Tissue Healing and ECM Role

Wound Healing and Tissue Repair

• Wound healing involves two main reactions: regeneration of injured tissue and scar formation by connective tissue deposition.
• Lecture objectives include describing cell and tissue regeneration, the repair process using connective tissue, angiogenesis and scar formation, and the mechanism of cutaneous wound healing.

Tissue Repair

• Tissue repair occurs through two main reactions: regeneration of the injured tissue and scar formation via connective tissue deposition.
• Tissue repair reactions vary based on injury severity. Mild injury demonstrates regeneration, while severe injury exhibits scar formation.

Cell and Tissue Regeneration

• Injured cell and tissue regeneration involves cell proliferation driven by growth factors. The process is greatly dependent on the integrity of the extracellular matrix.
• This process includes proliferation, differentiation and the role of stem cells.

Proliferative Capacities of Tissues

• Tissues are categorized as labile, stable, or permanent based on their ability to regenerate.
• Labile cells continuously divide (bone marrow, certain epithelium, skin).
• Stable cells are quiescent but can divide (liver, kidney, fibroblasts).
• Permanent cells do not divide (neurons, cardiac myocytes).

Stem Cells (Embryonic and Adult)

• Embryonic stem cells are pluripotent, capable of differentiating into any cell type.
• Adult stem cells are multipotent, able to differentiate into a limited range of cell types. Different types of adult stem cells exist (neural, mesenchymal, hematopoietic, muscle stem cells, epidermal/hair follicle).
• Induced pluripotent stem cells (iPS) are derived from mature cells by introducing genes from embryonic stem cells.

Growth Factors

• Growth factors are mostly proteins that stimulate cell survival, proliferation, migration, differentiation, angiogenesis, and fibrogenesis.
• Growth factors are crucial for repair processes, stimulating the function of growth control genes.
• Many growth factors involved in repair are produced by macrophages and lymphocytes, or parenchymal/stromal cells in response to injury. Specific examples given in a table.

Growth Factor Signaling

• Growth factor signaling can be categorized based on receptor types with or without intrinsic kinase activity.
• Receptor Tyrosine Kinases (RTKs) have intrinsic kinase activity, phosphorylating tyrosine residues to activate signaling pathways. Examples include EGFR and insulin receptor.
• G-Protein-Coupled Receptors (GPCRs) activate intracellular signaling pathways through G-proteins and indirectly influence pathways like cAMP, IP3. Examples include epinephrine and chemokine receptors.
• Some receptors (e.g., TGF-β receptor) lack kinase activity, relying on associated kinases for signaling.

Role of the Extracellular Matrix (ECM) in Tissue Repair

• The ECM is a complex protein network surrounding cells, providing structural support, turgor pressure, and a reservoir for growth factors.
• ECM is comprised of interstitial matrix and basement membrane, each with distinct components like collagen, fibronectin, elastin, proteoglycans, and hyaluronate.
• ECM regulates cell proliferation, movement, and differentiation, and plays a role in tissue regeneration and repair.
• ECM is constantly undergoing synthesis and degradation, which is critical in morphogenesis, wound healing, chronic fibrosis, and tumor invasion.

Important Functions of ECM

• Provides mechanical support
• Acts as a substrate
• Regulates cell proliferation and differentiation
• Allows regeneration if intact
• Supports repair with scar formation if damaged

Scar Formation

• Tissues can be repaired by regeneration (complete) or replacement with connective tissue (scar).
• Scar formation occurs when tissue injury is severe, prolonged, or damages parenchymal, epithelial, and connective tissue causing non-dividing cell harm.
• It involves angiogenesis, fibroblast migration and proliferation, collagen synthesis, and connective tissue remodeling that culminates in granulation tissue formation. Multiple growth factors are essential for scar formation.

Steps in Scar Formation

• A series of steps leads to scar formation: inflammation, formation of new blood vessels, formation of granulation tissues (migration of fibroblasts + deposition of connective tissues, interspersed leukocytes), and scar formation (maturation and reorganization of fibrous tissue).

Factors Influencing Wound Healing

• Infection, nutrition, mechanical factors (perfusion, type and extent of injury), and cell growth abnormalities (keloids) affect wound healing.

Clinical Examples of Tissue Repair (Cutaneous wound healing, Fibrosis)

• Cutaneous wound healing exemplifies the principles of tissue repair, involving epithelial regeneration and connective tissue scar formation.
• Healing follows different pathways (first and second intention) dependent on injury severity.

Healing by First Intention

• Healing by first intention describes rapid wound healing with minimal tissue loss, primarily epithelial regeneration and formation of a thin scar. It involves a series of cellular events including neutrophil migration, epithelial cell proliferation, macrophage activity and neovascularization.

Healing by Second Intention

• Healing by secondary intention involves a greater degree of tissue loss and the formation of prominent, thick scar tissue, requiring extensive ECM deposition, wound contraction from myofibroblasts. It is a more complex and prolonged repair process than healing by first intention.

Differences between Primary and Secondary Healing

• Differences in clot formation, inflammation intensity, granulation tissue volume, scar tissue mass, and wound contraction distinguish secondary from primary healing.