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.
GF and GFR Involved in Angiogenesis
**VEGF and **Angiopoietins
VEGF:
_Secreted by many Stromal Cells
_Increases Vascular Permeability
VEGFR-2:
_Essential in Angiogenesis
_Restricted to @*Endothelial Cells
During Angiogenesis from EPCs:
_VEGF/VEGFR-2 signals EPC Recruitment from Bone Marrow.
_EPCs initially form delicate capillary plexuses, then evolve into mature capillary networks.
During Angiogenesis from
Pre-Existing Vessels:
_VEGF and FGF-2 Stimulate Proliferation and Motility of Endothelial Cells and Capillary Branching.
____________________
New Vessels are Fragile and Need **Stabilization, which Requires Adding Pericytes, Smooth Muscle cells, and ECM.
1) *Angiopoietin 1 (Ang1):
=> Binds to Tie2 Receptor,
=> Signaling **Pericytes Recruitment
2) **PDGF Recruits **Smooth Muscle cells.
3) **TGF-Beta Enhances **ECM Production.
4) Ang2 Binds to Tie2 also, but has opposite effect of Ang1, loosening and sensitizing endothelial cells to VEGF or, in absence of VEGF, to angiogenesis inhibitors.
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(brown bold)
Migration of Endothelial Cells is Controlled by:
1) *Integrins, e.g. avBeta3:
_Endothelial cell expression is induced by hypoxia
_Interacts with metalloproteinases and VEGFR-2.
2) *Matricellular Proteins:
_Thrombospondin 1,
_SPARC
_Tenascin C
3) *Proteinases:
_Plasminogen Activator
4) *Matrix Metalloproteinases (MMPs):
_Cleave ECM Proteins, Facilitating endothelial cell access to VEGF and Migration.
Scar Formation
- *VEGF:
1) **Increases Vascular Permeability
2) and *Exudation of Plasma Proteins, such as *Fibrinogen,
3) Providing an *Initial Matrix for *Fibroblast and *Endothelial Cell Growth and Migration.
**TGF-Beta Triggers *Proliferation and *Migration of Fibroblasts.
**Macrophages Produce
TGF-Beta, PDGF, and FGF
= **Promoting Fibrosis
- Collagen Synthesis
- Begins 3-5 Days after Injury and
- Continues for Weeks.
*Vascular Regression:
=> Converts Granulation tissue into an avascular scar w/ fibroblasts and dense collagen.
Tissue Remodeling
4 Types of MMPs:
1) **Collagenases
2) **Gelatinases
3) **Stromelysins
4) **Membrane-Bound MMP
- *MMPs are Produced by
1) *Fibroblasts
2) *Macrophages
3) *Neutrophils
4) *Some Epithelial cells
MMPs Must Be *Cleaved to Become Active
MMPs *Secretion
=> *Induced by *PDGF and *FGF
=> *Inhibited by *TGF-Beta
Collagenases are Rapidly Inhibited by *Tissue Inhibitors (TIMPs) Produced by Stromal Cells.
Skin Wound Healing By
1st or 2nd Intention
Healing by 1st Intention: => Small, Superficial Injuries, e.g. Surgical Incision => Heals in 1 week with Minimal Scar or Retraction
Healing by 2nd Intention:
=> Extensive Injuries
=> Takes Longer to Heal
=> Requires More Remodeling and Contraction to close the gap
Factors Influencing Wound Healing
1) **Infection
2) **Poor Blood Supply/Circulation
3) **Diabetes
4) **Glucocorticosteroids
5) **Foreign Bodies
6) **Vitamin C Deficiency
Complications of Wound Healing
1) Deficient Granulation and Scar Formation:
=> Leads to ulceration: Rupture Wound
2) Excessive Wound Contraction
=> After serious burns
= Contractures
3) Excessive Granulation and Scar Formation:
(1) Keloid
(2) Pyogenic Granuloma
(3) Desmoids or Aggressive Fibromatosis
Excessive Granulation and Scar Formation
1) **Keloid:
= **An Excessive Deposition of Collagen or Hypertrophic Scar
that grows Beyond the Boundaries of the Original Wound
More common in African Americans
2) **Pyogenic Granuloma:
= An exuberant Granulation precluding epithelium from reconnecting
3) **Desmoids:
= Aggressive *Fibromatoses often seen at previous sites of Surgery
which lie in the interface of reactive cell growth as seen in repair and neoplasia, an uncontrolled autonomous cell growth.
