4. FM2004 PM2004 Repair and Regeneration 23-24.pdf

FM2004 & PM2004 Repair and Regeneration Dr Collette Hand UCC Department of Pathology [email protected] January 2024 Dr C. Hand Textbooks R9 R10 Robbins & Cotran Pathologic Basis of Disease U6 U7 Underwood General & Systemic Pathology RBP9 RBP10 Kumar, Abbas, Aster Robbins Basic Pathology Robbins & Cotra...

FM2004 & PM2004 Repair and Regeneration Dr Collette Hand UCC Department of Pathology [email protected] January 2024 Dr C. Hand Textbooks R9 R10 Robbins & Cotran Pathologic Basis of Disease U6 U7 Underwood General & Systemic Pathology RBP9 RBP10 Kumar, Abbas, Aster Robbins Basic Pathology Robbins & Cotran Atlas of Pathology A2 W5 Young, Stewart, O’Dowd Wheater’s Basic Pathology Dr C. Hand Repair and Regeneration The body’s ability to replace injured or dead cells and to repair tissues after inflammation is critical to survival Dr C. Hand Tissue injury outcomes 1. Resolution -little damage and little exudate removal of inflammatory exudate no tissue damage; tissue is left with original architecture intact 2. Regeneration little evidence on surface lost cells replaced by proliferation of cells of the same type reconstruct the original architecture may leave no residual trace of injury 3. Repair e.g. after myocardial infarction (no regen -> so scarring happens) - doesn't have function of original tissue lost tissue is replaced by connective (fibrous) tissue may result in formation of a scar complex tissue architecture may not be reconstructed Dr C. Hand Tissue Repair extent of injury and type of injury Mild injury which damages the epithelium but not underlying tissue is resolved by regeneration More severe injury with damage to the connective tissue, repair is by scar formation R9/R10: Fig 3.24; RBP10: Fig 3.23 Mechanisms of tissue repair: regeneration and scar formation. Dr C. Hand Healing of a minor abrasion The scab, a layer of fibrin, protects the epidermis as it grows to cover the defect. The scab is then shed and the skin is restored to normal U6/U7: Fig 5.4 Dr C. Hand Regeneration capacity Adult cells: 3 groups -> ability to proliferate 1. Labile (epithelial cells, mucosa, BM cells) 2. Stable (Quiescent) (hepatocytes) 3. Permanent SMC AND FB Dr C. Hand Labile Cells Continuously dividing/ proliferating – – maturation of tissue stem cells proliferation of mature cells Surface epithelia – Stratified squamous: skin, oral cavity, vagina, cervix – Cuboidal: ducts- salivary glands, pancreas, biliary tract – Columnar: GIT, uterus – Transitional: urinary tract Bone marrow and haematopoietic cells Readily regenerate if stem cells preserved Dr C. Hand Stable/ Quiescent Cells In the G0 stage of cell cycle – ie not proliferating Minimal proliferative activity in normal state Capable of dividing in response to injury or loss of tissue mass Parenchyma of most solid tissues – Liver, kidney, pancreas Endothelial cells, fibroblasts, smooth muscle cells Dr C. Hand Permanent Cells Terminally differentiated and nonproliferative postnatally – non-dividing cells Neurons, cardiac muscle skeletal muscle Dr C. Hand Regeneration Labile and stable cells can regenerate Epithelia: Injured cells replaced by – proliferation of residual cells and differentiation of stem cells – extent of damage/ integrity of stem cells – underlying support eg BM must be intact Parenchymal tissue with stable cells – limited other than liver Restoration of normal tissue architecture – only if residual tissue is structurally intact eg partial resection – if damaged by infection / inflammation there may be scarring if structure (not just the cells) is damaged it doesn't return back to original function -> liver disease Dr C. Hand Repair by scarring (Organisation) 1 Extensive tissue damage or damage to permanent/ non-dividing cells If lost tissue cannot be replaced – replacement of the injured cells with connective tissue -> formation of a scar – or by a combination of regeneration of some residual cells and scar formation Dr C. Hand Repair by scarring (Organisation) 2 1. Inflammation (6-48h) – removal of dead tissue / microbes by phagocytosis 2. Cell proliferation (up to 10 days) – epithelial cells: cover wound – endothelial and vascular cells: angiogenesis – fibroblasts: produce collagen fibre that form scar Granulation tissue 3. Remodelling (2-3 weeks – months) – connective tissue deposited by fibroblasts is reorganised – > fibrous scar Dr C. Hand Granulation Tissue Pink soft granular appearance on surface of wound Histologic features – new small capillary loops – fibroblasts / myofibroblasts – new and mature collagen R9/R10: Fig 3.27; RBP9: Fig 2.30; RBP10: Fig 3.26 A) Granulation tissue showing numerous blood vessels, oedema and a loose extracellular matrix containing occasional inflammatory cells. Collagen is stained blue by the trichrome stain; minimal mature collagen can be seen at this point. B) Trichrome stain of Mature scar, showing dense collagen (blue) and scattered Dr C. Hand vascular channels. Angiogenesis Process of new blood vessel development from existing vessels Capillary endothelial cells proliferate Grow into area to be repaired Solid buds -> vascular channels Series of loops arching into damaged site Vascular Endothelial Growth factors (VEGF) Dr C. Hand Proliferation of Fibroblasts Fibroblasts enter wound from edges, migrate towards centre fibroblasts produce collagen Some differentiate into myofibroblasts – smooth muscle actin; ↑ contractile activity – close the wound by pulling margins to centre – role in wound contraction *Combination of capillary loops and myofibroblasts = granulation tissue Dr C. Hand Wound contraction Contraction of myofibroblasts Reduces volume of tissue for repair (~80%) Myofibroblasts attach to each other & to adjacent matrix Granulation tissue as a whole contracts and draws together the surrounding tissue granulation tissue => repair is happening Very useful; but can also lead to problems – stricture: contraction circumferentially around a lumen of a tube eg GIT – contracture: shortening of muscle – burns to skin: cosmetic damage, reduced mobility Dr C. Hand Extracellular matrix (ECM) Complex of proteins that assemble into a network surrounding cells, large portion of any tissue Functions – Mechanical support: cell anchorage, cell migration – Control of cell proliferation: Growth factors, signalling – Scaffold for tissue renewal Components 1. Fibrous structural elements 2. Collagen and elastin: strength and recoil Gels 3. Proteoglycans, hyaluronan: resilience, lubrication Adhesive glycoproteins / link proteins Fibronectin, laminin: connect elements and cells Dr C. Hand Deposit of Extracellular matrix (ECM) As repair progresses: ↓ fibroblasts and new vessels fibroblasts; more synthetic phenotype: deposit ECM Collagen: strength in healing wound synthesis early (3-5 days) to weeks, depends on wound size granulation tissue scaffolding is converted into a scar richly vascularised granulation tissue -> pale, avascular scar Transforming Growth Factor β (TGF-β), Fibroblast growth factor (FGF), Platelet derived growth factor (PDGF) Dr C. Hand Tissue Remodelling After scar is formed it is remodelled to increase its strength and contract it Wound strength increases – – cross linking of collagen, ↑ size collagen fibres collagen type III (early) -> type I ECM synthesis vs degradation – – first breakdown tissue around wound before rebuilding properly -> remodelling of connective tissue framework -> size and nature of scar Degradation- matrix metalloproteinases (MMPs) – collagenases, stromelysins, gelatinases Dr C. Hand Wound Healing Complex but orderly process – – – – – – Induction of acute inflammation Regeneration of parenchymal cells Migration and proliferation of connective tissue Synthesis of ECM protein Remodelling of connective tissue Collagenisation and acquisition of wound strength Dr C. Hand Healing of Skin Wounds When injury involves only the epithelial layer, the principal mechanism of repair is epithelial regeneration also called primary union or healing by first intention When cell or tissue loss is more extensive, such as in large wounds, abscesses, ulceration, infarction, the repair process involves a combination of regeneration and scarring. Secondary union or healing by second intention Dr C. Hand First and Second Intention 1st intention (A) – little/no tissue lost – opposed edges edges close to each other 2nd intention (B) – – – – tissue lost unopposed edges more debris more granulation tissue – contraction R9/R10: Fig 3.29; RBP9: Fig 2.33 Dr C. Hand First vs Second Intention 1. Inflammatory reaction is more intense – 2. more debris and exudate Larger amounts of granulation tissue – 3. deep defects: granulation tissue responsible for closure as drainage to surface not possible Wound contraction – occurs in large wounds Whether a wound heals by first or second intention is determined by the nature of the wound rather than by the healing process Dr C. Hand Orderly phases of wound healing Wound Strength Week 1 - 2 – sutures removed – 10% strength of unwounded skin Next 4 weeks – strength increases rapidly 3 months – rate slows to plateau at ~ 70as long as there is inflammation still happening, we will not get to the end of healing process 80% strength Dr C. Hand Steps in repair by scar formation: skin wound healing RBP9: Fig 2.29; R9/R10: Fig 3.26 A Inflammation B Proliferation of epithelial cells; formation of granulation tissue by vessel growth and proliferation fibroblasts C Remodelling to produce fibrous scar Dr C. Hand Healing in specialised tissues Dr C. Hand Healing in Skin Regeneration of squamous epithelial cells Loss of specialised skin structures – eg sweat glands and hair follicles U6/U7: Fig 5.4 Dr C. Hand Healing in Gastrointestinal tract Depends on depth of injury Mucosal Erosion – loss of part of thickness – mucosa regenerates – covered in hours if cause is removed Ulcer – – – – loss of full thickness of mucosa often deeper- penetrates muscularis propria damaged blood vessels -> bleeding destroyed muscle cannot be regenerated Scar tissue may cause distortion / obstruction Reapir -> scarring -> narrowing Dr C. Hand Healing in Bone Haematoma organised – Dead bone removed Callus formed – Replaced by bone Remodelled woven to lamellar Healing delayed – – – – Movement Interposed soft tissue Gross misalignment U6/U7: Fig 5.7 Infection Dr C. Hand Healing in Liver Hepatocytes: excellent regenerative ability Hepatic architecture cannot be reconstructed if severely damaged Cirrhosis : hepatocyte regeneration with failure to reconstruct the architecture U6/U7: Fig 5.8 Dr C. Hand Factors that affect healing Healing processes modified – known and unknown influences Host factors 1. Local 2. Systemic IDEAS?? Dr C. Hand Local factors Systemic factors - Infection**** - Nutrition infection keeps inflammation so we cant get to the healing stage I F M S - Mechanical factors - Early motion, pressure - Foreign bodies - sutures, fragments, bone - Size, location and type of wound - Vitamin C - Metabolic status M N C H - Diabetes - Circulatory Status - poor perfusion - Hormones - Glucocorticoids Dr C. Hand Abnormal healing and scarring Chronic wounds – Often local ischaemia +/- systemic factors eg pressure sores, diabetic ulcers Deficient scar formation – mechanical stress: coughing, vomiting Formation of contractures – wound contraction: joint mobility Excessive scarring – hypertrophic scar: more common in darker skin grow rapidly, regress – keloid: beyond wound boundaries, R9: Fig 3.32; R10 Fig 3.31; doesn’t regress RBP10: Fig 3.28 A) Hypertrophic scar Dr C. Hand B) B) Keloid Mechanism of fibrosis RBP10: Fig 3.29; R9: Fig 3.31 Mechanism of fibrosis Persistent tissue injury leads to chronic inflammation and loss of tissue architecture. Cytokines produced by macrophages and other leukocytes stimulate the migration and proliferation of fibroblasts and myofibroblasts and the deposition of collagen and other ECM proteins. The net result is the replacement of normal tissue by fibrosis. Dr C. Hand Overview Not all injuries result in permanent damage – Some good return of normal structure / function More often, the injury and inflammation result in residual scarring Sometimes the scar is so large or located such that causes permanent dysfunction (MI) Dr C. Hand Commonly confused terms U7 Chapter 9 Dr C. Hand Learning Objectives Using examples, describe labile, stable and permanent / fixed cells in terms of their capacity for regeneration. Describe healing by primary and secondary intention. Describe the wound-healing process through the inflammatory, proliferative and remodelling phases Discuss complications of wound healing Dr C. Hand