tissue repair Cell regeneration and

Regeneration and tissue healing depend on two important factors:

1.The type of tissue damaged.
2.Severity of the injury.

Regeneration:The replacement of destroyed tissue by the same kind of cells
Fibrosis
Repair by fibrous connective tissue: formation of scar tissue.

Fibrosis (Scar Tissue)characterized by:
1. Lacks flexibility of normal tissues.
2. Loss normal functions of the tissue that it replaces e.g. Sweat glands are damaged or destroyed, hair does not grow back, less resistance to UV radiation.

Steps of tissue healing after injury:
1. Capillaries become very permeable, this will allows clotting proteins and other substances to seep into the injured area, then clot walls off the injured area

2. Granulation tissue formation:
Delicate pink tissue composed largely of new capillaries that grow into damaged area and contains phagocytes that dispose of blood clot and contains connective tissue cells (fibroblasts) that synthesize collagen fibers that form scar tissue.
3. Regeneration of surface epithelium:
Scab detaches, and the underlying surface is regenerated epithelium that covers the underlying area of fibrosis
Proliferative Potential of different cell types:
1. Labile (always dividing) cells: Replace dying cells e.g. Epithelia: skin, oral cavity, exocrine ducts, GI tract, GYN, hematopoietic.
2. Stable (quiescent) cells:Usually in G0 and low rate of division.Driven into G1 and rapid proliferation e.g.
Liver, kidney, pancreas, endothelium, fibroblasts
3. Permanent (non-dividing ) cells: Permanently removed from cell cycle, irreversible injury leads only to scar
e.g. Nerve cells, myocardium.

Wound repair, new tissue growth.
Hyperplasia is when tissues or organs enlarge due to an irritant or condition that stimulates the cells

Regulation of cell regeneration:
the process controlled by biochemical factors released in response to cell injury, cell death, or mechanical trauma
Most important control:
inducing resting cells to enter cell cycle.

Balance between stimulatory and inhibitory factors.
Shorten cell cycle.
Decrease rate of cell loss.
Intercellular Signaling
Three pathways
Autocrine: cells have receptors for their own secreted factors (liver regeneration)
Paracrine: cells respond to secretion of nearby cells (healing wounds)
Endocrine: cells respond to factors (hormones) produced by distant cells
Molecular events:Molecular control of cell regeneration)
Receptor activation: monomers > dimerization > autophosphorylation
Signal transduction and second messengers (e.g., GTP-binding proteins, phospholipases, MAP kinases)
Induce expression of transcription factor genes (e.g., myc, fos, jun)
Cell cycle (growth) regulated by cyclins
Growth Factors
Epidermal growth factor (EGF)
Keratinocytes, fibroblasts
Vascular endothelial growth factor (VEGF)
Angiogenesis
Transforming growth factor-? (TGF- ?)
Fibrogenesis
Platelet-derived growth factor (PDGF)
Migration and proliferation of fibroblasts, smooth muscle, and monocytes
Extracellular Matrix (ECM)
ECM provides turgor, rigidity, support, adhesion substrate, reservoir for factors
ECM must remain intact for parenchymal healing
Three ECM protein components
Collagens: most common; triple helix of polypeptide chains; extracellular framework of body
Extracellular Matrix (ECM)
Collagens:
14 types
I-III: interstitial/fibrillar, most abundant
IV-VI: non-fibrillar, basement membranes
Adhesive glycoproteins: e.g., Laminin, fibronectin, thrombospondin, integrins which bind ECM components to each other, and to other cells
Proteoglycans: sugars linked to proteins; influence ECM permeability and structure
Connective Tissue Repair (Scar Formation)
Loss of parenchyma and ECM
Formation of new blood vessels (angiogenesis), fibroblast migration and proliferation (lay down collagen) < 24 hr
“Granulation tissue”: pink, soft, granular grossly
Maturation and organization (remodeling) of fibrous tissue
Angiogenesis
Vessels derive from endothelial cell precursors (angioblasts) or from budding of pre-existing vessels
BM degradation
Endothelial migration
Endothelial proliferation
Endothelial maturation
Periendothelial cell recruitment (pericytes, smooth muscle)
Fibrosis (Fibroplasia)
Occurs within the granulation tissue framework (new blood vessels and loose ECM)
Proliferation of fibroblasts at site of injury
Growth factors (TGF-a, PDGF, EGF, FGF)
Cytokines (IL-1, TNF-a)
Deposition of ECM (collagen)
Scar Remodeling
Remodeling to strengthen repair
Metalloproteinases (interstitial collagenases, gelatinases, stromelysins)
Produced by macrophages, neutrophils, fibroblasts as inactive precursors
In response to local factors
Debris carried away by phagocytes (debridement)