Tissue Regeneration Versus Repair PDF

24 TISSUE REGENERATION VERSUS REPAIR ILOs By the end of this lecture, students will be able to 1. Appraise the role of adult stem cells in tissue regeneration 2. Clarify steps in scar formation in relevance to some disorders 3. Discuss angiogenesis and depo...

24 TISSUE REGENERATION VERSUS REPAIR ILOs By the end of this lecture, students will be able to 1. Appraise the role of adult stem cells in tissue regeneration 2. Clarify steps in scar formation in relevance to some disorders 3. Discuss angiogenesis and deposition and remodelling of connective tissue Repair or healing refers to restoration of tissue architecture and function after injury. Repair of damaged tissues occurs by two processes; regeneration (which restore normal tissues) and scarring (associated with deposition of fibrous tissues). Regeneration: Can occur through the proliferation of adjacent surviving cells or through the activity of tissue stem cells. (e.g., bone after a fracture or epithelium after a superficial skin wound). Scarring: Occurs when the restorative capacity is limited, severe tissue injury, and extensive damage of parenchyma and/or stromal elements cannot heal by regeneration. Then, fibroproliferative response (fibrosis) deposits collagen and other ECM components (scar) that “patch” rather than restore a tissue. Resolution of inflammatory exudates can also lead to fibrosis, a process called organization. In most cases healing is some combination of regeneration and scar; the outcome will be affected by; (1) proliferative capacity of the damaged tissue (2) integrity of the ECM (3) the chronicity of the associated inflammation. Cell and Tissue Regeneration Cell Proliferation: Signals and Control Mechanisms Multiple cell types proliferate during tissue repair, including: 1. Remnant cells of the injured tissue 2. Endothelial cells (angiogenesis to provide the nutrients needed for repair) 3. Fibroblasts (source of the scar extracellular matrix). The ability of the non-fibroblast and non-endothelial cells to restore normal tissue depends on their intrinsic proliferative capacity of cells: Labile (continuously dividing) tissues: Such cells are constantly replaced by proliferation of mature cells and/or maturation from tissue stem cells. Page 1 of 5  Examples: bone marrow hematopoietic cells and most surface epithelia (e.g., skin, oral cavity, ducts draining exocrine organs, GI tract, and urinary tract). Stable tissues: Such cells are quiescent with minimal baseline proliferative activity. However, they can divide after injury or loss of tissue mass. Examples: most solid tissue parenchyma (e.g., liver, kidney, and pancreas), endothelial cells, fibroblasts, and smooth muscle cells. Permanent tissues: These cells are terminally differentiated and non-proliferative in postnatal life Examples: cardiomyocytes and most neurons. Therefore, brain or cardiac injury is typically irreversible, resulting in scar. Mechanisms of Tissue Regeneration In labile tissues, injured cells are rapidly replaced by proliferation of residual cells and differentiation of tissue stem cells—so long as the underlying basement membrane is intact. Cell proliferation is driven by growth factors (synthesized by macrophages, epithelial, and stromal cells). Loss of blood cells is corrected by proliferation of hematopoietic stem cells, driven by growth factors called colony stimulating factors. Tissue regeneration in parenchyma composed mostly of stable cell populations is usually limited; pancreas, adrenal, thyroid, and lung have some regenerative capacity, and nephrectomy elicits compensatory hypertrophy and hyperplasia of proximal duct cells in the remaining kidney. The exception is liver, which has extraordinary regenerative capacity. Example of regeneration: Liver regeneration Liver regeneration occurs by two major mechanisms: proliferation of remaining hepatocytes and repopulation from liver progenitor cells. Regardless of proliferative capacity, extensive tissue damage leads to incomplete regeneration, accompanied by scarring. Therefore, a liver abscess will lead to scar formation even though the remaining liver cells have the capacity to regenerate. Repair by Connective Tissue Deposition (Repair by Scarring) Steps in Scar Formation Repair begins within 24 hours of injury; by 3 to 5 days, granulation tissue is apparent: Repair by connective tissue deposition consists of sequential processes that follow tissue injury: Page 2 of 5  1. Hemostatic plug formation. Within minutes after injury, composed of platelets, which entangle fibrin and stops bleeding and. 2. Inflammation. Breakdown products of complement activation, chemokines released from activated platelets, and other mediators produced at the site of injury function as chemotactic agents to recruit neutrophils and then monocytes over the next 6 to 48 hours. Macrophages play a central role in repair by: A. Clearing offending agents and dead tissue B. Providing growth factors for cellular proliferation C. Secreting cytokines that stimulate fibroblast proliferation and connective tissue synthesis and deposition. 3. Cell proliferation. Several cell types proliferate and migrate to close the clean wound. It takes up to 10 days. Epithelial cells respond to locally produced growth factors and migrate over the wound to cover it up. Endothelial cells and pericytes proliferate to form new blood vessels, a process known as angiogenesis. Fibroblasts proliferate and migrate into the site of injury and lay down collagen fibers that form the scar. Formation of granulation tissue. It is composed of migrating and proliferating fibroblasts and deposition of loose connective tissue, together with newly formed capillaries and interspersed mononuclear leukocytes. Grossly, appear as pink, soft, granular, such as that seen beneath the scab of a skin wound. Histologically, characterized by proliferation of fibroblasts and new thin-walled, delicate capillaries (angiogenesis) in a loose ECM, often with admixed inflammatory cells, mainly macrophages. Granulation tissue progressively fills the site of injury; the amount of granulation tissue that is formed depends on the size of the tissue defect created by the wound and the intensity of inflammation. Angiogenesis is the formation of new blood vessels from existing vessels; these are leaky (accounting for edema in healing wounds) because of incomplete interendothelial junctions and because VEGF increases vascular permeability. Page 3 of 5  Angiogenesis Deposition of Connective Tissue Deposition of connective tissue occurs through: A. Fibroblast migration and proliferation under the effect of TGF-β. B. As healing progresses, fibroblasts become progressively less proliferative and more synthetic, increasing the deposition of ECM (collagen is particularly critical to wound strength). C. Granulation tissue eventually becomes scar composed of largely inactive, spindle- shaped fibroblasts, dense collagen, and other ECM components. D. Progressive vascular regression leading to a largely avascular scar, whereas some fibroblasts develop additional smooth muscle-like features (called myofibroblasts) that contribute to scar contraction. 4. Remodelling of Connective Tissue The remodelling phase occurs concurrently with granulation tissue formation. The outcome of the repair process is influenced by a balance between synthesis and degradation of ECM proteins. Page 4 of 5  Purpose of remodeling is to increase wound strength and contract it through the formation of new epithelium and by degradation and realignment of collagen fibers. The realignment of collagen fibers transforms the initial, unorganized collagen matrix into a highly organized collagen matrix whose structure closely mimics that of the native tissue [collagen is remodelled from type III to type I]. The degradation of collagens and other ECM components is accomplished by a family of matrix metalloproteinases. This process begins about 21 days after an injury and can continue for a year or more to complete. In well-sutured skin wounds, strength may recover to 70% to 80% of normal skin by 3 months, and healed wound areas continue to be weaker than uninjured skin. Wound contraction is initially caused by myofibroblasts and later by cross-linking of collagen fibers. With time, the connective tissue is degraded and the scar shrinks. References: 1. Kumar, Abbas, Aster. Robbins Basic Pathology, 10th ed. Elsevier. 2. Mitchell, Kumar, Abbas, Aster. Pocket Companion to Robbins and Cotran Pathologic Basis of Disease, 9th ed. Elsevier. Page 5 of 5