Regeneration and Repair PDF

Regeneration and Repair Dr. Madeline Fitzpatrick November 28th, 2024 Outline Introduction Regeneration Connective tissue deposition Cutaneous wound healing Pathological aspects of repair Introduction Repair (healing): The restoration of tissue architecture and function after injury R...

Regeneration and Repair Dr. Madeline Fitzpatrick November 28th, 2024 Outline Introduction Regeneration Connective tissue deposition Cutaneous wound healing Pathological aspects of repair Introduction Repair (healing): The restoration of tissue architecture and function after injury Repair occurs by two main processes: 1. Regeneration: involves the proliferation of cells that survived the injury to replace the damaged or lost tissue 2. Connective tissue deposition: involves laying down of fibrous connective tissue to replace the damaged or lost tissue when repair cannot be accomplished by regeneration alone (ie. Fibrosis or scar formation) Terminology Connective tissue Term applied to tissues which provide general structure, mechanical strength, and/or physical and metabolic support for more specialized tissues Sometimes referred to as ‘supporting’ tissue Connective tissue is made up of: 1. Extracellular matrix (ECM): fibrous structural proteins (eg. Collagen), ground substance and basement membrane 2. Support (stromal) cells: responsible for making the ECM (eg. Fibroblasts) 3. Blood vessels, lymphatic vessels and nerves: to provide nutrients and factors required for tissue growth Organ based examples Skin (cutaneous organ) Specialized/functional tissue: epidermis (outer epithelial cell layer) Connective tissue: dermis (mesh of elastin and collagen fibers) Liver (parenchymal/solid organ): Specialized/functional tissue: made of hepatocytes (type of parenchymal cell) Connective tissue: delicate network of extracellular matrix (ie. Reticulin; a type of collagen fiber) Skin Liver Parenchymas cells (Hapatocytes), only fine and delicate connective tissue Terminology continued Collagen is the main fiber type found in most connective tissues Collagen is a fibrous protein; hence excess deposition of connective tissue is also referred to as fibrosis or scar formation Tissue repair Regeneration alone is not practical for humans in most settings Instead, we rely on a combination of regeneration and repair by connective tissue deposition Several cell types proliferate during repair: The surviving functional cells Vascular endothelial cells (to provide nutrients and growth factors needed for repair) Fibroblasts (the source of fibrous/scar tissue) The ability of a tissue to repair itself is known as the tissue’s intrinsic proliferative capacity Proliferative capacity is related to the cell cycle Different cells have different capacities for regeneration A cell’s intrinsic proliferation capacity depends on what part of the cell cycle they spend the most time in G0 is the resting phase; the remaining phases are all active phases of the cell cycle Three main tissue types Body tissues are divided into three categories depending on their proliferative capacity 1. Labile tissue: made up of cells that are continuously dividing/highly proliferative (cells that never spend time in G0) 2. Stable tissue: made up of cells with minimal proliferative capacity (cells that are in G0 in a normal state, but in response to injury, are capable of entering G1) 3. Permanent tissue: made up of cells that are not capable of proliferation (cells that are always in G0) Labile tissues Have the highest capacity for regeneration: The cells that make up labile tissues are capable of continuous cell renewal They also have an increased amount of stem cells in comparison to other tissue types In the setting of injury, cells are therefore rapidly replaced by: Proliferation of surviving cells Differentiation of stem cells into whatever functional cell type that was lost Examples include: Gastrointestinal epithelium Skin Oral mucosa Bone marrow Stable tissue Regeneration can occur, but is usually limited Cells of connective tissue (eg. Fibroblasts, smooth muscle cells) have a limited capacity for regeneration Most solid organs are also classified as stable tissues Kidney Pancreas Adrenal glands Lung * One exception is the liver, which has an increased capacity to regenerate Capable of regeneration even if up to 90% of the liver is resected! Permanent tissue Not capable of proliferation If tissue death occurs, the tissue has no choice but to repair itself by connective tissue deposition Functional cells are therefore replaced by non-functioning scar tissue, leading to reduced function of that organ The majority of neurons and cardiac muscle cells are not capable of proliferation Myocardial infarction -> death of cardiac muscle -> healing by connective tissue deposition -> reduced cardiac function Stroke -> death of neural tissue -> healing by connective tissue deposition (ie. Gliosis) -> reduced neuronal function Regeneration Complex process that involves interaction between growth signals and control mechanisms The replication of cells is influenced by: Growth factors, hormones, cytokines Promote cell proliferation and survival, cell migration, cell differentiation etc. Interaction of cells with the ECM Mechanical support, scaffold for tissue repair, microenvironment maintenance etc. Example: Liver regeneration Occurs by two major mechanisms Priming phase: cytokines, such as interlukon-6 (IL-6) from Kupffer cells, make remaining hepatocytes competent to respond to growth factor signals Proliferation phase: growth factors, such as hepatocyte growth factor (HGF) and transforming growth factor alpha (TGF-α), act on primed hepatocytes to stimulate entry into the cell cycle Limitations of regeneration Regeneration alone is not capable of repairing: 1. Any injury that is severe or chronic 2. Injury to connective tissue (eg. stromal/structural support cells or structural support framework) 3. Injury to non-dividing cells (eg. Permanent tissues) In such cases, connective tissue deposition participates in the repair process -> results in fibrosis/scar formation Limitations of regeneration: Liver Regeneration can occur only if the residual tissue is structurally intact Eg. After partial liver resection By contrast, if the tissue is damaged by infection or inflammation, regeneration alone is insufficient for repair and is accompanied by connective tissue deposition Extensive destruction of the liver with damage to the reticulin/supporting framework will lead to scar formation even though the remaining liver cells have the capacity to regenerate Eg. Liver abscess Repair by connective tissue deposition 1. Inflammatory phase Process begins within 24 hours of injury Remove damaged tissue and debris, secrete cytokines and growth factors to initiate repair process 2. Proliferative phase Proliferation of new blood vessels (ie. Angiogenesis) Proliferation of fibroblasts (resulting in deposition collagen and other ECM material) Within 3-5 days, granulation tissue is produced "Scab" ? Granulation tissue= combination of fibroblasts, thin-walled blood vessels and ECM material (ie. A form of immature connective tissue) Granulation tissue gradually accumulates connective tissue becoming a scar 3. Remodeling phase Connective tissue in the scar is remodeled over time Accomplished by matrix metalloproteinases (function to degrade ECM, including collagen) Cutaneous wound healing Involves epithelial regeneration and formation of connective tissue Divided into the following categories: Healing by primary (first) intention Healing by secondary intention Healing by tertiary intention (ie. Delayed primary closure; wound closure delayed typically for 4-5 days) Involves multiple stages: Formation of a blood clot Inflammatory response While the general steps are the same, the extent Formation of granulation tissue of each stage differs between primary and Re-epithelialization secondary intent Connective tissue deposition Wound contraction Remodeling Healing by primary intention Clean, uninfected opposed wound Eg. Well approximated sutured surgical incision site Injury involves mostly the epithelial layer and causes only focal disruption to the basement membrane and underlying connective tissue Epithelial regeneration predominates over fibrosis/scar formation Results in a small scar and very little wound contraction Epidermis is essentially restored to normal, but dermal appendages (eg. Hair follicles) are permanently lost Top-Down Healing by primary intention  Bottom-up Healing by secondary intention Large, infected or chronic injury results in more complex healing Eg. Ulcers, deep abrasions, infected surgical wounds, thermal burns Extensive injury resulting in a larger tissue defect that needs to be replaced *Differs from primary intention healing by: Larger scab over the surface of the wound More intense inflammatory response Extensive granulation tissue Wound contraction Fibrosis predominates over epithelial regeneration Healing by secondary intention Wound strength Healed skin is never as strong as the original tissue! In the setting of sutured wounds: 7-10 days = 10% of normal skin strength 3 months = 70-80% of normal skin strength > 3 months = very little increase in skin strength Pathological aspects of repair Complications of wound healing can be divided into two main categories: 1. Inadequate tissue repair 2. Excessive tissue repair Factors that influence tissue repair Infection Prolongs inflammation, has potential to increase local injury Foreign bodies Prolongs inflammation, has potential to increase local injury Nutritional status Eg. Vitamin C deficiency (vitamin C is a cofactor for the enzyme involved in collagen synthesis) Glucocorticoids (‘steroids’, eg. Suppress immune response/ impair function of TGF-beta, interfering with healing process Prednisone) Poor tissue perfusion/blood Decrease blood supply reduces delivery of oxygen, nutrients, growth factors (all which are needed to promote healing) supply Mechanical factors Eg. Pressure, which induces local ischemia, can result in non-healing ulcers/pressure sores Diabetes Microvascular disease leading to tissue ischemia, metabolic abnormalities Type and extent of injury The greater the extent of the injury leads to more connective tissue deposition Type of tissue affected Ie. Labile vs. stable vs. permanent tissues Inadequate tissue repair A product of inadequate formation of the components of the repair process Examples: Wound dehiscence: separation of the edges of a surgical wound Causes: infection, mechanical factors (pressure, torsion), etc. Ulcers Venous leg ulcers: due to chronic venous hypertension -> poor oxygen delivery Arterial ulcers: due to atherosclerosis of peripheral arteries -> poor oxygen delivery Diabetic ulcers: multifactorial (ischemia, neuropathy, metabolic abnormalities) Pressure ulcers: due to mechanical pressure causing local ischemia Wound dehiscence Ulcer Excessive tissue repair A product of excessive formation of the components of the repair process Examples: Hypertrophic scar: raised scar that does not grow beyond the boundary of the original wound Keloid scar: raised scar that grows beyond the boundary of the original wound ‘Proud flesh’: exuberant granulation tissue that protrudes above the level of the surrounding skin and prevents re-epithelialization Wound contractures: exaggerated form of wound contraction, may result in deformities of the wound and surrounding tissues Desmoid tumors: exuberant proliferation of fibroblasts and ECM (a type of low-grade tumor) Keloid scar Wound contracture In summary Tissue repair occurs via regeneration or connective tissue deposition Body tissues have different capacities for regeneration Depends on the intrinsic proliferation capacity of the cells that make up that tissue Tissues are repaired by replacement with connective tissue and scar formation if: The injured tissue is not capable of proliferation (eg. Heart, brain) If the structural framework is damaged and cannot support regeneration Cutaneous wound healing occurs by primary or secondary intention Inadequate or excessive connective tissue deposition can have pathologic consequences Wound dehiscence, ulcers (inadequate wound healing) Keloids, contractures, desmoid tumors, ‘proud flesh’ (excessive wound healing) References Material, diagrams, clinical and histologic images: Robbins and Cotran Pathologic Basis of Disease, 10th Edition Wheater’s Functional Histology, 6th Edition Other clinical images: Healed surgical wounds: jamaicahospital.org; pereaclinic.com Skin wound healing by secondary intention: DesJardins H, Char S, Marasco P, Hsu YC, Guo L. Efficacy of hydromechanical therapy in nonhealing, chronic wounds as a cost- and clinically effective wound care modality. Wounds. 2021;33(11):296-303. Wound dehiscence: medetec.co.uk Wound contracture: Wikipedia