells

• Cadherin transgene + With calcium = Cell Aggregation

• Cadherin transgene + Without calcium = No Cell Aggregation

• No cadherin transgene = No Cell Aggregation

Desmosomes

• Structure

  • Plasma membranes of adjacent cells.

  • Intercellular space.

  • Intermediate filaments.

  • Cytoplasmic plaques = (plakoglobin, desmoplakins, plakophilins)

  • Desmoglein and desmocollin (cadherins).

Tight Junctions

• Seal off body cavities.

• Restrict diffusion of membrane components between apical and basolateral membrane regions.

• GPI-anchored proteins and exoplasmic leaflet glycolipids are confined to the apical membrane region.

• Cytoplasmic leaflet has uniform lipid composition in apical and basolateral membrane regions (lipids can diffuse through TJ).

• Structure:

  • Linkage of rows of protein particles in adjacent cells.

  • Close contact between cells where the rows of proteins interact.

Transcellular and Paracellular Pathways of Transepithelial Transport

• Transcellular pathway: Transport across the cell.

• Paracellular pathway: Transport between cells, regulated by tight junctions.

Gap Junctions

• Structure

  • Connexon hemichannel

  • Intercellular gap

  • Gap-junction channel

• Measurements

  • Membrane to Cytosol: 19 \mathring{A}

  • Intercellular Gap: 38 \mathring{A}

  • Connexon hemichannel: 40 \mathring{A}

  • Channel diameter: ~14 \mathring{A}

  • Outermost diameter: ~90 \mathring{A}