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95 Cards in this Set

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What is Regeneration?
Regeneration: growth of cells to REPLACE lost structures.
(in mammals, only functional regeneration, not anatomical).
What is healing a response to?
1. Wound.
2. Inflammation in internal organs.
3. Cell necrosis in organs incapable of regeneration.
What happens when pleura/pericardium etc. heal?
Scar formation that creates adhesions between the two layers.
What is Organization?
(tissue repair)
Replacement of inflammatory infiltrates by granulation tissue -> scar tissue.
What is required for regeneration?
Intact collagenous (reticulin) framework- provide the framework for cell migration, maintain correct polarity, secrete agents critical for tissue repair.
(otherwise, we must heal)
Where do you physiologic hyperplasia?
* Endometrial cells under estrogen stimulation.
* Thyroid (becuase of TSH).
How is proliferation accomplished?
1. Conversion of quiescent cells into proliferating cells.
2. Shortening the cell-cycle.
Examples of labile tissues?
Ducts of glands.
Transitional epithelium of urinary tract.
Hematopoietic tissues in bone marrow!!
Examples of quiescent tissues
Mesenchyma: SMC, fibroblasts.
Hematopoietic: Leukocytes.
Parenchyma..
What happens when neurons are destroyed?
Glial cells proliferate.
Can skeletal muscle regenerate?
Rarely- the satellite cells are there, but the ends of the severed fibers have to be extra close.
Odd feature of beta-catenin, Wnt-pathway?
Maintain pluripotency of embryonic stem cells.
What is Therapeutic Cloning?
Use of embryonic stem cells (insert patient's nucleus into oocyte).
Where do stem cells reside in tissues?
"Niches":
* Base of crypts in colon.
* Bulge of hair follicles in skin.
* Limbus of cornea.
* Canal of Hering in Liver (called "oval cells").
What types of stem cells can you find in bone marrow?
Hematopoietic stem cells and stromal stem cells (chondrocytes, osteroblasts, adipocytes etc).
What is Transdifferentiation?
A change in stem cells differentiation from one cell type to another.
How can Hematopoietic Stem Cells contribute to the repair of non-hematopoietic tissues?
* Produce GF and cytokines.
* Promote injury repair.
* Promote cell replication.
What are Multipotent Adult Progenitor Cells?
Adult version of ESC- can transdifferentiate into mesoderm, ectoderm, neuroderm.
When are hepatic stem cells called into action?
When hepatocyte proliferation is slow/blocked-
liver cancer, chronic hepatitis or cirrhosis.
Where can you find neural stem cells?
Olfactory Bulb.
Dendate gyrus in Hippocampus.
(IF "nestin" is a marker for them)
Which receptor does TGFa use?
EGFR (like EGF..)
Which cells produce EGF?
Which cells does EGF effect?
Keratinocytes and inflammatory cells.
Epithelial (incl. hepatocytes), fibroblasts- important in granulation tissue!
What does TGFa do?
(3)
* Epithelial cell proliferation.
* Malignant transformation.
* Hepatocyte regeneration.
Basically, similar to EGF.
Who is ERB2?
Her2- type of EGFR.
What is HGF?
What does it affect?
Hepatocyte Growth Factor.
Affects epithelial cells.
What is the product of the protooncogen c-MET?
HGFR
What are the three types of receptors for VEGF?
R1: role in inflammation.
R2: main receptor for vasculogenesis and angiogenesis.
R3: for lymphatic vessels!
Where is PDGF stored?
When is it released?
alpha granules of platelets, released after platelet activation.
Also, can be produced by other cells- activated macrophages, endo, SMC and TUMOR CELLS.
What does PDGF do?
Causes migration and proliferation of fibroblasts, SMB and monocytes.
Participates in the activation of hepatic stellate cells at the beginning of fibrosis.
What is FGF?
What do they do?
Fibroblast Growth Factors.
* Induce angiogenesis.
* Wound repair- help migration of cells.
* Development of skeletal muscles and lungs.
* Hematopoiesis.
Why is TGF-beta a pleiotropic substance?
Because it has multiple, opposing effects.
What does the receptor for TGFb-beta do in the cell?
After TGF-beta binds receptor I AND THEN receptor II, it is activated-
Triggers phosphorylation of SMADs (transcription factors).
What does TGF-beta do?
* Growth inhibitor for most epithelial cells and leukocytes (loss of it can cause tumors).
* Stimulates proliferation of fibroblasts and SMC.
* Fibrogenic agent (eg, inhibits collgaen degradation by inhibiting MMP, induces chemotaxis).
* Strong anti-inflammatory effect.
Where do you often see autocrine signaling?
(tissue repair)
* Liver regeneration.
* Proliferation of antigen-stimulated lymphocytes.
* Tumors..
What is paracrine signaling?
From one cell type to a different one, close to it.
Where do you see paracrine signaling?
* Connective tissue repair of healing wounds.
* Hepatocyte replication during liver regeneration.
How do receptors with intrinsic tyrosine kinase activity work?
1. Dimer.
2. Tyrosine phosphorylation in receptor- activate the tyrosine kinase.
3. The activated tyrosine kinase phosphorylates others.
Common effector molecules for recptors with intrinsic tyrosine kinase activity?
* Phospholipase C, that breaks phospholipids to IP3 (raises Ca) and DAG (activates PKC).
* PI-3, that activate Akt- involved in proliferation, inhibition of apoptosis.
* MAP.
What is usually the type of activity of cytokine receptors?
They must recruit kinases.
Transmit signals to the nucleus using (ie) JAK/STAT pathway.
What stimulates cell replication?
GF/ECM components (through integrins),
Why are mammals incapable of true regeneration?
Because of rapid fibroproliferative response and scar formation.
Where do you see compensatory hyperplasia?
* Liver regeneration.
* Adrenal glands.
* Thyroid.
What type of compensatory growth do you see in kidney?
Hypertrophy.
(although, some replication occurs in proximal tubule cells).
Can pancreas cells regenerate?
Yes- beta cells regenerate using stem cell differentiation/transdifferentiation of dutcal cells.
Which cells replicate during liver regeneration?
Both hepatocytes (almost all of them, in several hours) and nonparenchymal cells (Kupffer, endothelium).
* hepatocytes replicate once or twice.
What is hepatocyte replication dependent on, except for the autocrine activity of TGFa?
Paracrine effects of GF and cytokines, produced by the hepatic nonparenchymal cells.
Which cytokines are responsible for the G0 -> G1 transition?
Which are involved in progression after G1?
G0-G1: TNF, IL-6.
onward: HGF, TGFa.
Which collagen do you find in basement membrane?
Only nonfibrillar (type 4).
Who produces the basement membrane?
Epithelial and mesenchymal cells.
What are elastic fibers made of?
Central core made of Elastin, surrounded by a network of microfibrils (mainly fibrillin).
What are CAMs?
Cell Adhesion Molecules.
What are Cadherins?
Ca-dependent CAMs.
Generally involved in homotypic interactions (same cell type).
What do Cadherins and Integrins bind to inside the cell?
Why?
Actins and IF.
That way, they can transmit mechanical force.
What is a Focal Adhesion Complex?
Clustering of Integrin receptors, after binding their ligand.
What cell-cell interactions are cadherins involved in?
1. Zonula Adherens- epithelial cells.
2. Desmosomes- present in epithelial or muscle cells.
Work with beta-catenin.
Important for contact inhibition!
What are proteoglycans?
Core protein linkes to 1+ GAGs (contain sulfate residue).
What is Hyaluronic Acid?
Belongs to the GAG family!
1. Binds water, creates gel, loves joints.
2. Inhibit fast movement of organisms and metastases.
3. Bind GF.
What is CD44?
A glycoprotein expressed by leukocytes, that binds HA.
Can retain T cells to tissues!
What do you see in granulation tissue?
* Angiogenesis.
* Proliferation of fibroblasts.
* Edema (cause the new BV are leaky).
What are the 2 methods for angiogenesis?
1. Branching and extension of adjacent BV.
2. Recruitment of endothelial progenitor cells from bone marrow.
What is Hemangioblast?
Common precursor for both the hematopoietic and vacular systems.
What are the steps of angiogenesis from pre-existing vessels?
VEGF!
1. Vasodilation inresponse to NO and VEGF- increases permeability.
2. Proteolytic degradatino of BM of parent vessels and disruption of cell-cell contact.
3. migration of endothelial cells.
4. Proliferation of endothelial cells.
5. Maturation of endothelial cells- inhibition of growth, remodelling into capillary tubes.
6. Recruitment of periendothelial cells.
What are periendothelial cells?
Pericytes for small capillaries.
SMC for larger vessels.
What are the steps in angiogenesis from bone marrow precursors?
VEGF!
1. Stimulate mobilizarion of precursors.
2. Enhance proliferation and differentiation at site of angiogenesis.
How are newly formed vessels stabilized?
By Recruitment of pericytes/SMC and deposition of ECM proteins.
Who is involved in stabilization of newly formed vessels?
Ang1: with receptor Tie2, recruits periendothelial cells.
PDGF: Recruitment of SMC.
TGFb: Enhances froduction of ECM proteins.
Ang2: with Tie2, opposite effect- makes cells more responsive to VEGF or more responsive to inhibitors of angiogenesis.
Which ECM proteins are important for angiogenesis?
1. Integrins- formation and maintenance of newlyformed.
2. Matricellular- destabilize cell-matrix interactions -> promote angiogenesis.
3. Proteinases- tissue remodeling.
How do proteinases help angiogenesis?
Tissue remodelin during endothelial invasion.
Release matrix-bound GF.

> Can also release inhibitors..
What does hypoxia activate on endothelial cells?
Integrins.
What cell type is the important constituent of granulation tissue?
Macrophages.
When does collagen synthesis by fibroblasts begins after injury?
3-5 days, continues for weeks.
What is the difference between a mature scar and granulation tissue?
Mature scar has more collagen, less blood vessels.
How are all MMPs synthesized?
propeptides- require proteolytic cleavage for activation.

> collagenase is a type of MMP!
Who can activate procollagenase?
Free radicals (from leukocytes, after oxidative burst).
Who inhibits collagenases?
TIMPs- Tissue Inhibitors of MetalloProteinases.
Who inhibits secretion of MMPs?
TGF-beta, steroids (they want to repair the tissue, not destroy).
What are the stages of healing by 1st intention?
1. The narrow incisional space immediately fills with clotted blood (fibrin and blood cells).
2. Within 24 hours, neutrophiles appear.
3. By day 3, macrophages replace neutrophiles.
4. By day 5, Neovascularizarion is maximal, epidermis is at normal thickness.
5. During 2nd week, leukocytes, edema and BV disappeared.
6. By end of 1st month- no inflammatory cells, just scar tissue.
How long does it take before a wounded area regains its maximal strength?
Months.
What happens in healing by 2nd intention?
Parenchymal cells cannot completely restore the original architecture, hence abundant granulation tissue grown in from the margin to complete the repair.
What do you see in healing by 2nd intention, compared to 1st?
* Inflammatory reaction is more intense.
* Much more granulation tissue.
* Substantial scar formation and thinning of epidermis.
* Wound contraction.
Example of nutritional effect on wound healing?
Scurvy- vitamin C deficiency - retards healing by inhibiting callgen synthesis.
Example of metabolic status effect on wound healing?
Diabetes Mellitus- delayed healing due to microangiopathy.
Examples of hormonal effect on wound healing?
Glucocorticoids- inhibit collagen synthesis.
What is most imporant cause of delay in healing?
Infection- results in persistent tissue injury and inflammation.
Why do wounds ulcerate?
Because of inadequate vascularization during healing.
What happens to wounds in areas devoid of sensation?
Non-healing wounds.
What is a Keloid?
When scar tissue grows beyond the boundaries of the original wound and does not regress.
(individual predisposition)
What happens when there is formation of excessive granulation tissue?
It blocks re-epitheliazation.
What are Desmoids?
Exuberant proliferation of fibroblasts & co, that may recur after excision- somewhere between benign and malignant.
What do you call over-contraction of a wound?
Contracture.
What causes under-contracture of a wound?
MMP3 deficiency- required for the assembly of myofibroblasts (containing actin -needed for contraction).
What happens in Fibrosis?
Lymphocyte-monocyte interactions sustain the synthesis and secretion of GF and fibrogenic cytokines, proteloytic enzymes and others.
What is Pneumoconicosis?
Chronic interstitial lung disease with fibrosis- due to inhalation of coal, silica or asbestos.
Macrophages promote fibrosis.
What does ionization (cancer treatment) cause?
Fibrosis.
What happens when you receive 1 large doe of CCl4?
Many small doses?
1 large dose: fibrosis (kills supportive framework!).
Many small doses: regeneration.