Wound Healing 3 - Tissue Repair and Regeneration

Wound Healing 3 - Learning Objectives

• Understand tissue repair and mechanisms of regeneration
• Identify factors that impair healing and repair
• Differentiate between types of tissue healing

Wound Healing 3 - Key Topics

• Cell Injury and Cell Death
• Cellular Response During Wound Healing
• Haemostasis
• Inflammation
• Proliferation and Angiogenesis
• Matrix Remodeling
• Tissue Repair
• Factors Impairing Healing and Repair
• Types of Tissue Healing

Tissue Repair

• Tissue repair can occur through regeneration or scar formation
• Mild injuries heal through regeneration
• Severe injuries require scar formation to repair underlying connective tissue

Tissue Regeneration

• The ability of tissues to repair themselves is influenced by their intrinsic proliferative capacity
• Mechanisms regulating cell populations can be altered by:
  • Increased or decreased rates of stem cell input
  • Cell death (apoptosis)
  • Changes in proliferation or differentiation rates

Tissue Types and Proliferative Capacity

• Labile Tissues: High proliferation capacity for successful regeneration as long as the stem cell pool is maintained, e.g., skin, oral cavity, fallopian tubes, haematopoietic cells
• Stable Tissues: Minimal replicative activity in their normal state, with limited regeneration capacity but can proliferate in response to injury or loss of tissue mass, e.g., liver, kidney, pancreas
• Permanent Tissues: Insufficient proliferative capacity to regenerate; repair typically involves scar formation, e.g., brain, heart

Stem Cells

• Two varieties: embryonic and tissue stem cells
• Present in many labile and stable populations
• Located in discrete compartments (e.g. basal layer of epidermis, hair follicle)
• The ability of a tissue to regenerate depends on the integrity of the stem cell population
• A separate stem cell pool exists in bone marrow (haemopoietic stem cells)

Mechanisms of Tissue Regeneration

• Tissues are composed of continuously dividing cells (e.g., epithelia, haemopoietic tissues), quiescent cells capable of proliferation (e.g., most parenchymal organs), and non-dividing cells (e.g., neurons, skeletal/cardiac muscle)
• Cell proliferation is regulated by the cell cycle, stimulated by growth factors, and interactions with extracellular matrix
• The liver can regenerate through cytokines and growth factors in response to inflammation and loss of liver mass – regeneration can happen by surviving hepatocytes or from progenitor cells

Tissue Regeneration in Different Tissue Types

• In epithelia (e.g., intestinal tract, skin), injured cells can be replaced by cells & differentiation of tissue stem cells
• Some organs (e.g., pancreas, adrenal gland, thyroid, and lungs) have limited regenerative abilities
• Kidney repair involves hypertrophy and hyperplasia of proximal duct cells in response to surgical removal
• Tissue architecture must remain intact for effective regeneration. Damage from infection/inflammation can result in scarring
• Liver abscesses can cause extensive destruction, leading to scar formation despite remaining cells' regenerative ability

Scar Formation

• If regeneration is insufficient, injured cells are replaced by connective tissue, forming a scar
• Scarring occurs with severe or long-lasting tissue damage, including harm to parenchymal, epithelial, and connective tissue
• Scar formation is distinct from tissue regeneration (restoring tissue components)
• Scar refers to the replacement of parenchymal cells by collagen, common after myocardial infarction

Scar Formation - Main Steps

• Clot formation, inflammation, angiogenesis, and formation of granulation tissue
• Fibroblasts migrate, proliferate, and produce collagen; connective tissue remodeling
• Laying down of fibrous tissues
• Macrophages eliminate offending agents and stimulate cell proliferation; TGF-β is a contributor to fibrosis
• Maintaining a balance of factors (fibrogenic agents, extracellular matrix (ECM) and tissue inhibitors of MMPs (TIMPs)) to manage ECM remodeling

Granulation Tissue

• The combination of proliferating fibroblasts, loose connective tissue, and new blood vessels forms granulation tissue
• It is unique to wound healing
• Its gross appearance is pink, soft, and granular (e.g., beneath a skin wound scab)
• Resident and mesenchymal-derived fibroblasts become pro-fibrotic, laying down ECM proteins, and differentiating into myofibroblasts for contraction

Factors Impairing Healing and Repair

• Tissue repair can be impaired by various reducing quality/adequacy of reparative process
• Extrinsic factors (e.g., infection), intrinsic factors (e.g., to injured tissue), or systemic/local factors

Factors Impairing Healing and Repair - Examples

• Denervation
• Ischemia (e.g., bone ends movement)
• Poor blood supply
• Glucocorticoids
• Location of injury
• Age
• Diabetes mellitus
• Steroid therapy and anti-cancer drugs
• Immunosuppression
• Nutritional status
• Neoplastic disorders
• Vascular disturbances
• Infection
• Type and extent of tissue injury

Types of Tissue Healing

Detailed descriptions and illustrations of examples would need an image of the types of tissue healing.