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Repair: involves a combination of regeneration and scar formation by the deposition of collagen. Requires:
cannot undergo mitotic cell division
ex. neurons, cardiac myocytes, and skeletal myocytes
G1/S phase transition
Once cells have entered the S phase, they are committed to divide so this is a critical point for regulation.
Critical "checkpoints" during the cell cycle
The G1/S checkpoint checks the integrity of the DNA before replication and the G2/M checkpoint ensures the DNA was appropriately replicated before mitosis. If DNA damage is detected, it is repaired and if not able to be repaired, the cell is targeted for apoptosis.
Activity of cyclins and CDKs are controlled by activators (growth factors) and growth regulators TGF-B or p53 via like the CDK inhibitor p16 (prevent uncontrolled growth) – either promote or inhibit the G1-->S transition
- signal from the surface is transduced to the nucleus, causing the nucleus to alter the proportions of proteins that it makes
- via through 3 receptor types: receptor tyrosine kinases, G coupled protein receptors, and receptors without tyrosine kinase activity (JAK-STAT)
- polypeptides bind specific receptors and stimulate/inhibit cell proliferation.
- can also affect cell motility, contractility, differentiation, angiogenesis.
Autocrine = cells respond so substances they release themselves (ex. TGF-β)
Paracrine = cells release soluable factors directed to target cell in the immediate vicinity (ex. neurotransmitters)
Endocrine = hormones released into bloodstream to reach target cells (ex. steroid hormones)
Juxacrine = target cells bind a signalling molecule bone the plasma membrane of the signalling cells (ex. some EGFs); ligand is bound to cell surface
TGF-a facilitates regeneration of epithelium and is overproduced in the hyperproliferative skin disease psoriasis --> plaques of keratinocytes
PDGF is the primary mitogenic protein for cells of mesenchymal origin in the blood.
Functions: (1) Chemokine--attracts neutrophils, mac's, and fibroblasts, (2) Mitogen-- ↑ fibroblast proliferation (3) Stim. fibroblasts to secret matrix glycos-aminoglycans (GAGs) and adhesion proteins (4) Stim. fibroblasts to secrete fibroblast-derived collagenase
PDGF is the primary mitogenic protein for cells of mesenchymal origin in the blood. There are no PDGF receptors on epithelial cells.
- doesn’t affect keratinocytes of the epithelium, who have their own growth factors
- produced by platelets, fibroblasts, endothelial cells, and nonparenchymal liver cells.
Receptor: c-MET proto-oncogene
- mitogenic for most epithelial cells (hepatocytes, biliary epithelium, lungs, mammary gland, skin, etc)
- morphogen during embryonic development (promotes cell migration) .
Insulin-like growth factor type 1 (IGF-1)
- stimulates collagen synthesis by fibroblasts
- acts synergistically with PDGF and certain FGFs to help facilitate fibroblast proliferation
IFN-γ causes macrophage to release TNF-α, which self-stimulates as well as stimulating T-cell (along with IL-1) to continue releasing IFN-γ
1.Derived from the inner cell mass of the blastocyst
- the expression of certain special genes can convert highly differentiated fibroblasts into iSP's
- iPS cells are not derived from an aborted human embryo (but there are arguments) and they can be derived directly from each individual patient, thereby avoiding possible transplant rejection issues
- iPS cells could induce tumor formation--teratomas
- Replacing lost cells doesn't treat underlying disease - in neural path, transplanted neurons might not establish "correct" synaptic connections
- more restricted ability to differentiate than ESCs,
- exist in small reservoirs/niches, regenerate cells lost by normal wear and tear (tissue homeostasis)
- Capable of trans-differentiation if taken out of niche
- cannot regenerate large numbers of cells quickly
- Skin stem cells -- bulge area of hair follicle, sebaceous glands, and lower layer of epidermis
- Small intestine -- near the base of a crypt
- Liver stem/progenitor cells-canals of Hering, connect bile ductules w/ parenchymal hepatocytes (CK7 stain)
- Corneal stem cells are in the limbus region.
True regeneration of injured tissues is limited by the rapid fibroproliferative response and scar formation (replacement).
The mechanisms by which each occurs can differ. Regeneration of pancreatic islets involves stem cell replication and differentiation, whereas liver regeneration following partial hepatectomy involves having hepatocytes reenter the cell-cycle without stem cell activation.
*Both types are comprised of:
- Embryonic collagen
- In adults: found in blood vessels, uterus & GI tract
- First collagen deposited during wound healing. Eventually degraded and replaced by Type I collagen.
- basement membranes
- due to fibrillin polymorphism
- tend to be tall and lanky
Weakened elastic fibers in arteries (aortic dissection), ligaments (hypermobility), and ciliary zonules of the eye (lens dislocation). Also mutant fibrillin is unable to bind and sequester TGF-beta that is thought to provoke an inflammatory reaction that releases proteases that degrade elastic fibers.
Provides structural support - does not regenerate normal tissue.
Begins 2-3 days after injury.
2) Formation of granulation tissue
5) Wound contraction
Lots of thin-walled vessels, lots of ECM (spaces in between cells, filled w/ fibronectin, type III collagen, hyaluronic acid)
Fibroblasts mediating fibroplasia in granulation tissue
Neutrophil = “popcorn-like” nucleus
Not much collagen (moreso in the maturation phase)
Basal keratinocytes from wound edges proliferate at edges of wound and migrate across surface, until stopped by contact inhibition. Migration occurs as result of dec↓ contact inhibition and by NO stim. Epithelial cells dissolve their desmosomes. Cell surface integrins are released from intermediate filaments and relocate to actin filaments, allowing cellular pseudopodia to interact with provisional ECM and thereby move the cell. Cells produce new BMZ, and desmosomes are re-established
Rupture of the wound and most commonly occurs after abdominal surgery due to increased abdominal pressure (coughing, vomiting, ileus).
A result of inadequate scar formation.
can occur due to poor vascularization during healing (diabetic foot ulcer).
The accumulation of excessive amounts of collagen in the wound can give rise to a raised scar
scar that grows beyond the borders of the original wound and does not regress
higher incidence in African-Americans
keloids show broad hypocellular bundles of collagen histologically
A rare complication of excessive proliferation of fibroblasts after an injury can result in a mass lesion referred to as a desmoid or aggressive fibromatosis. These lesions can appear to be neoplastic and their behavior can range from totally benign to aggressive.
- Excessive contraction
- Besides the effects on the skin, the excessive contraction can result in permanent muscle or joint fixation.
- These are more likely to occur on the palms, soles of the feet, and the anterior thorax, especially after burns.
when the edges of the wound are closely opposed by
suture, staples, tape, glue, or other means
Delayed primary intention (closure)
the wound was initially left open. When the bed of the wound (granulation tissue) is judged to be sufficiently clean and vital, the wound is closed in a fashion similar to primary closure.
Secondary intention (closure)
- when wound is contaminated or tissue has questionable vitality.
- dirty and infected wounds do better when they are left open (wartime)
-wounds into body cavities are usually sealed, but the remaining tissues are left open to scar in from bottom up
Major differences between primary and secondary intention (closure)
Secondary deals with larger tissue defects and the inflammatory response is usually greater.
Larger amounts of granulation tissue are formed in secondary intention.
Wound contraction by myofibroblasts and collagen cross-linking is greater in secondary intention.
1. New thin walled blood vessels
2. Fibroblasts and myofibroblasts
3. Inflammatory cells
4. Extracellular matrix
New ECM facilitates cell migration by being comprised primarily of fibronectin and hyaluronin rather than the fibrous structural proteins like collagen and elastin.
A local defect of the surface of an organ or tissue that is produced by the sloughing of inflamed necrotic tissue. Ulceration can only occur when tissue necrosis and resultant inflammation exist on or near a surface.
(granulation tissue, blood pooled in the base)
Instead of subcutaneous tissue below and dermal appendages above, you just see one big thickened dermis full of collagen; smooth surface of tissue because it pushes the tissue up
A keloid is a tumor-like overgrowth of connective tissue, a hyperplastic scar.
Chronic passive congestion: Stasis of poorly oxygenated blood leads to congestion and hypoxia centered around the central veins ⇒ congestion and possibly necrosis and/or fibrosis in a centrilobular distribution which spares the portal areas.
Cirrhosis: Death and damage to hepatocytes leads to collagen deposition (fibrosis) that links portal tracts with one another and portal tracts with central veins. Regeneration of hepatocytes between the fibrosis gives rise to a nodular appearance. Damage to the hepatocytes is diffuse and accordingly, so is the fibrosis.
Why are unruptured varices difficult to identify at autopsy?
Pulmonaryembolism - lung is generally congested, w/ many RBCs, proteinaceous fluid and pigmented macrophages in the alveoli. In some of the thrombi you may be able to make out the alternating layers of red cells, white cells and fibrin--“Lines of Zahn”
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