Lecture 19: Cell-cell Interactions: Part 1

Tissue Composition

• Tissues are composed of cells and extracellular matrix

• The extracellular matrix (ECM) is created when cells secrete proteins outside the cell to create it

• The ECM cushions cells and organizes tissues

• To build a tissue, there needs to be interactions between adjacent cells, and interactions between cells and the ECM

Extravasation

• Process

  • When there is an infection, white blood cells (leukocytes) need to migrate to the site of infection

    • Rather than floating around

  • When these cells sense inflammatory signals, they make contact with the endothelial cells that line the blood vessel, and roll along the surface

  • This rolling is mediated by loose cell-to-cell interactions (weak adhesion)

    • Cell-cell contacts made and broken quickly

  • When the cell reaches the site of infection, a strong interaction is formed, which stops the rolling (strong adhesion)

  • The leukocyte can then exit the blood vessel and help fight the infection

Cell Adhesion

• Cells interact with other cells and with the ECM using “adhesion molecules,” which are typically transmembrane proteins

• Interactions can be homophilic

  • Mediated by the same protein on each cells

• Interactions can also be heterophilic

  • Different protein on cell #1 than on cell #2

Cell-cell Interactions: Epithelial Cells

• Epithelial cells form our skin and line internal cavities

• Cells can be packed together in different ways to form an epithelial sheet

  • Cell sheets function as barriers

• Epithelial cells have polarity

  • An “apical” and a “basal” surface

• The basal side sits on a thin layer of ECM that is the basal lamina

• The basal lamina is on the basal surface in all cases

Major Cell Junctions

• Cell-cell

  • Tight junctions

  • Gap junctions

  • Adherens junctions

  • Desmosomes

• Cell-ECM

  • Hemidesmosomes

  • Focal adhesions

Tight Junctions

• These junctions are specific to epithelial cells

• They create barriers that seal off particular body cavities

  • For example, intestinal epithelial cells prevent intestinal enzymes from spreading to other tissues

• Experiment

  • If a tracer molecule is injected on one side of an epithelial cell sheet, it can’t pass to the other side

• Cells are sealed together by branching strands of transmembrane proteins, claudins and occludins

• Rows of these proteins in adjacent cells form the junctions

  • Like seal on Ziploc bag

• Tight junctions can also help polarize epithelial cells

  • Some proteins only localize to either the apical or the basal membrane

  • Tight junctions can keep proteins restricted to their proper domain

Gap Junctions

• Allow the passage of small molecules and metabolites

  • Up to 1000 daltons, so proteins can’t fit through

• Important for cell-cell communication and metabolic coupling of cells

  • Bring cell membranes close together

• Composition

  • Composed of the protein connexin

  • Each cell has a “hemi-channel” (or connexon) of 6 connexin subunits

  • The gap junction is made up of two hemichannels (one from each cell) that connect to form a pore that spans the two cells

• Gap junctions can be opened/closed in response to extra/intra-cellular signals

Adherens Junctions

• Process

  • Cadherin proteins are a class of cell adhesion proteins

  • Cadherins on one cell form homophilic interactions with cadherins on another cell

  • A variety of linker proteins then connect the junctions to the actin cytoskeleton

• Adherens junctions form “adhesion belts”

  • Bundles of actin filaments run along the plasma membrane inside the cell

  • Bundles are linked to adherens junctions

  • The actin bundles contain myosins and can contract, allowing the cells to change shape

  • Sheets of cells can also be mechanically linked, such that contracyion buckles the cell sheet

• Cell shape changes drive formation during development

Desmosomes

• Similar to adherens junctions

  • Cadherins link adjacent cells

  • Linker proteins link these junctions to the cytoskeleton

• Difference from adheren junctions

  • Desmosomes are linked to intermediate filaments

    • Specifically, desmosomes are the sites of connection that intermediate filaments link to with neighboring cells

    • Linking cells mechanically couples them, giving structure to sheets of cells

• Specifically, linker proteins can connect cadherin proteins to keratin filaments
  
  

Hemidesmosomes

• Hemidesmosomes are similar to desmosomes in that they are places where intermediate filaments are linked to the plasma membrane

  • Transmembrane → linker protein → intermediate filaments

• Differences of desmosomes

  • They link intermediate filaments to the ECM instead of to another cell

  • Inegrins form the connection between the cell and ECM (not cadherins)

Desmosomes and Hemidesmosomes Work Together

• Desmosomes link cells together

• Hemidesmosomes link cells to ECM

• This creates a strong sheet of cells that are mechanically linked

  • As well as creating strong networks of cells

Focal Adhesions

• Cell-ECM contacts, linked to the actin cytoskeleton

• Integrins are the transmembrane proteins that form the connection between the cell and ECM

• There are linker proteins inside the cell that connect the integrins to actin filaments

• More abundant in crawling cells than in stationary epithelial cells

  • Form at the leading edge as cells crawl forward