Interactions Between Cells and Their Environment

Interactions Between Cells and Their Environment

Overview of Cell Interactions

  • Cells aggregate to form tissues, which then create organs.

    • cells → tissues → organs

  • The extracellular matrix (ECM) + cells is crucial for cell function in animals cells only

  • ECM: outside of cells, help support and organize

  • Key components:

    • proteins (collegen)

    • glycoproteins (sugars)

    • carbohydrates

Extracellular Matrix (ECM)

  • Definition: A network of materials outside plasma membrane, providing structural support and influencing cell shape and activities.

  • Components/proteins:

  • most proteins (synthesized in RER) inside cells are globular and secreted to extracellular space

    • Collagen: Most abundant protein in humans, contributes to tissue strength.

    • Proteoglycans: Complex of proteins and polysaccharides, involved in cell signaling and providing hydration.

    • Fibronectin: Binds components in ECM to integrins and is important in cell migration and tissue repair. (wound healing)

    • Laminin: Glycoprotein that helps organize the ECM and is critical for cell migration.

  • Integrins: Receptors that link the ECM to the cell's cytoskeleton, facilitating signaling and attachment.

    • are heterodimers

Cell Types and Adhesion

  • Cell Types in Tissues:

    • Epithelial cells: Form barriers, line internal and external

      • skin (external) , gut lining (lumen/internal), kidney tubules, glands, trachea in lung

      • cell-cell adhesion

      • epidermis

      • concentrated cells, well-organized, less space between cells

      • cell-ECM adhesion (basement membrane)

    • Endothelial cells: Line blood vessels, lymphatic vessels, etc.

      • line only internal

      • tight juntion (cell-cell)

    • Mesenchymal cells: Present in connective tissues with a role in tissue flexibility, development, and regeneration

      • multipotent stem cells

      • present in dermal layer:underlying the epidermis

      • more intracellular space

      • poor cell adhesion

      • cell-ECM adhesion

  • Cell Adhesion Types:

    • Cadherins:

      • Calcium-dependent molecules for cell-cell adhesion, crucial in tissue architecture.

    • Selectins:

      • Bind to specific carbohydrates on other cells, facilitate transient interactions (e.g., during inflammation).

  • Focal Adhesions: Sites in cells where integrins interact with the ECM, linked to the actin cytoskeleton, important for cell movement and signaling

Functions of the ECM

  • Provides anchorage for cells

  • enables migration

  • creates barriers

  • tracks cellular paths

  • transmits signals (e.g., growth factors).

  • Proteoglycans: play a pivotal role in signaling and cell behavior changes by serving as reservoirs for growth factors.

Collagen Types and Functions

  • Produced by:

    • fibroblasts: maintain the structural framework of tissues.

    • smooth muscle cells

    • epithelial cells

  • Structure:

    • triple alpha helical chain attached side by side by hydrogen bonds(secondary structures). covalent x links present in lysine and hydroxylysine residues

    • hydroxylated proline and lysine → H bonds for stability

    • Vitamin C: coenzyme for enzymes producing collagen

      • lack vitamin C → loose teeth, brittle bones, poor wound healing

      • Collagen synthesis requires vitamin C for modifications in amino acids critical for collagen structure

    • different domains of the same collagen have unique functions

      • tissue build up, break down, signaling fragments

  • Fibrillar Collagens (Type I):

    • Support tensile strength → resist stretching/pulling

    • e.g when running, exercising

      • e.g., tendons connecting muscle with bone, cornea, skin

    • cornea: collagen in stroma makes it tough and transparent, provides support to our eyes

  • Non-fibrillar Collagens (Type IV):

    • triple helices form a lattice in basement membranes providing a structural scaffold and filtration.

    • under epithelial layer

    • 1st line of defense, acts a a barrier

    • attached with different proteins

    • e.g. can be found in lungs

Proteoglycans

  • protein-polysaccharide complex, attached to carbohydrate

  • made of core protein attached to GAG (Glycosaminoglycans) added to hyaluronic acid → proteoglycan structure

  • GAGs:

    • long chain of repeating disaccharides (sugar pairs)

    • acidic (-): carboxyl & sulfate groups → absorb H2O and cations (e.g. Na+)

  • Functions:

    • gel-like matrix that resists compression (e.g. cushion).

    • Proteogylcans + fibrillar collagens →Important in cartilage and the vitreous (jelly-like sub. b/w retina and lens) of the eye.

Fibronectin

  • Structure:

    • Dimer: made of monomers linked through disulfide bonds, covalent, strong

    • each monomer has ~30 domains (repeated regions) with different functions

    • RGD motif: binds to integrins on cell

      • R: asparagine

      • G: glycine

      • D: aspartic acid

  • Function:

    • Binds ECM components (collagen, proteoglycans) through integrins

    • tissue structure (coordinates cell positioning)

    • guide cell migration during development:

      • Neural crest cell migration: depend on fribronectin

      • start: neural tube → fibronectin = make:

        • facial bones and cartilage

        • melanocytes (pigment cells in skin)

Laminin

  • glycoprotein in basement membrane

  • Trimer (3-part structure) linked by disulfide bonds

  • Binds:

    • ECM components, interacts with cell surface receptors

    • integrins on cell membrane

  • Also guides cell migration:

    • primordial germ cells (early reproductive cells) during development

Basement Membrane

  • Thin, flexible layer of ECM primarily composed of type IV collagen (non-fibrilar)(forms lattice) and laminin.

  • AKA basal lamina

  • Function:

    • Provides anchorage for epithelial cells

    • serves as a barrier between different tissue types. e.g epidermis from dermis

  • Critical in cancer metastasis (spreading); many cancer cells can breach this barrier (basement membrane).

ECM Remodeling

  • ECM is not static → constantly broken down and rebuilt

  • occurs in:

    • wound healing

    • development

    • cancer metastasis (allows cancer cells to move)

  • Degradation:

    • catalyzed by Matrix Metalloproteinases (MMPs), require metals for enzymatic activity (zinc, iron?)

    • break down ECM components so tissues can be remodeled

Integrins

cell surface receptors that connect ECM to actin filaments

  • Integrins undergo conformational changes that affect cell behavior.

  • function as TM proteins links

  • Structure:

    • heterodimers made of alpha and beta subunit, different in their structure depending on their ligands

  • Bind to ligands (e.g. collagen or fibronectin)

    • some ligands have RDG motif: sequence recognized by integrins

Conformations:

  • Bent → inactive

  • Upright → active

    • Active: bind to extracellular ligands like collagen

    • when active, binds to Intracellular proteins like talin to transfer signal

Signaling:

  • Outside-in signaling: (E.g ECM)

    • Binding of extracellular ligands (ECM components) activates integrins → transmit signals affecting cell functions and behavior. Changes bent → upright

    • ECM → integrin → cell changes

    • movement, growth, survival, polarity, interactions with cytoskeletal structures

  • Inside-out signaling:

    • Signaling from inside the cell (like growth factors) activates integrin by triggering intracellular proteins (like talin or kindlin) activity → ECM binding

    • change shape (bent → upright) → integrin can bind to ECM: affects how cell adheres/moves through tissues and ECM assmembly

Focal Adhesion Dynamics

  • discrete, scattered anchorage site to ECM

  • linked to actin (focal addition points) cytoskeleton, basal membrane side of epithelial cells

  • important for how cells move and interact with the ECM.

  • act as traction point and signaling hubs

  • are dynamic

  • Cell Migration:

    • Actin polymerization and focal adhesion dynamics enable cells to move toward stimuli (chemotaxis) and resist mechanical forces.

    • trigger outside-in signal changes structure

Focal Adhesion Structure

  • Integrin IC (intracellular/cytoplasm) domain links ECM to actin cytoskeleton inside cell

  • Adaptor proteins helping build:

    • Talin: Binds directly to integrin and actin, stabilizing the link.

    • vinculin: Strengthens the connection between talin and actin.

    • a-actinin: helps bundle actin filaments and connect them to the adhesion site.

  • signaling proteins:

    • FAK (focal adhesion kinase):

      • Activated when integrins bind to ECM.

      • interact with signaling molecules within cell like: Src activating downstream signals that regulate cell shape, migration, and survival

    • Src: promotes intracellular signaling and activating pathways for cell migration and growth

Focal Adhesion: force generation

  • connects actin and non-muscle myosin II → create contractile force → lets cell pull itself forward during migration

  • Result: ECM stiffness (mechanotransduction)affects cell fate (e.g. mesenchymal stem cells):

  • Cell Differentiation:

  • Soft ECM → neurons

  • Medium ECM → muscle

  • Hard ECM → osteoblasts → bone

  • stiffness determines what kind of cell a stem becomes

Hemidesmosomes

  • found at basal surface of epithelial cells

  • anchors epithelial cells to basement membrane

  • contain dense cytoplasmic plaques with keratin filaments (IF)

  • Use integrins to link ECM to IF cytoskeleton (keratin) with help from plectin

  • Structure flow:

    • ECM (outside) → Integrins → Plectins → IF (keratin/inside cell)

  • Function:

    • strong, stable adhesion to keep epithelial sheets intact

    • defective hemidesmosomes = skin blistering bc of weak attachment between layers

Cell sorting and organization

  • tissues formed by selective adhesion between cells of same and different types

  • cells of different types mixed → re-sorted themselves → arranged adjacent to cells of their own type

    • cells can recognize and stick to similar cells → organized tissues

Selectins (cell-cell Adhesion)

  • Family of Integral membrane glycoproteins (sugar chains), pass across membrane

  • bind to specific sugars (oligosaccharides) on other cells, proteins undergo modifications

  • require calcium ions (Ca2+) to bind for cell-cell interactions

  • Terminal oligosaccharide:

    • N-acetylglucosamine often sulfated

    • Frucose and sialic acid for selecting recognition

  • Types:

    • E-selectin → endothelial cells (cells lining blood vessels)

    • P-selectin → platelets and endothelial cells

    • L-selectin → leukocytes (white blood cells)

  • Function

    • mediate transient interactions (brief “rolling” contact) between white blood cells and blood vessel walls

    • important for inflammation and clotting → help immune cells get to injury/infection site, and destroy invading pathogen

Immunoglobulin Superfamily (IgSF)

  • large group of proteins with immunoglobin (Ig) domains

  • most used for immune system but originally evolved for cell adhesion

  • dont need Ca2+

  • proteins with similar features

  • Key roles in nervous system development:

    • neuron growth

    • cell recognition

    • wiring circuits

    • cell adhesion

  • E.g

    • L1 → nerve growth

    • VCAM (vascular cell adhesion molecule) → helps immune cells stick to blood vessels

    • IgSF → interacts with integrins of other cell membranes

    • IgG

Cell Adhesion in inflammation and Metastasis

  • inflammation is a natural immune response to infection or injury

  • side effects: redness, fever, swelling, pain

  • Leukocytes: following puncture, white blood cells leave the bloodstream → travel through endothelial layer that lines venules (smallest veins) → enter tissues to fight infection

  • WBC recruited by selectins, integrins, IgSF proteins

  • Molecules involved in leukocyte recruitment:

    1. Selectins:

      • help WBCs “roll” along blood vessel walls → tissue

      • E-selectin & P-selectin displayed on endothelial cells, allowing them to become more adhesive to circulate neutrophils

    2. Integrins:

      • protein in WBCs, become activated (strong binding/help them stick) by PAF (Platelet Activating Factor) from endothelial cells

      • binding activity on neutrophils (type of WBC)

      • allow WBCs to change shape, stick tightly and squeeze between cells → damaged tissue

    3. Ig Superfamily (IgSF)

      • help leukocytes adhere to and migrate across vessel wall

Cancer Metastasis

  • cancer cells lose normal control and adhesiveness → divide uncontrollably

  • Metastasis = cancer spreads to new areas

  • Steps of Metastasis:

    1. tumor cells lose adhesion (by reducing cadherins)

    2. gain motility and invasiveness (mesenchymal-like traits)

    3. break through basement membrane and enter blood or lymph vessels

    4. travel through circulation

    5. exit into a new tissue

    6. form secondary tumors (new cancer growths)

  • called CTCs (circulating tumor cells), can be detected in blood samples

Cadherins (cell-cell adhesion)

  • family of glycoproteins (Integral membrane protein)

  • Cadherins are linked to the actin cytoskeleton

  • mediate calcium-dependent cell adhesion

  • binds cells of same type - essential for sorting and tissue formation

  • important during embryo development and maintaining adult tissue structure

  • cadherin loss → malignancy/cancer progression

  • Special roles

    • Cadherin 23 and Protocadherin 15 form tip links on stereocilia located in inner ear hair cells

    • these convert sound vibrations (mechanical) into electrical signals

    • mutations → usher syndrome ( deafness + vision loss)

Key Adherens and Junctions of cadherins

  • Adherens Junctions: (zonula adherens) present in apical lateral part of epithelial cells

    • Connect adjacent/neighboring cells, providing structural integrity through cadherins.

    • form continuous belt around cell for structure and tensile strength

  • Tight Junctions: (zonula adherens)

    • Prevent paracellular transport/mixing between epithelial cells, maintaining distinct compartments.

    • seal spaces between cells

    • found near apical (top) surface of epithelial cells

  • Gap Junctions:

    • direct cytoplasmic exchange between adjacent cells via connexons.

    • channels connect neighboring (cytoplasmic) cells directly

    • made of connexins → connexons span the membrane

    • allow ion, sugar, and small molecule passage

    • cell-cell (intercellular) communication (e.g. heart muscle and neurons)

  • Desmosomes: (macula adherens) present between epithelial cells (basal lateral)

    • spot welds using cadherins linked to intermediate filaments (e.g. keratin)

    • provide mechanical strength

    • located deeper along lateral surfaces

  • Hemidesmosomes:

    • cell-to-basement membrane (basal cell surface)

    • anchors cells via integrins and IF

Intercellular Communication in Plants

  • Plasmodesmata:

    • Cytoplasmic channels pass through cell walls, connecting cytoplasm of adjacent cells → allow communication and movement of nutrients, RNAs, and proteins

    • plant = gap junctions

    • regulate and can dilate or restrict passage of molecules through the pore