Lecture 12, Tissue Repair and Regeneration PDF

By the end of this session students should be able to: ◦ Classify cell types according to their regenerative ability. Session’s Objectives ◦ Identify repair by fibrosis regarding definition, conditions, and pathogenesis. ◦ Recognize wound healing: healing by first intention and by second intention....

By the end of this session students should be able to: ◦ Classify cell types according to their regenerative ability. Session’s Objectives ◦ Identify repair by fibrosis regarding definition, conditions, and pathogenesis. ◦ Recognize wound healing: healing by first intention and by second intention. ◦ Identify pathologic aspect of repair. ◦ Tissue repair: ◦ Restoration of tissue architecture and function after an injury. ◦ Repair of damaged tissue occurs by two types of processes: 1. Regeneration: proliferation of residual undamaged cells. 2. Scar formation: If the injured tissues are incapable of complete Terminology & Definitions restitution and regeneration, or if the supporting structures of the tissue are severely damaged, repair occurs by laying down of connective (fibrous) tissue i.e. scar formation. ◦ Commonly combination of the two processes takes place in tissue repair. ◦ Fibrosis (scar formation): ◦ Extensive deposition of collagen that occurs in the skin, lungs, liver, kidney, and other organs after chronic inflammation, and in myocardium after infarction. ◦ Organization: ◦ Fibrosis in a tissue space occupied by an inflammatory exudate e.g. organizing pneumonia affecting the lungs. Proliferative Capacities of Tissues ◦ Based on intrinsic proliferative capacity, tissues are divided into three groups: ◦ Labile tissues. ◦ Stable tissues (Quiescent tissue). ◦ Permanent tissues (Nondividing tissue). ◦ Labile tissues: Proliferative Capacities of Tissues ◦ Cells are continuously being lost and replaced by maturation from stem cells and by proliferation of mature cells. ◦ Examples: ◦ Hematopoietic cells of bone marrow ◦ Surface epithelia of the ◦ Skin, oral cavity, vagina, cervix ◦ Exocrine glands ◦ GIT, uterus, fallopian tubes ◦ Urinary tract. ◦ Stable tissue: Proliferative Capacities of Tissues ◦ Cells are quiescent (G0 stage of the cell cycle) ◦ Minimal replicative activity in normal state. ◦ Cells are capable of proliferating in response to an injury ◦ With the exception of liver, stable tissues have a limited capacity to regenerate after injury. ◦ Examples: ◦ Parenchyma of most solid tissues as liver, kidney, pancreas. ◦ Endothelial cells, fibroblasts, and smooth muscle cells. Proliferative Capacities of Tissues ◦ Permanent tissue: ◦ Terminally differentiated and have non proliferative capacity in postnatal life (nondividing tissue). ◦ Examples: Neural tissue, Cardiac & Skeletal muscle ◦ When damaged, they are repaired by scar formation (fibrous tissue formation). Proliferative Capacities of Tissues ◦ In labile tissues mature cells are short-lived & the tissue is replenished by differentiation of stem cells. ◦ There is an equilibrium between the replication and differentiation of stem cells and the death of mature cells. Role of Stem Cells ◦ Located near the basal layer of the epithelium in skin & GIT. ◦ Properties of Stem cells: 1. Self-renewal capacity. 2. Asymmetric replication i.e. after each cell division, some cells enter a differentiation pathway, while others remain undifferentiated, retaining their selfrenewal capacity. Stem Cells Types: 1. Embryonic Stem Cells: Can be isolated from embryo. Generate multiple cell lineages (pluripotent). 2. Tissue /Adult Stem Cells: Present in bone marrow and several tissues of adult individuals. Tissue Proliferation, Differentiation and Death ◦ Expand cell population by stimulating cell division and promoting cell survival. ◦ May stimulate proliferation of some cells and inhibit others by binding to specific receptors. Role of Growth Factors (GF) ◦ Stimulate the function of growth control genes (Protooncogenes). ◦ A GF may act on a specific or multiple cell types. ◦ Most GF have multiple effects. ◦ Growth factors involved in repair are produced by leukocytes, parenchymal cells or stromal cells. Signaling Mechanisms of GF ◦ Signaling may occur as ◦ Autocrine: ◦ Directly in the same cell ◦ Paracrine: ◦ Between adjacent cells ◦ Endocrine: ◦ Over greater distance Growth Factors Growth Promoters Growth Inhibitors ◦ Epidermal Growth Factor (EGF) ◦ Transforming growth factor beta (TGF-b) ◦ Platelet derived growth factor (PDGF) ◦ Interferon alpha (INF-a) ◦ Fibroblastic growth factor (FGF) ◦ Interleukin-I (IL-1) ◦ Tumor necrosis factor (TNF) ◦ Vascular endothelial growth factor (VEGF) ◦ ECM regulates the proliferation, movement, and differentiation of the cells living within it. Role of Extracellular Matrix (ECM) ◦ An intact ECM is required for tissue regeneration and if the ECM is damaged, repair can only be accomplished by scar formation. 1. Labile Tissue: Repair by Tissue Regeneration Process of regeneration is seen in labile & stable tissues ◦ Cell renewal occurs continuously in labile tissues e.g. bone marrow, gut epithelium, skin. ◦ Damage to epithelia is corrected by the proliferation and differentiation of stem cells. ◦ An increased loss of blood cells - proliferation of more differentiated progenitors occurs in the bone marrow, this is driven by growth factors. 2. Stable Tissue: ◦ Regeneration or compensatory hyperplasia can occur only if residual tissue is structurally and functionally intact. Repair by Tissue Regeneration ◦ 40% to 60% of the liver may be removed in living donor or for tumor removal. Process of regeneration is seen in labile & stable tissues ◦ Pancreas, adrenal, thyroid, and lung tissues have some regenerative capacity. ◦ ◦ Removal of a kidney elicits a compensatory response in the other kidney involving both hypertrophy and hyperplasia of proximal duct cells. Liver Repair After Injury ◦ Repair cannot be accomplished by regeneration alone when there is: ◦ severe damage to parenchyma/ epithelia/ stromal framework ◦ injury to permanent cells Repair by Scar Formation ◦ Now repair occurs either by ◦ Combination of regeneration and scar formation. ◦ Replacement of the non regenerated cells by connective tissue ◦ Repair begins within 24 hours - Emigration & proliferation of fibroblasts and endothelial cells (Granulation Tissue). ◦ By 3 to 5 days, Granulation Tissue is apparent (characteristic of healing by connective tissue) ◦ Granulation tissue accumulates connective tissue matrix, forming a scar which remodels over time. Granulation Tissue (Repair tissue) ◦ Gross appearance: ◦ Pink, soft, granular. ◦ Microscopic appearance: ◦ Proliferating fibroblasts. ◦ New thin-walled delicate capillaries (angiogenesis) ◦ Loose ECM. ◦ Granulation tissue is edematous as newly formed vessels are leaky because of ◦ Incompletely formed inter-endothelial junctions ◦ VEGF increases vessel permeability Granulation tissue with new blood vessels, edema, loose ECM and minimal collagen stained blue with trichome stain Mature Scar tissue with dense collagen tissue stained blue with trichome stain and scarse blood vessels