Professional Documents
Culture Documents
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Outline
1. Overview
2. Cell Regeneration
• Control of cell growth, cell cycle
• Growth factors
• Extracellular matrix
3. Repair by Connective Tissue
• Angiogenesis
• Fibrosis (Scar formation)
• Scar Remodeling
4. Wound Healing
• Healing by first intention
• Healing by second intention
• Wound strength
5. Factors Affecting Healing
6. Overview of the Inflammatory-Reparative Response
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Overview
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Overview
Regeneration or Fibrosis??
(Scar)
Cells ECM
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The Cell Cycle
(S) DNA synthesis phase (G2) Premitotic growth phase
Cell cycle is the sequence of events that control DNA replication and mitosis
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Cell Cycle Regulation
Progression through the cell cycle from G1 is regulated by proteins called cyclins.
Cyclin form complexes with enzymes called cyclin-dependent kinases (CDKs)
which become activated.
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Proliferative Capacities of Tissues
Labile tissues Stable tissues Permanent tissues
(Continuously dividing) - Quiescent in the G0 stage. - Terminally differentiated
- Cells are continuously being - Minimal replicative activity and nonproliferative in
lost and replaced. in their normal state. postnatal life
- Can readily regenerate after - Capable of proliferating in - Repair is typically
injury. response to injury or loss of dominated by scar
tissue mass. formation
Examples:
Examples: Examples:
Hematopoietic cells in BM
Liver Cardiac muscle
Stratified squamous
surfaces (skin, oral cavity, Kidney Skeletal muscle
vagina, and cervix) Pancreas Neurons
Columnar epithelium of Endothelial cells,
GIT, uterus fibroblasts, and smooth
muscle cells
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How Does Regeneration Occur?
Growth factor (GF)
ECM
Cell Response
(proliferation, locomotion, and differentiation)
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Soluble Mediators
Definition:
by convention "growth factor" is used for a protein that expands cell populations by
stimulating cell division and by promoting cell survival.
General Properties:
Most growth factors have pleiotropic effects: in addition to stimulating cellular
proliferation, they stimulate migration, differentiation and contractility, and
enhance the synthesis of specialized proteins (such as collagen in fibroblasts)
A growth factor may act on a specific cell type or on multiple cell types
They induce cell proliferation by binding to specific receptors and affecting the
expression of growth control genes
Adjacent cells communicate via gap junctions (narrow, hydrophilic channels that
effectively connect the two cell cytoplasm), allowing movement of small ions,
various metabolites, second messengers but not larger macromolecules.
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Soluble Mediators
Extracellular Signaling Mechanisms
Intracellular Receptors
ligands must be sufficiently hydrophobic to enter the cell (e.g., vitamin D, or steroid and
thyroid hormones). Ligand binding leads to the formation of receptor-ligand complexes that
directly associate with nuclear DNA and activate or turn off gene transcription.
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Cell Surface Receptors
epinephrine, vasopressin ,
serotonin, histamine, and
EGF, VEGF, FGF, HGF glucgon
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Extra-Cellular Matrix (ECM)
Components:
The interstitial matrix between cells
The basement membranes (nonfibrillar collagen and laminin)
Integrins are transmembrane glycoproteins, the main cellular receptors for
ECM components
Collagen is a structural proteins that confer tensile strength
Elastin confers tissue elasticity (ability of tissues to recoil and return to a
baseline structure after physical stress)
Adhesive glycoproteins connect cells to underlying ECM components. They
include fibronectin (major component of the interstitial ECM) and laminin
(major constituent of basement membrane)
Proteoglycans form highly hydrated compressible gels conferring lubrication
(such as in the cartilage in joints) and serve as reservoirs for growth factors
secreted into the ECM
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Extra-Cellular Matrix (ECM)
Functions:
Mechanical support to tissues (collagens and elastin)
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Repair by Connective Tissue
When?
If nondividing cells are injured.
If tissue injury is severe or chronic, and results in damage to parenchymal cells and
epithelia as well as the stromal framework
How?
1. within 24 hours of injury: fibroblasts emigration, and fibroblast and endothelial
cell proliferation.
VEGF
FGF
Capillary sprouting
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Repair by Connective Tissue
Angiogenesis is a critical process in:
Healing at sites of injury
Development of collateral circulations at sites of
ischemia
Allowing tumors to increase in size beyond the
constraints of their original blood supply
Targeting angiogenesis:
• Stimulation, e.g., to improve blood flow to a heart
ravaged by coronary atherosclerosis.
• Inhibition, to frustrate tumor growth.
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Repair by Connective Tissue
2. Migration and Proliferation of Fibroblasts
Driven by PDGF, FGF, and TGF-β secreted by activated endothelium
and chronic inflammatory cells.
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Keloid
Excess collagen deposition in the skin forming
a raised scar
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Repair by Connective Tissue
The outcome of the repair process is, in part, a balance between
ECM synthesis and degradation
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Wound Healing
Large wounds, abscess formation, ulceration, infarction
Healing by second intention or secondary union Wound Care in the Wilderness, January 24, 2013
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Wound Healing by First Intention
Neutrophils are seen at the incision margin, migrating
toward the fibrin clot.
Basal cells of the epidermis begin to show increased mitotic
activity.
By the end of the first month, the scar comprises a cellular
connective tissue largely devoid of inflammatory cells and
covered by an essentially normal epidermis.
The tensile strength of the wound increases with time to
reach 70%-80% by 3 months 26
Wound Healing by Second Intention
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Factors Affecting Healing
Infection is the single most important cause of delay in healing; it prolongs
the inflammation phase of the process and potentially increases the local
tissue injury.
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Pathways of Reparative Responses
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• Complete restoration can occur only in tissues composed of stable and
labile cells.
• Even if cells are able to divide, extensive injury will probably result in
incomplete tissue regeneration and at least partial loss of function.
• Depending on the type and extent of injury, the nature of the injured
tissue, and persistence of inflammatory stimuli, injury results often in
some degree of residual scarring.
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References
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