pathology cptr3 regeneration & healing
TRANSCRIPT
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REGENERATION
HEALING (repair)
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LEARNING OBJECTIVES• Review the normal physiology and concepts
of cell proliferation, cell growth, cell “cycle”, and cell differentiation
• Understand the basic factors of tissue regeneration
• Understand the relationships between cells and their ExtraCellular Matrix (ECM)
• Understand the roles of the major players of healing---angiogenesis, growth factors (GFs), and fibrosis
• Differentiate 1st & 2nd intention healing
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DEFINITIONS:•REGENERATION: Growth of
cells to replace lost tissues
•HEALING: A reparative tissue response to a wound, inflammation or necrosis, often leads to fibrosis
• GRANULATION TISSUE• “ORGANIZING” INFLAMATION
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REGENERATION• Replacement of lost structures• Is dependent on the type of
normal turnover the original tissue has
• Can be differentiated from “compensatory” growth
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HEALING (repair)• Needs a wound, inflammatory process, or
necrosis• Many disease appearances anatomically are
the result of “healing” such as atherosclerosis
• Often ends with a scar• Fibrosis, as one of the 3 possible outcomes
of inflammation, follows “healing”• Requires a connective tissue “scaffold”• Fibrosis occurs in proportion to the damage
of the ECM
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Cell Population Fates• PROLIFERATION
– Hormonal, especially steroid hormones– eg., EPO, CSF
• DIFFERENTIATION*– UNIDIRECTIONAL, GAIN and LOSS
• APOPTOSIS
*One of the most KEY concepts in neoplasia
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ECTODERM
MESODERM
ENDODERM
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CELL CYCLE• G0
– Quiescent (not a very long or dominent phase)• G1
– PRE-synthetic, but cell GROWTH taking place• S
– Cells which have continuous “turnover” have longer, or larger S-phases, i.e., DNA synthesis
– S-phase of TUMOR CELLS can be prognostic• G2
– PRE-mitotic• M (Mitotic:, P,M,A,T, Cytokinesis)
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CELL TYPES• Labile: eg., marrow, GI• Quiescent: liver, kidney• NON-mitotic: neuron,
striated muscle
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STEM CELLS(TOTIPOTENTIAL*)
•EMBRYONIC•ADULT
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EMBRYONICSTEM CELLS
• DIFFERENTIATION
• KNOCKOUT MICE ( mice raised with specific gene defects)
• REPOPULATION OF DAMAGED TISSUES, in research
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ADULTSTEM CELLS
• MARROW (HEMOCYTOBLAST)
(hematopoetic stem cells)
• NON-MARROW
(RESERVE)
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MARROW STROMAL CELL
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ADULT TISSUE DIFFERENTIATION and REGENERATION PARALLELS EMBRYONIC
DEVELOPMENT
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Growth Factors (GFs)• Polypeptides• Cytokines
• LOCOMOTION• CONTRACTILITY• DIFFERENTIATION• ANGIOGENESIS
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Growth Factors (GFs)• Epidermal• Transforming (alpha, beta)• Hepatocyte• Vascular Endothelial• Platelet Derived• Fibroblast• Keratinocyte• Cytokines (TNF, IL-1, Interferons)
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CELL PLAYERS (source AND targets)
• Lymphocytes, especially T-cells• Macrophages• Platelets• Endothelial cells• Fibroblasts• Keratinocytes• “Mesenchymal” cells• Smooth muscle cells
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E(Epidermal) GF• Made in platelets, macrophages• Present in saliva, milk, urine, plasma• Acts on keratinocytes to migrate, divide• Acts on fibroblasts to produce
“granulation” tissue
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T(Transforming) GF-alpha• Made in macrophages, T-cells,
keratinocytes• Similar to EGF, also effect on
hepatocytes
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H(Hepatocyte) GF• Made in “mesenchymal” cells• Proliferation of epithelium,
endothelium, hepatocytes• Effect on cell “motility”
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VE(Vascular Endothelial) GF
• Made in mesenchymal cells• Triggered by HYPOXIA• Increases vascular permeability• Mitogenic for endothelial cells• KEY substance in promoting
“granulation” tissue
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PD(Platelet Derived) GF• Made in platelets, but also MANY
other cell types• Chemotactic for MANY cells• Mitogen for fibroblasts• Angiogenesis• Another KEY player in granulation
tissue
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F(Fibroblast) GF• Made in MANY cells• Chemotactic and mitogenic, for
fibroblasts and keratinocytes• Re-epithelialization• Angiogenesis, wound contraction• Hematopoesis• Cardiac/Skeletal (striated) muscle
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T(Transforming) GF-beta• Made in MANY CELLS• Chemotactic for PMNs and MANY
other types of cells• Inhibits epithelial cells• Fibrogenic• Anti-Inflammatory
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K(Keratinocyte) GF• Made in fibroblasts• Stimulates
keratinocytes:–Migration–Proliferation–Differentiation
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I(Insulin-like) GF-1• Made in macrophages, fibroblasts• Stimulates:
–Sulfated proteoglycans–Collagen–Keratinocyte migration–Fibroblast proliferation
• Action similar to GH (Pituitary Growth Hormone)
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TNF (Tumor Necrosis Factor)
• Made in macrophages, mast cells, T-cells
• Activates macrophages• KEY influence on other
cytokines
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Interleukins• Made in macrophages, mast cells,
T-cells, but also MANY other cells• MANY functions:
–Chemotaxis–Angiogenesis–REGULATION of other cytokines
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INTERFERONS• Made by lymphocytes,
fibroblasts• Activates MACROPHAGES• Inhibits FIBROBLASTS• REGULATES other cytokines
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SIGNALING• Autocrine (same cell)
• Paracrine (next door neighbor) (many GFs)
• Endocrine (far away, delivered by blood, steroid hormones)
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TRANSCRIPTION FACTORSHEPATIC
REGENERATION
TNFIL6HGF
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ExtraCellular Matrix (ECM)• Collagen(s) I-XVIII• Elastin• Fibrillin• CAMs (Cell Adhesion Molecules)
– Immunoglobulins, cadherins, integrins, selectins
• Proteoglycans• Hyaluronic Acid
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ECM• Maintain cell differentiation• “Scaffolding”• Establish microenvironment• Storage of GF’s
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Collagen One - bONE (main component of bone)
Collagen Two - carTWOlage (main component of cartilage)
Collagen Three - reTHREEculate (main component of reticular fibers)
Collagen Four - FLOOR - forms the basement membrane
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GENETIC COLLAGEN DISORDERS• I OSTEOGENESIS IMPERFECTA, E-D• II ACHONDROGENESIS TYPE II• III VASCULAR EHLERS-DANLOS• V CLASSICAL E-D• IX STICKLER SYNDROME• IV ALPORT SYNDROME• VI BETHLEM MYOPATHY• VII DYSTROPHIC EPIDERMOLYSIS
BULLOS.• IX EPIPHYSEAL DYSPLASIAS• XVII GEN. EPIDERMOLYSYS BULLOSA• XV, XVIII KNOBLOCH SYNDROME
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DEFINITIONS:•REGENERATION:
Growth of cells to replace lost tissues
•HEALING: A reparative tissue response to a wound, inflammation or necrosis
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HEALING• FOLLOWS INFLAMMATION• PROLIFERATION and MIGRATION of
connective tissue cells• ANGIOGENESIS (Neovascularization)• Collagen, other ECM protein synthesis• Tissue Remodeling• Wound contraction• Increase in wound strength (scar = fibrosis)
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ANGIOGENESIS(NEOVASCULARIZATION)
• From endothelial precursor cells• From PRE-existing vessels• Stimulated/Regulated by GF’s,
especially VEGF• Also regulated by ECM proteins• aka, “GRANULATION”, “GRANULATION
TISSUE”, “ORGANIZATION”, “ORGANIZING INFLAMMATION”
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WOUND HEALING• 1st INTENTION
• Edges lined up
• 2nd INTENTION
• Edges NOT lined up• Ergo….• More granulation• More
epithelialization• MORE FIBROSIS
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“HEALTHY” Granulation Tissue
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FIBROSIS/SCARRING• DEPOSITION OF COLLAGEN by
FIBROBLASTS• With time (weeks, months,
years?) the collagen becomes more dense, ergo, the tissue becomes “STRONGER”
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Wound RETARDING factors(LOCAL)
• DECREASED Blood supply• Denervation
• Local Infection• FB
• Hematoma• Mechanical stress• Necrotic tissue
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Wound RETARDING factors(SYSTEMIC)
• DECREASED Blood supply• Age
• Anemia• Malignancy• Malnutrition
• Obesity• Infection
• Organ failure