Lecture 11: Tissue Repair and Healing PDF

Lecture 11 Tissue Repair: Regeneration and Healing Dr Mohammad Shahid Iqbal M.D Assistant Professor of Pathology 1  Overview of tissue repair Repair (Healing)  Refers to the restoration of tissue architecture and function after an injury It occurs by two typ...

Lecture 11 Tissue Repair: Regeneration and Healing Dr Mohammad Shahid Iqbal M.D Assistant Professor of Pathology 1  Overview of tissue repair Repair (Healing)  Refers to the restoration of tissue architecture and function after an injury It occurs by two types of reactions 1. Regeneration 2. Scar formation by the deposition of connective tissue Overview of tissue repair  Regeneration  Regeneration: Process by which tissues are able to replace the damaged cells and essentially return to a normal state  Occurs by: 1. Proliferation of residual (uninjured) cells 2. Replacement from tissue stem cells  Ex: Rapidly dividing epithelia of the skin and intestines, and some parenchymal organs, notably the liver.  FIBROSIS: Extensive deposition of collagen that occurs in the lungs, liver, kidney, and other organs as a consequence of chronic inflammation, or extensive ischemic necrosis  Repair (Scar formation)  Repair occurs by the laying down of connective (Fibrous) tissue:  Seen in tissues incapable of regeneration, or if the supporting structures of the tissue are severely damaged,  Structure is restored; Function of lost parenchymal cells is gone  Provides enough structural stability  The control of cell proliferation  Cell proliferation: Driven by growth factors  DNA replication & Mitosis: Key processes in the proliferation of cells  Cell Cycle: The sequence of events that control these two processes  Several cell types proliferate during tissue repair. These include a. The remnants of the injured tissue b. Vascular endothelial cells c. Fibroblasts  Types of regenerating tissues  Tissues of the body are divided into three groups based on the proliferative capacity 1. Labile (continuously dividing) tissues 2. Stable tissues 3. Permanent tissues Labile Tissues: Cells are continuously being lost and replaced by maturation from stem cells and by proliferation of mature cells Examples: Hematopoietic cells Surface epithelia: Skin, vagina, cervix Duct epithelium: Salivary gland, Biliary tract Epithelium in GIT, Genitourinary tract  Stable Tissues  Stable Tissues: Cells of these tissues are quiescent(in G0 phase)  Have only minimal replicative activity in their normal state  Capable of proliferating in response to injury or loss of tissue mass  Example: Parenchyma of liver, kidney, and pancreas Endothelial cells, fibroblasts, and smooth muscle cells ❑ With the exception of liver, stable tissues have a limited capacity to regenerate after injury  Permanent Tissues ❑ Permanent Tissues: ❑ Terminally differentiated and non-proliferative in postnatal life ❑ Examples: Most neurons and cardiac muscle cells ❑ Injury to brain or heart is irreversible and results in a scar  Steps in Scar Formation Hemostatic plug Inflammation Macrophages (M2 type) are the central cellular players in the repair process. Cell proliferation Epithelial cells Endothelial cells proliferate to form new vessels Vascular endothelial growth factor (VEGF) stimulates proliferation and migration of endothelial cells Fibroblasts: Proliferate and migrate into the site of injury Lay down collagen fibers that form the scar. Formation of granulation tissue & Angiogenesis Deposition of connective tissue  Steps in scar formation: Angiogenesis Angiogenesis: Formation of new blood vessels Involves sprouting of new vessels from existing ones  Steps in scar formation: Angiogenesis Migration of endothelial cells toward the area of tissue injury. Proliferation of endothelial cells just behind the leading front (“tip”) of migrating cells. Remodeling into capillary tubes. Recruitment of periendothelial cells (pericytes for small capillaries and smooth muscle cells for larger vessels) to form the mature vessel Suppression of endothelial proliferation and migration and deposition of the basement membrane.  Steps in Scar Formation: Granulation tissue and Deposition of connective tissue Granulation tissue: The combination of proliferating fibroblasts, myofibroblasts , loose connective tissue, new blood vessels and scattered chronic inflammatory cells It is unique to healing wounds Gross: Pink, soft, granular Migration and proliferation of fibroblasts and deposition of loose connective tissue together with the vessels and interspersed mononuclear leukocytes forms granulation tissue Steps in Scar Formation: Granulation tissue and Deposition of connective tissue Granulation tissue showing numerous blood vessels, edema, and a loose Trichrome stain of mature scar, extracellular matrix containing showing dense collagen (blue occasional inflammatory cells. colour), with only scattered vascular channels. GRANULATION TISSUE  Steps in Scar Formation: Granulation tissue and Deposition of connective tissue Collagen synthesis is necessary for the healing wound to become strong and mechanically stable. Fibroblasts deposit type III collagen Capillaries provide nutrients Granulation tissue is progressively replaced by deposition of collagen  Steps in Scar Formation: Granulation tissue and Deposition of connective tissue Connective tissue deposition: Occurs in 2 steps (1) Migration and proliferation of fibroblasts into the site of injury (2) Deposition of ECM proteins (mainly collagen) produced by these cells. Mediated by PDGF, Fibroblast growth factor-2 (FGF) and TGF- β: Factors derived from M2 macrophages and inflammatory cells  Steps in Scar Formation: Granulation tissue and Deposition of connective tissue As the scar matures, there is progressive vascular regression Transforms the highly vascularized granulation tissue into a pale, largely avascular scar. Myofibroblasts: Fibroblasts with acquired features of smooth muscle cells, including the presence of actin filaments Contribute to the contraction of the scar over time  Steps in Scar Formation: Granulation tissue and Deposition of connective tissue Remodeling: Connective tissue in the scar continues to be modified and remodeled Matrix metalloproteinases (MMPs): Degradation of collagens and other ECM components Granulation tissue to scar  FACTORS THAT INFLUENCE TISSUE REPAIR Infection Diabetes Nutritional status: Vitamin C deficiency inhibits collagen synthesis and retard healing, copper and zinc deficiency lead to poor collagen formation Glucocorticoids: Inhibit TGF-β production and diminish fibrosis. Mechanical factors Poor perfusion Foreign bodies Type and extent of injury Location of the injury  References: Kumar V. et al, 2021. Robbins & Cotran Pathologic basis of disease, 10th ed. Chapter 3, P 71-125 Thank You