TISSUE REPAIR; REGENERATION, HEALING, and FIBROSIS

1. TISSUE REPAIR; REGENERATION, HEALING, and FIBROSIS

2. Tissue repair • Repair refers to the restoration of tissue architecture and function after an injury. • It occurs by two types of reactions: 1- Regeneration: tissues are able to replace the damaged components and essentially return to a normal state. 2- Scar formation: If the injured tissues are incapable of complete restitution, or if the supporting structures of the tissue are severely damaged, repair occurs by laying down of connective (fibrous) tissue

3. Repair involves the proliferation of various cells, and close interactions between cells and the extracellular matrix (ECM). • several cell types proliferate during tissue repair. These include: • the remnants of the injured tissue (which attempt to restore normal structure) • vascular endothelial cells (to create new vessels) • fibroblasts (the source of the fibrous tissue that forms the scar to fill defects that cannot be corrected by regeneration). • The proliferation of these cell types is driven by proteins that are collectively called growthfactors

4. Cell cycle

5. Cell cycle • The sequence of events that control DNA replication and mitosis is known as the cell cycle. • the cell cycle has multiple controls, both positive and negative. • The cell cycle consists of: 1- the presynthetic growth phase 1 (G1) 2- the DNA synthesis phase (S) 3- the premitotic growth phase 2 (G2) 4- the mitotic phase (M

6. Non-dividing cells are either in cell cycle arrest in G1 or they exit the cycle to enter a phase called G0. • Any stimulus that initiates cell proliferation, such as exposure to growth factors, needs to promote the G0/G1 transition and the entry of cells into the first phase of the cycle, G1 . • Further progression is determined by the ability of the cell to overcome checkpointcontrol. • Checkpoint controls prevent DNA replication or mitosis of damaged cells and either transiently stop the cell cycle to allow for DNA repair or eliminate irreversibly damaged cells by apoptosis.

7. Stem cells • Stem cells are characterized by two important properties: self-renewalcapacityand asymmetric replication. • Asymmetric replication of stem cells means that after each cell division, some progeny enter a differentiation pathway, while others remain undifferentiated, retaining their self-renewal capacity. • Types of Stem cells: 1- embryonicstem (ES) cells(pluripotent stem cells): can be isolated from embryos and can produce multiple cell lineages 2- tissuestemcells or adult stem cells: stem cells with the capacity to generate multiple lineages are present in the bone marrow and several other tissues of adult individuals.

8. Mechanisms regulating cell populations

9. Signaling Mechanisms of Growth Factor Receptors • Growth factor receptors induce intracellular signaling pathways similar to those of many other cellular receptors that recognize extracellular ligands. • The binding of a ligand to its receptor triggers a series of events by which extracellular signals are transduced into the cell, leading to the stimulation or repression of gene expression. • Signaling may occur directly in the same cell, between adjacent cells, or over greater distances

10. Patterns of intercellular signaling 1- Autocrinesignaling: in which a substance acts predominantly on the cell that secretes it. • This pathway is important in the immune response (e.g. lymphocyte proliferation induced by some cytokines) and in compensatory epithelial hyperplasia (e.g., liver regeneration). 2- Paracrinesignaling, in which a substance affects cells in the immediate vicinity of the cell that released the agent. • This pathway is important for recruiting inflammatory cells to the site of infection, and for wound healing. 3- Endocrinesignaling, in which a regulatory substance, such as a hormone, is released into the bloodstream and acts on target cells at a distance.

12. signal transduction originating from three types of receptors: • 1)receptors with tyrosine kinase activity • 2) G-protein-coupled receptors • 3) receptors without intrinsic enzymatic activity

14. THE NATURE AND MECHANISMS OF ACTION OF GROWTH FACTORS • There is a huge (and ever-increasing) list of known growth factors. • we will highlight only selected molecules that contribute to tissue repair. • Many that are involved in repair are produced by leukocytes that are recruited to the site of injury or are activated at this site, as part of the inflammatory process. • Other growth factors are produced by the parenchymal cells or the stromal (connective tissue) cells in response to cell injury or loss

16. Receptor proteins are generally located on the cell surface, but they may be intracellular; in the latter case, the ligands must be sufficiently hydrophobic to enter the cell (e.g., vitamin D, or steroid and thyroid hormones). • The binding of a ligand to its cell surface receptor leads to a cascade of secondary intracellular events that culminate in transcription factor activation or repression, leading to cellular responses

17. EXTRACELLULAR MATRIX (ECM) AND CELL-MATRIX INTERACTIONS • The ECM is a dynamic, constantly remodeling macromolecular complex synthesized locally, which assembles into a network that surrounds cells. • It constitutes a significant proportion of any tissue. • ECM is important for cell adhesion and serve as a reservoir for growth factors, thus, ECM regulates the proliferation, movement, and differentiation of the cells living within it. • Synthesis and degradation of ECM accompanies morphogenesis, wound healing, chronic fibrotic processes, and tumor invasion and metastasis

18. ECM • ECM occurs in two basic forms: interstitial matrix and basement membrane 1- Interstitial Matrix: • present in the spaces between cells in connective tissue; • it is synthesized by mesenchymal cells (e.g., fibroblasts) • and tends to form a three-dimensional, amorphous gel. • Its major constituents are fibrillar and nonfibrillar collagens, as well as fibronectin, elastin, proteoglycans, hyaluronate, and other elements

19. ECM 2- The basement membrane: • lies beneath the epithelium • is synthesized by overlying epithelium and underlying mesenchymal cells • it tends to form a platelike "chicken wire" mesh. • Its major constituents are amorphous nonfibrillar type IV collagen and laminin

20. ECM functions 1- Mechanical support for cell anchorage and cell migration 2-maintenance of cell polarity 3- Control of cell growth: by signaling through cellular receptors of the integrin family. 4- Maintenance of cell differentiation, also acting largely via cell surface integrins. 5- Scaffolding for tissue renewal. The maintenance of normal tissue structure requires a basement membrane or stromal scaffold. It is particularly noteworthy that although labile and stable cells are capable of regeneration, injury to these tissues results in restitution of the normal structure only if the ECM is not damaged. Disruption of these structures leads to collagen deposition and scar formation. 6- Establishment of tissue microenvironments. Basement membrane acts as a boundary and also forms part of the filtration apparatus in the kidney. 7- Storage and presentation of regulatory molecules: FGF and HGF are excreted and stored in the ECM. This allows the rapid deployment of growth factors after local injury

21. Components of ECM • There are three basic components of ECM: (1) fibrous structural proteins such as collagens and elastins, which confer tensile strength and recoil (2) water-hydrated gels such as proteoglycans and hyaluronan, which permit resilience and lubrication (3) adhesive glycoproteins that connect the matrix elements to one another and to cells

23. Collagens • are fibrous structural proteins that confer tensile strength. • are composed of three separate polypeptide chains braided into a ropelike triple helix. • About 30 collagen types have been identified • Some collagen types (e.g., types I, II, III, and V) form fibrils by virtue of lateral cross-linking of the triple helices. These are called the fibrillarcollagens, and form a major proportion of the connective tissue in healing wounds and particularly in scars • Other collagens are nonfibrillar and present in basement membrane (type IV) • The tensile strength of the fibrillar collagens derives from their cross-linking, which is the result of covalent bonds. This process is dependent on vitamin C; therefore, children with scurvey have skeletal deformities, bleed easily because of weak vascular wall basement membrane, and heal poorly

24. Elastin • the ability of tissues to recoil and return to a baseline structure after physical stress is conferred by elastic tissue. • This is especially important in the walls of: vessels , the uterus, skin, and ligaments. • Morphologically, elastic fibers consist of a central core of elastin surrounded by a meshlike network of fibrillin glycoprotein.

25. Proteoglycans and Hyaluronan • Proteoglycans form highly hydrated compressible gels conferring resilience and lubrication (such as in the cartilage in joints). They consist of long polysaccharides called glycosaminoglycans (examples are dermatan sulfate and heparan sulfate) linked to a protein backbone. • Hyaluronan, a huge molecule composed of many disaccharide repeats without a protein core, is also an important constituent of the ECM. Because of its ability to bind water, it forms a viscous, gelatin-like matrix

26. Adhesive glycoproteins and adhesion receptors • are structurally diverse molecules involved in cell-to-cell adhesion, the linkage between cells and ECM, and binding between ECM components. • The adhesive glycoproteins include fibronectin (major component of the interstitial ECM) and laminin (major constituent of basement membrane. • The adhesion receptors, also known as cell adhesion molecules (CAMs), are grouped into four families: immunoglobulins, cadherins, selectins, and integrins