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93 Cards in this Set

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Define healing.
repair involving a combination of regeneration and connective tissue deposition
Why does scarring occur?
occurs when tissues are intrinsically unable to regenerate, if the underlying connective tissue scaffolding is disrupted, or following extensive exudates
Define regeneration.
Cell or tissue growth that replaces lost structures. It generally involves proliferation of the same cell type, although stem cells may proliferate and differentiate to replace dead cells. Regeneration requires intact tissue scaffolding.
What are 2 ways in which you can increase cell proliferation?
1. shortening the cell cycle
2. recruiting quiescent cells into the cycle
What are the phases of the cell cycle?
G1 (presynthetic)
S (DNA synthesis)
G2 (pre-mitotic)
M (mitosis)
What is G0?
quiescent cells are in this pahse.

Most tissues are composed mainly of cells in G0 that can periodically enter the cell cycle
What are the 3 classes tissues can be divided into based on their proliferative capacity?
1. Labile - continuously dividing
2. Stable - quiescent cells
3. Permanent - non-dividing cells
Describe labile cells.
Cells proliferate throughout life, replacing those that are destroyed. Typically, mature cells derive from stem cells with unlimited capacity to regenerate and varying capacity to regenerate
Describe quiescent(stable) cells.
Cells are normally involved in low level replicatoin but are capable of rapid division in response to stimuli
Describe permanent cells.
These are cells that cannot undergo division in postnatal life - neurons, skeletal muscle, and cardiac muscle
Describe stem cells.
prolonged self renewal and asymmetric replication - with each cell division, one cell contains self-renewing property while the other differentiates to become a mature nondividing cell
What are pleuripotent cells and where are they isolated from?
these stems cells are capable of differentiating into any tissue type and are isolated from normal blastocytsts
how are embryonic stem cells different from adult stem cells?
Embryonic stem cells are pleuripotent. Adult stem cells have a more restricted differentiation capability and tend to be lineage specific

Nevertheless, adult stem cells with relatively broad differentiation potential occur in bone marrow and in tissue stem cells outside the bone marrow
What are hematopoietic stem cells?
cells capable of regenerating all blood cell elements
What are multipotential stromal cells?
cells capable of differentiating for instance into bone, cartilage, fat or muscle.
What are the hematopoietic stems cells of mesodermal linage capable of differentiating into?
neurons (ectoderm), hepatocytes (endoderm) and other adult cell lineages -- this is transdifferentiation
What is transdifferentiation?
Conversion of one differentiated cell type into another differentiated cell type
Do hematopoietic stem cells contribute significantly to normal tissue homeostasis or to replacement of injured tissues
No, they do not contribute significantly.

their role may be in local production of growth factors to promote healing
Define plasticity.
breadth of differentiation potential
Where are multipotent adult progenitor cells found and describe the replication properties?
found in bone marrow and toher tissues (brain, skin, and muscle)

these cells proliferate in culture without senescence and have broad developmental capacity
What is the role of tissue stem cells?
Responsible for generating the mature cells of the organ in which they reside, thereby maintaining normal tissue homeostasis

Also have variable potential to differentiate more broadly and to repopulate tissues following injury
Describe the epithelium and its ability to regenerate.
most epithelial surfaces are constantly maintained by stem cells with a discrete set of differentiation lineages. Terminally differentiated cells do not divide and are continuously sloghed at the external surface. After injury, stem cells repopulate the tissue
Describe the liver and its ability to regenerate.
liver stem cells reside in the canals of Hering - jxn of hepatocytes and bile duct system

liver stem cells give rise to oval bodies with a capacity to form hepatocytes or biliary epithelium

they are typically only active if direct heptaocyte proliferation is not possible
Describe the brain and its ability to regenerate.
neural stem cells exist and can even be integrated into neural circuits
Describe the striated muscle and its ability to regenerate.
skeletal and cardiac myocytes cannot proliferate

regeneration of injured skeletal muscle is accomplished by proliferation of satellite cells, a stem cell poll in adult muscle
What are the fxns of epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha)?
bind to the same EGF receptor - EGFR1 or ERB B1 - transmembrane molecule with intrinsic tyrosine kinase activity

They are mitogenic for epithelial cells, hepatocytes, and fibroblasts
What is the fxn of hepatocyte growth factor (HGF)?
produced by fibroblasts, endothelial cells, and hepatocytes

it has mitogenic effects on most epithelial cells as well as promoting embryonic development
What is the fxn of vascular endothelial growth factor (VEGF)?
promotes blood vessel formation in eary development (vasculogenesis) and plays a role in new blood vessel growth in adults (angiogenesis)

It is particularly important in angiogenesis associated with chronic inflammatory states and in healing wounds

VEGF members act by binding to receptors with intrinsic tyrosine kinase activity

VEGFR-2 is expressed by endothelial cells and is the receptor for vasculogenesis and angiogenesis

VEGF-C and -D bind to VEGFR-3 to induce lymhatic endothelial proliferation (lymphangiogenesis)
What is the fxn of platelet derived growth factor (PDGF)?
found in platelet alpha granules and made in endothelial cells, macrophages, and smooth muscle cells

causes migration and proliferation of fibroblasts, monocytes, and smooth muscle cells
What is the fxn of Fibroblast growth factor (FGF)?
acidic and basic forms - bind to extracellular matrix heparan sulfate to form reservoirs of inactive forms

Basic FGF has the ability to induce all the steps necessary for angiogenesis and FGF members are centrally involved in wound repair, tissue development, and hematopoiesis.
What is the fxn of TGF-beta?
growth inhibitor for most epithelial cells via receptor kinases that posphorylate Smad cytoplasmic transcription factors

Has potent anti-inflammatory effects

promotes fibrosis by stimulating fibroblast chemotaxis, proliferation, and ECM synthesis and by inhibiting collagen degradation
What is the function of cytokines?
mediators of immune and inflammatory responses and also have growth promoting activities
Describe autocrine signaling.
cells respond to signaling substances produced by themselves
Descrive paracrine signaling.
A cell produces substances that affect target cells in close proximity
Describe endocrine signaling.
cells synthesize hormones that circulate in the blood to act on distant targets
How do receptors with intrinsic kinase activity induce intracellular signaling?
Intrinsic kinase activity is usually activated following ligand binding. The active kinases then posphorylate downstream effector molecules leading to their activation

Examples:
Ras signlaing - binds to Raf which phosphorylates MAPs

PI-3-kinase - activates series of kinases leading to cell survival

Phosphlipase C-gamma - leads to calcium release from ER and DAG formation with protein kinase C activation
How do receptors without intrinsic kinase activity induce intracellular signaling?
Receptors associate with and and activate cytosolic protein kinases

Example:
Janus kinases (JAKs) link activated receptors with downstrream STATs that shuttle into the nucleus and activate gene transcription
How do G protein-linked receptors induce intracellular signaling?
receptors are 7-transmembrane spans (ex - chemokine, epi, and glucagon receptors)

ligand binding activates a signal transducing the G protein complex, generating intracellular 2nd messengers including calcium and cAMP
How do steroid hormone receptors induce intracellular signaling?
ligands for these receptors are lipophilic; they directly diffuse through plasma membranes; receptors are typically intranuclear transcription factors that are activated by ligand binding
What is the end result of most signal transduction?
altered gene transcription driving by changes in transcription activity.

The rapid responses demanded by cell signaling do not permit synthesis of new transcription factors but rather rely on post-translational modifications that allow transcription factor migration into nucleus
What are CDKs?
cyclin dependent kinases

they are constitutively expressed protein kinases that become active only after forming complexes with specific cyclins
What are cyclins?
regulatory proteins whose concentrations rise and fall during the cell cycle
How do cyclin-CDK complexes regulate the cell cycle?
by phosphorylating various target proteins
What is p53?
a tumor supressor gene that is activated in response to DNA damage and inhibits further progression through the cell cycle by increasing expression of a CDK inhibitor
In mammals, why is their inadequacy of true regeneration of of tissues?
due to a rapid fibroproliferative response and scar formation after wounding
Describe the components of the ECM.
consists of fibrous structural proteins - collagen and elastin - and adhesive glycoproteins embedded in a gel of proteoglycans and hyaluronan

These macromolecules assemble into an intersitial matrix, present in the spaces b/w cells, or into a basement membrane.
Describe collagen and what is its fxn?
provides tensile strength

Composed of a triple helix braid of 3 polypeptide chains each having a primary glycine-X-Y repeating sequence

Procollagens are synthesized as alpha chains, followed by enzymatic hydroxylation of prolines and lysines. 3 chains then align to form a triple helix and the product is secreted. The globular C- and N- terminal fragments are proteolytically cleaved and lysine oxidase oxidizes lysines and hydroxylysines to permit interchain cross-linking and stabilize the fibrils
Where do you find each of the following types of collagen:

I?
II?
IV?

Which ones are fibrillar collagens and which ones form sheets?
I - skin and bone
II - cartilage
IV -forms sheets and is found in basement membranes

Fibrillar collagen and most abundant - I, II, III, V, XI

Sheets - IV
Describe elastin and what is its fxn?
provides ECM with elasticity (stretch and recoil)

elastic fibers consist of elastin central core with an associated scaffolding network of fibrillin
What are the 4 main families cell adhesion proteins can be broken down into?
1. Immunoglobulin family
2. Cadherins
3. Integrins
4. Selectins
What are cadherins and what is their role in cells?
Cell adhesion proteins that mediate calcium-dependent interactions with cadherins on adjacent cells and interact with the cytoskeletonvia catenins

Cadherins bind beta-catenins that link to alpha-catenins that connect to actin

These connections play major roles in cell motility and cell differentiation; they also account for the contact inhibition of cell proliferation when cells touch
What are integrins and what is their role in cells?
participate in cell-cell adhesion as well as adhesion to the ECM by binding to fibronectin and laminin
What is fibronectin and what is their role in cells?
binds to many molecules

alternate splicing produces either tissue fibronectin or plasma fibronectin

Tissue fibronectin - forming fibrillar aggregates at sites of wound healing

Plasma fibronectin - forming provisional blood clots in wounds preceding ECM deposition
What are laminin and what is their role in cells?
most abundant glycoprotein in the basement membrane

has binding domains for EXM and cell surface receptors
What are focal adhesion complexes?
ligand binding to integrins causes clustering and formation of focal adhesion complexes that function as activated receptors to trigger signal transduction pathways
What is SPARC and what is its function?
secreted protein acidic and rish in cystein

aka osteonectin

contributes to tissue remodeling after injury and is an engiogenesis inhibitor
What is the fxn of thrombospondins?
ibhibit angiogenesis
What is the fxn of osteopontin?
regulates calcification and also mediates leukocyte migration
What is the fxn of tenacins?
involved in morphogenesis and cell adhesion
What is glycoaminoglycans?
long repeating polymers of modified disaccharides

ECM components have a core protein linked to one or more glycosaminoglycans
What is hyaluronan?
molecule with many disaccharide repeats that serves as a ligand for cell surface receptors and other core proteins

binds large amounts of water giving ECM its turgor and ability to resist compression
What is the name of preteoglycans that are integral membrane proteins?
syndecans
What is the difference between regeneration and healing?
Regeneration involves restitution of tissue identical to that lost by injury

Healing is a fibroproliferative response that "patches" rather restore a tissue
What do we produce scars?
repair for tissues incapable of regeneration -- get ECM deposition producing a scar
What is fibrosis?
ECM deposition in a setting where inflammation is chronic and tissue damage and repair occur concurrently

Generically, fibrosis applies to any abnormal deposition of connective tissue
Describe the sequence of healing.
1. inflammatory response to eliminate initial stimulus, remove injured stimulus, and intitiate ECM deposition
2. Proliferation and migration of parenchymal and connective tissue cells
3. formation of new blood vessels and granulation tissue
4. Synthesis of ECM proteins
5. Tissue remodeling
6. Wound contraction and acquisition of wound strength
Histologically, describe granulation tissue.
proliferating fibroblasts with numerous new blood vessels in a loose matrix
What is the difference between angiogenesis and vasculogenesis?
during embryonic development -vessels arise by vasculogenesis - primitive vascular network assembled from EC precursor angioblasts

Adult tissues - vessel formation is angiogenesis - branching of preexisting vessels and by recruitment of endothelial cell precursors from bones marrow
In embryonic development, what generates both hematopoietic stem cells and angioblasts?
hemangioblasts
What can angioblasts proliferate and form?
differentiate into endothelial cells, pericytes, and vascular smooth muscle cells
Describe the steps of angiogenesis.
1. NO dilates preexisting vessels
2. VEGF induces increased permeability
3. Metalloproteinases degrade the basement membranes
4. Plasminogen activator disrupts endothelial cell-cell contact
5. endothelial cells proliferate and migrate toward the angiogenic stimulus
6. Endothelial cell maturation occurs, including growth inhibition and remodeling into capillary tubes
7. Periendothelial cells are recruited
What are the 2 most important growth factors in angiogenesis?
VEGF and angiopoietins
What is the most important receptor for angiogenesis?
VEGFR-2 tyrosine kinase receptor -- it is largely restricted to endothelial cells and endothelial cell precursors
What is the importance of VEGF/VEGFR-2 interactions?
1. mobilize endothelial cell precursor cells from bone marrow and enhance their proliferation and differentiation at sites of angiogenesis

2. stimulate proliferation and motility of existing endothelial cells, promoting capillary sprouting
What is the fxn of angiopoietin 1?
interacts with endothelial cell receptor Tie2 to recruit periendothelial cells

interaction also mediates vessel maturation from simple tubes into more elaborate vascular structures and helps maintain endothelial cell quiescence

Angiopoietin-2:Tie-2 interactions are opposite
What is the fxn of PDGF?
recruits smooth muscle cells
What is the fxn of TGF-beta?
stabilizes newly formed vessels by enhancing ECM production
What proteins are involved in the directed migration of endothelial cells in angiogenesis? What is the fxn of each?
integrins - critical for forming and maintaining newly formed vessels

matricellular proteins

proteases - remodel tissue during endothelial cell invasion; they release matrix bound VEGF and FGF-2 to stimulate angiogenesis as well as inhibitors of angiogenesis (endostatin)
What are the 3 general steps involved in scar formation?
1. fibroblast migration and proliferation
2. ECM deposition and scar formation
3. Tissue remodeling
What repair progresses in the healing/scarring process, what happens to the number of endothelial cells and fibroblasts
numbers of proliferating endothelial cells and fibroblasts decrease; fibroblasts become more synthetic and deposit more collagen and other ECM components

Eventually the granulation tissue scafolding is converted into a scar composed of fibroblasts and collagen
What are matrix metalloproteinases? What is required for their activity
MMPs - family of more than 20 enzymes that degrade ECM; they are secreted as proenzymes and activated extracellularly

Need zinc to be active
What are interstitial collagenases?
cleave fibrillar collagen types I, II, and III
What are gelatinases?
degrade amorphous collagen as well as fibronectin
What are stromelysins?
act on a variety of ECM components, including proteoglycans, laminin, fibronectin, and amorphous collagen
What are ADAMs?
disintegrin and metalloproteinase-domain

membrane bound MMPs that release extraceullar domains of cell surface proteins
What inhibits MMPs?
tissue inhibitors of metalloproteinases (TIMPs)
What is the next effect of TIMPs and MMPs?
net effect of ECM synthesis versus degradation results in debridement of injured sites and remodeling of the connective tissues framework
Describe the generalized steps involved in wound healing.
1. induction of inflammation by the initial injury
2. granulation tissue formation and reepithelialization
3. ECM deposition and remodeling with wound contraction
What is the difference between healing by first intention and second intention?
first intention - wounds with opposed edges where the scar consists of connective tissues devoid of inflammation covered by intact epidermis

2nd intention - wounds with separated edges - abundance of granulation tissue - substantial scar deposition and overlying epidermis is thin - characterized by wound contracture in which the defect is markedly smaller than its original size - this is largely through the contractile activity of myofibroblasts
What are some factors that influence wound healing?
local factors that delay healing - infections, mechanical forces, and foreign bodies

system factors - nutritional status of host, metabolic status, circulatory status or vascular adequacy, and hormones
What is deficient scar formation?
inadequate granulation tissue or collagen deposition and remodeling that can lead to either wound dehiscence or ulceration
What is excessive repair?
excessive granulation can protrude adove the surrounding skin and block reepithelization (exuberant granulation or proud flesh)

excessive collagen accumulations form a raise hypertrophic scar and progression beyond the original area of injury without subsequent regression is known as a keloid
What does it mean when you have formation of contractures in a complications of wound healing?
exaggerated process of wound contraction