Regeneration, Repair, and Wound Healing Flashcards
1
Q
regeneration
A
- restoration of damaged or lost cells or tissues to their original state
- requires cell proliferation (parenchyma or stem cell pop) and an intact ECM scaffold
- eg normal/homeostatic replacement of skin cells
2
Q
repair
A
- involves a combination of regeneration and scar formation by collagen deposition
- requires cell proliferation; ECM is usually damaged and new ECM (collagen) is deposited
- eg burn healing
3
Q
regulation of cell cycle
A
- G1-S checkpoint
- cylicns (D) bind to cyclin dependent kinase ->form heterodimer -> phophorylate retinoblastoma protein -> release E2F -> protein transcripton
- CDK inhibited by growth inhibitors (TGF-B, p53), activated by growth factors (EGF, PDGF)
4
Q
growth factors
A
- polypeptides that bind cellular receptors and stimulate cell proliferation
- can also stimulate cytoskeletal rearrangement (alter cellular motility and contractility), cellular differentiation, angiogenesis
5
Q
Epidermal growth factor (EGF)
A
- includes EGF, TGF-a
- receptor EGRF1, tyrosine kinase, juxtacrine
- from macrophages, inflammatory cells, platelets
- acts on epithelial cells, fibroblasts
- effects cellular proliferation
- diseases: psoriasis (TGF-a), Her2 receptor + breast cancer
6
Q
Platelet derived growth factor (PDGF)
A
- secreted proteins
- PDGRF a and B, receptor tyrosine kinase
- from platelets, macrophages, endothelial cells, fibroblasts
- acts on mesenchymal cells (hematopoietic cells, fibroblasts)
- primary chemokine and mitogen for mesenchymal cells, stimulates fibroblasts to secrete ECM and collagenase, attract inflammatory cells-secrete growth factors
- chronic eosinophilic leukemia-receptor gene fusion-uncontrolled eosinophil proliferation
7
Q
Fibroblast growth factor (FGF)
A
- receptor tyrosine kinase; FGF must be bound to extracellular matrix to activate
- from macrophages, endothelial cells
- target fibroblasts, endothelial cells
- fibroblast chemotaxis and proliferation, ECM deposition, angiogenesis
- lots of diseases
8
Q
Vascular endothelial growth factor (VEG-F)
A
- polypeptide growth factors
- receptor tyrosine kinase
- from variety of mesenchymal cells (leukocytes and fibroblasts)
- target endothelial cells
- angiogenesis, endothelial cell proliferations and migration, increase vascular permeability
9
Q
Transforming growth factor B (TGF-B)
A
- polypeptide growth factors
- receptor serine/threonine kinase
- from platelets, endothelial cells, fibroblasts, macrophages, lymphocytes
- target fibroblasts, leukocytes
- multiple opposing effects: promotes fibrogenesis, stimulate fibroblast and smooth muscle proliferation, inhibit epithelial and mesenchymal cell growth, strong anti-inflammatory agent, attract neutrophils, fibroblasts, macrophages
10
Q
Interferon
A
- cytokine
- from T-cells
- target macrophages and fibroblasts
- role in wound healing: activates macrophages (major mediator of wound healing), down regulates collagen synthesis, inhibit fibroblast proliferation
11
Q
Interleukin-1
A
- cytokine
- from macrophages
- target inflammatory cells and fibroblasts
- wound healing: mediates inflammatory cell fxns in wound, neutrophil and fibroblast chemotaxis
12
Q
Tumor necrosis factor
A
- cytokine
- from macrophages and t-cells
- target macrophages and t-cells (autocrine)
- wound healing: activates macrophages, stimulate IL-1 production, activate t-cells, induce collagen production in fibroblasts, attract neutrophils
13
Q
Embryonic stem cells
A
- derived from inner cell mass of blastocyst
- each cell is pluripotent
- have self renewal capacity
- uses-treatment of ds where there is a loss of critical cell types (MI, Alzheimers, Parkinsons, spinal cord injury, DM type 1)
- challenges- ethical issues, transplant rejection, tumor formation (teratoma), persistence of underlying ds, making differentiated cells fxn normally
14
Q
induced pluripotent stem cells
A
-skin cells -> transduce in certain genes -> proteins -> induce cells back to pluripotent state
15
Q
Adult stem cells
A
- small reservoirs of self-renewing cells in multiple tissues
- restricted in their differentiation potential
- fxn is to regenerate cells lost by normal wear and tear (hair follicle, GI crypts, liver, eye)
- if moved to different tissue, can transdifferentiate in vitro; otherwise restricted niches
16
Q
ECM fxns
A
- provide turgor by sequestering water or rigidity by sequestering minerals
- reservoir for secreted growth factors
- framework for cells to adhere, migrate and proliferate in
- mediates cell-cell interactions
- site of remodeling during wound healing
17
Q
ECM composition
A
- fibrous structural proteins
- adhesive glycoproteins
- proteoglycans and hyaluronic acid
18
Q
Col I
A
most common type in mammals
bone, tendon, mature scars
fibrillar
19
Q
Col II
A
articular and hyaline cartilage
fibrillar
20
Q
Col III
A
- embryonic collagen
- in adults, found in bv, uterus, and GI tract
- 1st collagen deposited in wound healing; eventually degraded and replaced by Col I
- fibrillar
21
Q
Col IV
A
Basement membrane
Non-fibrillar (sheet)
22
Q
Elastic fibers
A
- core of elastin surrounded by fibrillin
- specialized fiber that allows for recoil after stretching
- found in arteries, skin, uterus, lung
- Marfans-mutation in fibrillin-aortic dissection, corneal dislocation, tall stature
23
Q
fibronectin
A
- secreted cell adhesion protein
- in plasma-stabilizes early clot (fibrin plug)
- in cells (secreted from fibroblasts, macrophages, endothelial cells)
- binds numerous molecules
- first ECM deposited in wound healing
24
Q
functions of fibronectin
A
- adds structural integrity to clot
- chemotactic for many cells
- substrate for cellular adhesion (RGD dominant)
- substrate for other ECM protein attachment and assembly
25
laminin
- secreted cell adhesion protein
- found primarily in BM-forms tight polymer networks w/ Col IV to maintain BM integrity
- similar fxns to fibronectin: substrate for ECM protein binding and cell adhesion
26
Integrins
- cell surface bound adhesion protein
- transmembrane receptors
- facilitate cell-cell interaction
- facilitate cellular interaction w/ ECM by binding collagen, fibronectin, and laminin
- links cell surface to cytoskeleton-conformation changes may -> cell proliferation, apoptosis, differentiation, etc
27
cadherins
- cell surface bound adhesion protein
- facilitate cell-cell interactions between similar cell types
- facilitate formation of cell jxns
- linked to cytoskeleton through catenins to regulate cell motility, proliferation, and differentiation
28
proteoglycans
- repeating polymers of disaccharides bound to a protein core
- forms an ECM scaffold for tissue structure and permeability
29
Hyaluronic acid
- huge molecule of long repeating polysaccharides w/o a protein core
- can bind large amount of H20-forms viscous hydrated gel; allows ECM to resist compressive forces, deposited early during wound healing to facilitate cell migration and proliferation
30
Hemostasis phase of wound healing
- 1st phase
- stop bleeding and facilitate inflammation
- platelets activated by exposed collagen
- serum fibrin/fibronectin forms plug
- platelets release thromboxane
- vasodilation and increased permeability
31
Inflammatory phase of wound healing
- 2nd phase
| - stop infection, clear debris, induce repair
32
early inflammatory phase
- neutrophils come (attracted by chemokines) -> phagocytosis
| - Macrophages come -> predominate, secrete stuff, phagocytosis; orchestrate wound healing
33
late inflammatory phase
- macrophage secretion peaks
- secreted factors attract and activate cells needed for proliferative phase
- neutrophils and macrophages decrease
- fibroblasts predominate
- early wound ECM consists of fibrin, fibronectin, and HA-anchor for cell adhesion and collagen deposition
34
Proliferative phase of wound healing
- 3rd phase
- replacement of lost tissue with scar
- provides structural support
- consists of: angiogenesis, formulation of granulation tissue, fibroplasia, epithelialization, wound contraction
- fibroblast activity, ECM deposition, tissue remodeling
35
Angiogenesis
- restore perfusion to wound
- VEGF -> increase vascular permeability, endothelial cell migration, promote angiogenesis
- fibronectin/fibrin in ECM facilitate endothelial cell migration; proteases degrade existing ECM
- new thin walled vessels in wound site
- most vessels regress
36
Granulation tissue
- fills defects left by injury prior to vigorous collagen deposition
- 2-5 days after injury
- highly vascular loose fibrous tissue w/ scattered inflammatory cells and fibroblasts
- ECM-fibronectin, Col III, HA
- growth factors- PDGF and TGF-B
37
Fibroplasia
- influx and proliferation of fibroblasts w/ subsequent collagen deposition
- fibroblasts attracted and activated by TFG-B, PDGF, EGF, FGF, and cytokines
- 2-4 weeks
38
TGF-B in fibrogenesis
- increase fibroblast proliferation/migration
- increase Col and fibronectin synthesis
- decrease ECM degradation
- chemotactic for monocytes
39
Epithelialization
- restoration of injured epithelium
- basal keratinocytes proliferate from edges of wound-migrate in
- stimulated by EGF, KGF, FGF
- migration facilitated by interaction w/ fibronectin/fibrin in provisional ECM of granulation tissue (migrate over gran tissue and under scab)
40
Contraction
- pulls edges of wound together to reduce the wound surface area
- decrease wound size by 40-80%
- mediated by myofibroblasts
- TGF-B induces differentiation of fibroblasts and myofibroblasts
- myofibroblasts contain actin filaments that are linked to ECM and facilitate contraction
41
Maturatoin phase
- remodeling of ECM w/ mature scar formation to increase tensile strength
- collagen production = degradation
- can last over a year
- matrix metalloproteinase degrade collagen and ECM
- replace Col III w/ Col I -organized, cross linked, aligned along lines of tension (final strength 80%)
- replace HA w/ proteoglycans
- mature scar- dense Col I, elastic fibers, proteoglycans, scattered fibroblasts
42
Local factors that affect wound healing
- size, type, location of wound
- vascular supply
- oxygen supply
- infection
- necrosis-lowers tissue pH, causes inflammation, prevents healing
- foreign material
- movement
- radiation
43
Systemic factors that affect wound healing
- circulatory compromise
- nutritional status (protein, zinc, vit C, A, thiamine and riboflavin)
- diabetes
- obesity
- hormones
- chemotherapy
44
Fibrosis
- persistent stimulus (chronic inflammation) -> chronic activation of macrophages and lymphocytes
- proliferation of fibroblasts, endothelial cells, and specialized fibrogenic cells; increase collagen synthesis, decrease collagen degradation
45
healing by primary intention
-clean edges, close w/ stitches, glue, staples, etc
46
healing by delayed primary intention
-wound is initially left open, when granulation tissue is judged clean and viable wound is closed by primary intention
47
secondary intention
- considered for contaminated or necrotic wounds, left open to scar in from below
- greater inflammatory response, more granulation tissue, increased wound contraction, often larger scar
