Tissue Repair Flashcards
Regeneration vs. Healing
Regeneration
= Growth of cells/tissue identical to the lost tissue.
=> Requires
(1)Stem Cells to be intact and
(2)Intact Extracellular Matrix
_ECM is essential for migration and maintaining cell polarity.
Healing
= Replacement of Lost tissue by a Fibroproliferative Response
= Scar
=> Occurs when **ECM is Extensively Destroyed
Types of Cells
- *Non-Dividing / Permanent Cells:
1) *Neurons
2) *Skeletal Muscle
3) *Cardiac Muscle
**Quiescent / Stable Cells:
1) *Most Mesenchymal Cells
(@ Connective Tissue)
(e.g. Endothelial cells, Fibroblasts, Smooth Muscle cells)
2) *Parenchymal Cells
@ Liver, Kidney, Pancreas
- *Continuously Dividing / Labile Cells:
1) *Hematopoietic Cells (BM)
2) *Glandular Epithelial Cells:
e. g. @ *Skin, @ *GI, etc.
Stem Cells
**Stem Cells are responsible for *Tissue Regeneration.
*Located in Niches in a Variety of Tissues.
Have Prolonged self-renewal capacity (High Telomerase Activity) and Asymmetric Division.
*Express Characteristic Phenotypic Markers.
Cell Differentiation blocks cell division.
Most tissues contain undifferentiated Stem cells that can divide to regenerate tissue.
=> **Embryonic Stem Cells: Are Not Committed and have the **Highest Plasticity or Totipotential.
=> **Adult Stem Cells: *Are More Tissue Specific, Committed to Differentiated along Specific Cell Lineages or Multipotential.
Growth Inhibition
**Contact Inhibition
- *TGF-Beta: *Inhibits Growth by
- *Increasing CDKIs, which block progression of cell cycle.
TGF-Beta:
1) *Growth Inhibition for Most *Epithelial Cells
2) *Stimulates Growth of *Fibroblasts
3) *Collagen Production
4) *Strong Anti-Inflammatory
Tissue Regeneration @ Liver
*Mammalian Regeneration occurs by *Hypertrophy or *Hyperplasia
ECM Functions
Functions:
1) *Retains Water and Minerals, providing *Rigidity
2) *Mediates Cell-to-Cell Interactions, providing a *Substratum for cells to Adhere, Migrate, and Proliferate.
**Synthesis and **Degradation of ECM is Part of _Embryogenesis _Wound Healing _Fibrosis _Tumor Invasion _Metastasis
ECM Components
3 Groups of Macromolecules constitute the ECM:
1) **Fibrous Structural Proteins:
* *Collagens, **Elastins, **Fibrillin
2) **Adhesive Glycoproteins:
e. g. **Fibronectin and **Laminin
3) **Proteoglycans:
* *Hyaluronic Acid
These macromolecules assemble into
1) **Interstitial Matrix
2) **Basement Membrane
Fibronectin
**Fibronectin:
=> A large **Interstitial Matrix Protein
=> **Binds to Many Molecules.
=> 2 forms:
(1) Tissue Fibronectin: Forms Aggregates @ Wound Healing Sites
(2) Plasma Fibronectin: Binds to Fibrin, Forming a Provisional Clot Filling the Wound Space
Laminin
**Laminin:
=> *The Most Abundant Glycoprotein in the Basement membrane
=> Laminin and Collagen Type IV form a tight network in Basement Membrane
Elastin and Fibrillin
**Elastin and **Fibrillin:
=> Key components of elastic tissues.
=> Provide the ability to stretch
=> Cross-linking regulates elasticity
=> Elastic Fibers:
_Central Core of Elastin
_Surrounded by a peripheral network of Fibrillin microfibers
Proteoglycans
Proteoglycans:
=> *Protein linked to **Glycosaminoglycans, resulting in a *Long Repeating Polymer of *Disaccharides with *Sulfate Residues.
=> *Regulate Basement Membrane Structure and *Permeability.
Hyaluronic Acid
Hyaluronic Acid
=> Is a *Huge Polymer
=> One of the *Glycosaminoglycans
=> Retains Water, Creating a
*Viscous Gel that *Provides Resistance to Compression
=> Abundant in cartilage and joints (lubricant)
=> Binds to Collagen and Leukocytes via CD44, Facilitating Cell Migration
=> Abundant in Matrix of Migrating and Proliferating Cells
Cell Adhesive Proteins
Cell Adhesive Proteins
=> Located @ *Cell Membranes
=> Link ECM to Cells
1) **Cadherins
2) **Integrins
3) **Selectins
**Cadherins and **Integrins:
1) *Link Cell Surface to Cytoskeleton
2) *Major Role in Regulating Cell Motility,
Cell Growth, and Cell Differentiation
______________________
**Cadherins:
1) *Regulate Adhesions Between Cell of Same Type
2) *Contact Inhibition
3) Link Cell Surface to Cytoskeleton vis **Catenins
4) *Beta-Catenin:
=» Links Cadherin to alpha-catenin, which connects to actin and **Intermediate Filaments
______________________
**Integrins:
1) Are Surface *Receptors that
2) *Mediate Attachment of Cells to
=> *Laminin in *BM
=>or *Fibronectin in
*Interstitial Matrix
3) *Mediate Cell-to-Cell Contacts
Other Secreted Adhesive Proteins
Interact with ECM and Cell Receptors.
1) SPARC (Osteonectin):
=> *Inhibits Angiogenesis
(Secreted Protein Acidic and Rich in Cysteine)
2) **Thrombospondin:
=> *Inhibits Angiogenesis
3) **Osteopontin:
=> *Regulates Calcification
=> *Mediates Leukocyte Migration
(b/c is a ligand for CD44)
Angiogenesis
Angiogenesis (Neovascularization)
= Blood Vessels develop in adults
2 Methods:
1) *Branching of adjacent blood vessels
2) * Recruitment of **Endothelial Progenitor Cells (EPCs) from Bone Marrow
____________________
Angiogenesis from Pre-Existing Vessels:
Requires
1) *Vasodilation and Increased Permeability of *Existing Vessels,
2) Degradation of ECM
3) *Migration of Endothelial Cells
1) *Nitric Oxide:
=> Induces Vasodilation
2) VEGF:
=> Increases Permeability
3) *Metalloproteinases:
=> Degrade Basement Membrane
=> Plasminogen activator disrupts endothelial cell junctions.
4) *Endothelial Cells Proliferate,
migrate and mature, then recruit periendothelial cells.
____________________
Angiogenesis from
Endothelial Progenitor Cells:
*EPCs are **Adult Angioblast-Like Cells Stored @ *Bone Marrow
that are *Recruited into Tissues
to Initiate Angiogenesis.
EPCs Express Hematopoietic Stem cell and Endothelial-specific Cell Markers, such as
_Vascular Endothelial Cadherin
_E-Selectin
_*Tie2 Receptor
EPCs function to replace lost endothelial cells.
Hematopoietic and Vascular Systems share a common cell precursor, the **Hemangioblast, which Generates
*Hematopoietic Stem Cells and *Angioblasts.
Angioblasts Migrate to Peripheral sites and Differentiate into Endothelial Cells and Periendothelial cells: Pericytes and Smooth Muscle Cells.
