Anaplasia
total loss of differentiation as might occasionally be seen in malignant neoplasms
More than just an increased N/C ratio, the nucleus
Congenital / Developmental Change: Hypoplasia and Agenesis
- Hypoplasia – defective formation or incomplete development of a part
- Agenesis – absence/failure of formation
Pathological definition of Repair
deposition of collagen and other extracellular matrix components, causing the formation of scar
• “patches rather than restores”
Pathological definition of Regeneration
proliferation of cells and tissues to replace lost structures
• restores
What are the 5 overlapping processes involved in tissue repair.
- Hemostasis – Plts, coagulation
- Inflammation – PMNs, macrophages, lymphocytes, mast cells
- Regeneration – stem cells and differentiated cells (part of proliferation phase)
- Fibrosis – macrophages, granulation tissue (fibroblasts, angiogenesis), type II collagen (part of proliferation phase)
- Remodeling–macrophages,fibroblasts, converting collagen III to I
Inflammatory Phase
- Redness, swelling, pain, heat & inflammation
- Capillary permeability increases & fluid moves in
- Phagocytic cells come in to prevent infection and release GF
- GF’s recruit fibroblasts, which marks beginning of the proliferative phase
Proliferative Phase
- Begun by fibroblasts that secrete collagen and cause angiogenesis
- This leads to epithelialization, and causes granulation tissue to form
- Plasma leaks in, and epithelialization is the last of this stage
- Here a new surface area, similar to the old one, is formed
Remodeling Phase
- Remodeling begins after 3 weeks, and continues 6 moths or longer (tensile strength can be 70-80% at end of 3 months)
- Synthesis and lysis of collagen occurs simultaneously
Wound Healing - Primary Intention
Primary Intention (primary union) • Regeneration • Edges are approximated • eschar (scab) • Epidermal cells proliferate under scab • Dermal healing is by routine scarring
Wound Healing - Second Intention (secondary union)
- Occurs with failure of first intention t
- poor apposition or dehiscence
- Foreign material
- Extensive necrosis
- Infection
- More fibrin, more granulation tissue
- Wound contraction
Wound healing - Tertiary Intention
- Surgical
* Sutures are placed later to help approximate the tissue
Etiology of scar formation:
- When resolution fails in acute inflammation
- Ongoing necrosis and chronic inflammation (eg.chronic hepatitis cirrhosis)
- When cell necrosis cannot be repaired (eg.myocardial infarction)
Stages of scar formation
• Bleeding
• Preparation – removal of inflammatory debris and necrotic tissue by phagocytes
• Granulation tissue (highly vascularized
connective tissue)
• Fibronectin produced by fibroblasts
Granulation Tissue
- Formed by fibroblasts and vascular endothelial cells.
- Grossly it has a pink, soft, grainy appearance.
- It is often edematous
- Eventually it is converted to a pale avascular scar composed of fibroblasts, dense collagen III, fragments of elastic tissue and other ECM.
Repair - Scar
- Collagenation – tensile strength
- Collagen produced by fibroblasts
- Maturation – pale/lacking circulation
- Contraction and strengthening
- Myofibroblasts contract early
- Collagencontracts in late scars (type III becomes type I)
Factors causing defective scar forming
Deficiencies of vitamin B2, C, bioflavonoids and Zinc
Angiogeneisis
formation of new blood vessels (also called neovascularization)
• Branching of adjacent vessels
• Recruitment of endothelial progenitor cells
• From bone marrow
The collagen triple helix.
The individual α chains are left-handed helices with approximately three residues per turn. The chains are in turn coiled around each other following a right-handed twist. The hydrogen bonds which stabilize the triple helix (not shown) form between opposing residues in different chains (inter-peptide hydrogen bonding) and are therefore quite different from α helices which occur between amino acids located within the same polypeptide
Collagen Types:
(over 29) In the remodeling phase, type III collagen is laid down in granulation tissue, then converted to type I collagen
Type I
Most common, and is the strongest as it is located in bones, skin, tendons, fascia, cornea, teeth and mature scars.
Type II
little bit less strength seen in cartilage, vitreous humor, and nucleus pulposus
Type III
is even weaker as it is present in granulation tissue, embryonic tissue, uterus, blood vessels, and keloids.
Type IV
is the weakest is it only supports a row of epithelial cells as it’s found only in basement membranes.
Hydroxylation of collagen is mediated by vitamin C. What cofactor is required? What is cross-linking performed by?
Cross-linking of collagen is performed by lysyl oxidase; Copper is a required cofactor
What causes scurvy?
Vitamin C deficiency
• First affects collagen with highest hydroxyproline content, such as that in blood vessels
• Early symptom then is bleeding gums
What is Ehlers-Danlos (ED) Syndrome?
Defect in collagen synthesis or structure
• Nine different types
• ED type IV is a defect in type III collagen
Osteogenesis Imperfecta
• Defect in collagen type I
Other Extracellular Matrix Components
• Elastic fibers: Elastin proteins are aligned on a
fibrillin framework; Defects in fibrillin framework; Defects in fibrillin are found in Marfan syndrome
• Adhesion molecules: Fibronectin; Laminin
• Proteoglycans and glycosaminoglycans: Heparan sulfate and Chondroitin sulfate
What charge does the basement membrane have?
What is it comprised of?
net negative charge
- Collagen type IV
- Proteoglycans (heparin sulfate) • Laminin
- Fibronectin
Regeneration Overview: Healing and Regeneration
Different tissues have different regenerative capacities
• Healing – replacement by connective tissue
• Regeneration – Repair of injured tissue by parenchymal cells of the same type
Stem Cell Overview
How are they distinguished?
Stem cells have the potential to develop into many different cell types in the body during early life and growth
• internal repair system, dividing without limit to replenish other cells
• stem cell divides to either stem cell or another specialized type
Distinguished from other cell types by two important characteristics:
• unspecialized cells capable of renewing themselves through cell division, sometimes after long periods of inactivity
• Under certain physiologic or experimental conditions, they can be induced to become tissue- or organ-specific cells with special functions
Stem cells—three general properties:
- They are capable of dividing and renewing themselves for long periods
- They are unspecialized
- They can give rise to specialized cell types.
3 types of Stem Cells: Based on Proliferative Potential
- Labile cells
- Stable cells
- Permanent cells
Labile Cells
continuously dividing (Epidermis, mucosal epithelium, GI tract epithelium etc.)
Regenerate through life
• Examples: Surface epithelial cells (skin and
mucosal lining cells)
• Hematopoietic cells, stem cells, etc.
Stable cells
low level of replication (Hepatocytes, renal tubular epithelium, pancreatic acini)
- Replicate at a low level throughout life
- Have the capacity to divide if stimulated by some initiating event
- Examples: Hepatocytes, Proximal tubule cells, Endothelium
Permanent cells
never divide (Nerve cells, cardiac myocytes, skeletal mm)
Few stem cells and/or differentiated cells with the capacity to replicate
• Very low level of replicative capacity
• Examples: Neurons, Cardiac Muscle
Cell cycle: 5 phases of cell cycle
What regulates the transition between the phases?
- G0 (Quiescent phase)
- G1 (Pre synthetic phase)
- S (phase of DNA synthesis)
- G2 (premitotic growth phase)
- M (mitotic phase)
• Transition between the phases regulated by cyclins and CDKs (cyclin dependent kinases)
• kinases phosphorylate proteins, form mitotic spindles, cause dissolution of nuclear membranes and chromosome condensation
- CDK inhibitors like TP53 are important for buying time for DNA repair, or to induce apoptosis if the DNA cannot be repaired.
Repair in Specific Organs - Liver
- Mild injury: repaired by regeneration of hepatocytes, sometimes with restoration of normal pathology
- Severe or persistent injury causes formation of regenerative nodules that may be surrounded by fibrosis, leading to hepatic cirrhosis
Repair in Specific Organs - Brain
- Neurons are thought not to regenerate
* Microglia remove debris and astrocytes proliferate, gliosis
Repair in Specific Organs - Heart
• Damaged heat muscle cannot regenerate, so the heart heals by fibrosis
Repair in Specific Organs - Lung
• Type II pneumocytes replace both type I and type II pneumocytes after injury
Repair in Specific Organs – Peripheral Nerves
- Distal Part of the axon degenerates
* Proximal part regrows slowly using axonal sprouts to follow Schwann cells to the muscle
Three Stages of Fracture Healing
- Procallus – provides anchorage, but no structural rigidity
- Fibrocartilagenous callous
- Osseous callous
Greenstick Fracture
In this particular fracture, the periosteum will need to be broken so that the fracture does not heal at an angle
Comminuted Fracture
Will need ORIF or more likely, an external fixator
