Lecture 21 - Extracellular Matrix Notes

LECTURE 21 - Extracellular Matrix

Overview of Extracellular Matrix (ECM)

  • Definition: The Extracellular Matrix (ECM) is a three-dimensional network of extracellular macromolecules, which provides structural and biochemical support to surrounding cells. It is a dynamic entity, constantly being remodeled and influencing cell behavior, proliferation, and differentiation.

  • Quote: As stated by Dr. Mina Bissell, "Half of the secrets of the cell are outside the cell."

Components of the ECM

  • The ECM consists of various molecules including:

    • Fibrous Proteins: Collagen, Elastin

    • Glycoproteins: Fibronectin, Integrin, Laminin

    • Glycosaminoglycans (GAGs): Highly charged polysaccharide chains linked to proteins forming proteoglycans.

Extracellular Matrix in Different Organisms

  • Plants: The ECM is primarily composed of the Cell Wall, which serves as a rigid covering that supports the plant cell.

  • Animals: In animal cells, the ECM consists of:

    • Collagen

    • Proteoglycans

    • Fibronectin

    • Laminin

Importance of ECM in Multicellular Animals

  • Structural Support: Maintains cellular organization and integrity (for instance, in epithelial tubes).

  • Tissue Compartmentalization: Differentiation of tissues (example: epidermis vs. dermis in skin).

  • Mechanical Properties: Provides hardness and rigidity to structures such as bones and teeth through mineralization of collagen.

  • Cell Communication: Facilitates communication between adjacent cells through receptors on the plasma membrane.

  • Cell Migration: Acts as a pathway for cell migration during development, tissue remodeling, and disease conditions such as wound healing.

Broad Categories of Tissues

  • Connective Tissue: Can be classified into:

    • Loose Connective Tissue

    • Dense Connective Tissue

  • Epithelial Tissue: Includes various types of epithelial structures.

  • Nervous Tissue

  • Muscle Tissue

Major Components of ECM
1. Fibrous Proteins

  • Collagen:

    • Definition: The main structural protein in the ECM of connective tissue, consisting of a large family of proteins (over 40 genes).

    • Structure: Forms a triple helix composed of two identical α−1\alpha-1 chains and one α−2\alpha-2 chain. Sequence includes Gly-X-Y (where X is often proline and Y is often hydroxyproline). The hydroxylation of proline and lysine residues, catalyzed by prolyl and lysyl hydroxylases respectively, is critical for stabilizing the triple helix structure through hydrogen bonding and allowing for subsequent glycosylation and cross-linking.

    • Hydroxyproline: Formed through hydroxylation of proline by prolyl hydroxylase, facilitating collagen's structural twist, accounting for 13.5%13.5\% of mammalian collagen,

    • Hydroxylysine: Formed similarly and allows glycosylation and crosslinking of collagen fibrils, about 1.0%1.0\% of mammalian collagen.

    • Biosynthesis Process:

    1. Synthesis of pro-α\alpha chains in the ER, containing Gly-X-Y repeats and telopeptides.

    2. Hydroxylation of proline and lysine residues, and glycosylation of some hydroxylysine residues in the ER lumen.

    3. Assembly of three pro-α\alpha chains into a triple helix (procollagen) within the ER.

    4. Secretion of procollagen molecules into the extracellular space via exocytosis.

    5. Cleavage of N- and C-terminal propeptides by specific proteases (procollagen peptidases) outside the cell, forming insoluble tropocollagen.

    6. Spontaneous self-assembly of tropocollagen molecules into collagen fibrils, followed by covalent cross-linking mediated by lysyl oxidase to form mature collagen fibers.

    • Types of Collagen:

    • Fibril Forming (Type I, II, III): Characterized by a rope-like structure.

    • Network Forming (Type IV, VIII): Form three-dimensional meshes.

    • Fibril Associated Collagens: Link collagen fibers and other ECM components.

2. Glycoproteins

  • Fibronectin:

    • Definition: A glycoprotein that binds to cellular receptors, acting in early wound healing as soluble plasma fibronectin and late wound healing as insoluble cellular fibronectin.

  • Integrin: A transmembrane protein mediating ECM attachment and signal transduction. It forms a heterodimer of α\alpha and β\beta subunits.

    • Functions:

    • Attaches cells to ECM.

    • Facilitates signal transduction.

    • Focal Adhesion:

    • Components: Talin (links integrin to cytoskeleton), Vinculin (involved in linkage and signal transduction), Focal Adhesion Kinase (regulates recruitment in focal adhesions).

    • Cell Signaling: Includes "Inside Out" signaling (regulating integrin affinity) and "Outside In" signaling (mediating signals from ECM).

    • "Inside-Out Signaling": Intracellular signals from the cell can activate integrins, increasing their affinity for ECM ligands.

    • "Outside-In Signaling": Binding of ECM ligands to integrins triggers intracellular signaling cascades, influencing cell survival, growth, and gene expression.

  • Laminin: An important glycoprotein in basal laminae, it plays a crucial role in cell adhesion, migration, and differentiation, particularly important in supporting epithelial layers.

3. Glycosaminoglycans (GAGs)

  • Definition: Long linear polysaccharides, negatively charged due to sulfate and carboxyl groups.

  • Functions: Highly polar and attract water, providing turgor and cushioning effects. Their strong negative charge attracts a large amount of water and cations, forming a hydrated gel-like substance that gives the ECM its turgor and resilience, allowing it to resist compressive forces.

  • Proteoglycans:

    • Composed of core protein with attached GAG chain(s).

    • Key in maintaining structural properties of ECM, particularly in cartilage, which consists mainly of collagen and proteoglycan.

    • Biosynthesis: Proteoglycans synthesized via ribosomes, modified in ER, glycosylated in Golgi, then exported to ECM.

ECM and Wound Healing

  1. Hemostasis:

    • Platelet Aggregation: Rapid response to injury involves vasoconstriction and platelet plug formation, where fibronectin helps bridge platelets to the exposed collagen.

  2. Inflammation:

    • Process: Localized swelling and heat; immune cells (e.g., neutrophils, macrophages) infiltrate to clear debris and pathogens. Growth factors released by these cells modulate ECM synthesis and breakdown.

  3. Proliferation:

    • Tissue Reconstruction: Fibroblasts migrate into the wound, depositing temporary ECM components like fibronectin and Type III collagen. Angiogenesis (new blood vessel formation) is critical, guided by ECM components. Epithelial cells re-epithelialize the wound surface.

  4. Remodeling:

    • Scar Formation: Myofibroblasts repair tissues, contributing to scar formation; the provisional matrix is gradually replaced by a more organized, mature ECM, primarily Type I collagen. Myofibroblasts contract the wound edges, and collagen cross-linking increases tensile strength.

Take Home Messages

  • ECM surrounds eukaryotic cells, providing various functions based on cell type and environment.

  • Fibrous proteins confer mechanical strength and shape.

  • Glycoproteins facilitate cellular attachment and act as sites for signal transduction.

  • GAGs enhance physical properties and functionality of ECM beyond structural proteins alone.

  • ECM components are essential for effective wound healing processes.