Tissue Repair

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Tissue Repair

• Objectives
• What is tissue repair ?
• Cell cycle
• Regulation of Tissue Growth Proliferation
• Mechanisms of Tissue Regeneration
• Repair by Regeneration
• Repair by Scar Formation
• Role Extra cellular Matrix (ECM) in repair
• Cutaneous Wound Healing
• Fibrosis

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What is tissue repair ?
Regeneration
Normal
Scar formation
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What is tissue repair ?
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Tissue Repair

• Objectives
• What is tissue repair ?
• Cell cycle
• Regulation of Tissue Growth Proliferation
• Mechanisms of Tissue Regeneration
• Repair by Regeneration
• Repair by Scar Formation
• Role Extra cellular Matrix (ECM) in repair
• Cutaneous Wound Healing
• Fibrosis

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Cell cycle

• Proto-oncogenes - regulation of normal cell
  proliferation
• Oncogenes -defects in proto-oncogenes
• Growth factors or Integrins stimulate replication
  of cells
• Cyclins Cyclin-dependent kinases (CDKs-
  Retinoblastoma susceptibility (RB) protein )
  regulate G1/S transition
• CDK inhibitors -regulate activity of cyclin-CDK
  complexes

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Tissue Repair

• Objectives
• What is tissue repair ?
• Cell cycle
• Regulation of Tissue Growth Proliferation
• Mechanisms of Tissue Regeneration
• Repair by Regeneration
• Repair by Scar Formation
• Role Extra cellular Matrix (ECM) in repair
• Cutaneous Wound Healing
• Fibrosis

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Regulation of Tissue Proliferation Growth
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Tissue-proliferative activity
skeletal myocyte
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Regulation of Tissue Proliferation Growth
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Stem cells

• Self -renewal capacity
• Asymmetric replication

Stem cells
Embryonic
Marrow or Hemopoietic
Adult
Tissue specific
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Stem cells

• Embryonic Stem Cells
• Pluripotent
• Isolated from Blastocysts
• (32-cell stage)
• These cells express unique transcription factors
• homeobox protein Nanog
• Wnt -ß- catenin

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Stem cells
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Trans-differentiation
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Stem cells

• Adult Stem Cells
• Restricted differentiation capacity
• Lineage-specific

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Intestinal stem cells
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Corneal stem cells (Limbus region)
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Epidermal stem cells
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Liver stem cells (oval cells)
canals of Hering
Bile ductules
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Hematopoietic stem cells (HSCs)

• Trans-differentiation
• differentiation from one cell type to another
• Developmental plasticity
• multiplicity of stem cell differentiation

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Bone marrow stromal cells
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Multipotent adult progenitor cells - MAPC

• Closely related to ES cells
• Found in adult bone marrow, Muscle, Brain, Skin

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Growth Factors

• Have cell proliferating Growth-promoting effects
• 1 2. Epidermal Growth Factor (EGF) and
  Transforming Growth Factor-a (TGF-a)
• share a common receptor
• Role in Healing of skin wounds EGF
• EGFR2/ ERB B2 receptor /HER-2/Neu
• ?Over expressed in breast cancers

Bad Prognosis
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Growth Factors

• 3. Fibroblast Growth Factor (FGF)
• Role in New blood vessel formation
  (angiogenesis) FGF-2
• Wound repair
• 4. TGF-ß
• TGF-ß1 widespread distribution
• Smads Triggers the Phosphorylation of
  transcription factors
• Growth inhibitory, anti inflammatory
  proliferative ( fibroblasts and SMCs) effects
• 5. Hepatocyte Growth Factor
• proliferative effects on Hepatocytes Biliary
  epithelium
• c-MET Proto-oncogene Receptor for HGF
• Over expressed in human tumors

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Growth Factors

• 6. Vascular Endothelial Growth Factor (VEGF)
• Role in Vasculogenesis( blood vessel formation)
  Angiogenesis ( growth of new blood vessels)
• VEGFR-1 Role in Mobilization of endothelial stem
  cells in inflammation
• VEGFR-2 Present on Endothelial cells
• has vasculogenic and Angiogenic effects
• VEGFR-3 role in lymphangiogenesis
• 7. Platelet-Derived Growth Factor (PDGF)
• Released on platelet activation
• Migration and proliferation Effects on
  Fibroblasts SMCs

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Tissue Repair

• Objectives
• What is tissue repair ?
• Cell cycle
• Regulation of Tissue Growth Proliferation
• Mechanisms of Tissue Regeneration
• Repair by Regeneration
• Repair by Scar Formation
• Role Extra cellular Matrix (ECM) in repair
• Cutaneous Wound Healing
• Fibrosis

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Mechanisms Tissue Proliferation Growth

• Recruitment of quiescent cells into the cycle -
  Most important
• Shortening of Cell-cycle time less important

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Mechanisms of Tissue Regeneration

• Effects
• Transcription of many genes
• Entry of the cells into the cell cycle

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Receptors and Signal Transduction Pathways
Mechanisms Tissue Proliferation Growth
All Growth Factors Insulin
IL, Interferons Hormones (GH, PRL, Epo)
Most hormones, amines Drugs
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Mechanisms Tissue Proliferation Growth
Transcription Factors
Regulate cell proliferation
c-MYC, c-JUN p53
Nuclear Receptors Estrogen, Retniods, Vit. D,
Thyroid hormones
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Tissue Repair

• Objectives
• What is tissue repair ?
• Cell cycle
• Regulation of Tissue Growth Proliferation
• Mechanisms of Tissue Regeneration
• Repair by Regeneration
• Repair by Scar Formation
• Role Extra cellular Matrix (ECM) in repair
• Cutaneous Wound Healing
• Fibrosis

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Repair by Regeneration

• Capacity of quiescent cells to reenter the cell
  cycle
• ( G0?G1)
• By Differentiation of stem cells
• Organs regenerate
• Liver
• Kidney
• Pancreas
• Adrenal glands
• Thyroid
• Lungs

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Repair by Regeneration
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Repair by Regeneration
Before the operation
1 WEEK AFTER OPERATION
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Tissue Repair

• Objectives
• What is tissue repair ?
• Cell cycle
• Regulation of Tissue Growth Proliferation
• Mechanisms of Tissue Regeneration
• Repair by Regeneration
• Repair by Scar Formation
• Role Extra cellular Matrix (ECM) in repair
• Cutaneous Wound Healing
• Fibrosis

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Repair by Scar Formation

• Fibroproliferative response
• "patches" rather than restores a tissue
• Steps
• Inflammatory response to initial injury
• Proliferation and migration of parenchymal and
  connective tissue (ECM) cells
• Angiogenesis and granulation tissue ( hall mark)
• Synthesis of ECM proteins and collagen deposition
• Tissue remodeling
• Wound contraction
• Acquisition of wound strength

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Repair by Scar Formation

• Granulation tissue
• the hallmark of healing
• Pink , soft, granular appearance on the surface
  of wounds
• Histology
• Proliferation of fibroblasts
• angiogenesis

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Granulation tissue
COLLAGEN TISSUE
HE STAIN
TRICHROME STAIN
BLOOD VESSELS
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Granulation tissue
Fibroblasts
Capillaries
Inflammatory cells
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Repair by Scar Formation

• Angiogenesis
• Critical to
• Chronic inflammation and fibrosis
• Tumor growth
• Ischemic tissues

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Angiogenesis

• In Embryogenesis
• ?
• Hematopoietic and Vascular systems
• ?
• Hemangioblast
• Hemopoietic stem cell Angioblast
• endothelial cell
• Pericytes
• SMCs

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ANGIOGENESIS
Vasculogenesis
Angiogenesis
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Angiogenesis

• Growth factors responsible
• VEGF
• Angiopoietins
• VEGFR-2
• most important in angiogenesis
• largely restricted to endothelial cells and their
  precursors
• VEGF acting through it
• stimulates the mobilization of endothelial cell
  precursors from the bone marrow

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Angiogenesis

• Angiopoietins
• Ang1 and Ang2
• Ang1- binds with Tie2 (EC receptor) to recruit
  periendothelial cells
• Ang2 /Tie2 interaction lead to
• If VEGF() if VEGF(-)
• EC are more responsive to EC are more responsive
  to
• stimulators of angiogenesis

inhibitors of angiogenesis
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Repair by Scar Formation

• Fibroproliferative response
• "patches" rather than restores a tissue
• Steps
• Inflammatory response to initial injury
• Proliferation and migration of parenchymal and
  connective tissue (ECM) cells
• Angiogenesis and granulation tissue ( hall mark)
• Synthesis of ECM proteins and collagen deposition
• Tissue remodeling
• Wound contraction
• Acquisition of wound strength

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Repair by Scar Formation

• Tissue remodeling
• Granulation tissue ?Tissue remodeling ? Scar
• involves Changes in the composition of the ECM
• TGFß - most important in fibrous tissue
  deposition
• Matrix metalloproteinases (MMPs) most important
  in remodeling
• Collagenases
• Gelatinases
• Stromelysins

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Tissue remodeling
Scar
Granulation tissue
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Tissue remodeling
Free radicals proteinases
MMPs
(produced by mesenchymal cells)
Matrix metalloproteinases (MMPs)