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CONTROL
GROWTH
OF
NORMAL
CELL
PROLIFERATION
AND
TISSUE
2.
-
skeletal
muscle
have
a
regenerative capacity through the
differentiation of the satellite cells
that
are
attached
to
the
endomysial sheath
Stem cells
self- renewal properties
capacity to generate differential cell lineage
stochastic differentiation
stem cell population is cell maintained by a balance
between stem cell divisions that generate either two
self-renewing stem cells or two cells that will
differentiate
In the early stages of development
o
stem cells are known as embryonic stem cells or
ES cells and are pluripotent.
Pluripotent
o
can generate all tissues of the body
o
give rise to multipotent stem cells
CHAPTER 3
TISSUE RENEWAL, REGENERATION, and REPAIR
Bone marrow
The bone marrow contains HSCs and stromal cells (also
known as multipotent stromal cells, mesenchymal stem
cells or MSCs).
o
Hematopoietic Stem Cells.
D.
E.
G0 or
after
completing
meiosis
(continuously
replicating cells)
Quiescent cells first must go through the transition
from G0 to G1
o
first decision step
o
functions as gateway to the cell cycle
o
involves the transcriptional activation of pro
oncogenes and genes required for ribosome
synthesis and protein translation
Restriction point
CHAPTER 3
TISSUE RENEWAL, REGENERATION, and REPAIR
Cells in G1 progress through the cycle and
reach a critical stage at the G1/S transition
known as restriction point.
o
rate limiting step for replication
o
regulated by cyclins and associated enzymes
called cyclin-dependent kinase
RB Protein Checkpoints - ensure that cells with damaged DNA or
chromosomes do not complete replication
G1/S checkpoint - monitors the integrity of DNA before
replication
G2/M checkpoint checks DNA after replication; monitors
whether the cell can safely enter mitosis.
Senescence
o
non replicative stage
o
p53 dependent mechanism
o
o
3.
GROWTH FACTORS
1.
2.
Growth Factors
polypeptides
restricted or multiple targets
promote
survival,
locomotion,
contractility,
differentiation and angiogenesis
all GF function as ligands that binds to specific receptors
which deliver signals to the target cells
signals stimulate the transcription of genes that may be
silent in resting cells
Epidermal Growth Factor (EGF) and Transforming Growth
Factor (TGF-)
EGF family
common receptor EGFR
EGF
mitogenic for EC, hepatocytes and fibroblasts
widely distributed in tissue secretions and fluids
healing wounds of the skin produced by
keratinocytes, macrophages and other inflammatory
cells that migrate into the area
TGF-a
extracted from the sarcoma virus-transformed cells
involved in EC proliferation in embryos and adults
also in malignant transformation of normal cells to
cancer
Best characterized EGFR (EGF receptor) is EGFR1, ERB B1 or
simply EGFR.
responds to EGF, TGF-a and other ligands such as HB
-EGF and amphiregulin
EGFR 1
o
causes cancer of the lungs, head and neck,
and breast
o
glioblastoma
o
other cancers
ERB B2 receptor
o
HER-2/HER2/Neu
o
overexpressed in subset of breast cancer
Hepatocyte Growth Factor (HGF)
originally isolated from platelets and serum
Scatter factor - HGF is identical to; factor isolated from
fibroblasts
HGF/SF
mitogenic
functions:
a.
acts as morphogen in embryonic development
b.
promotes cell scattering and migration
c.
enhances the survival of hepatocytes
produced by
a.
fibroblasts
b.
most mesenchymal cells
c.
endothelial cells
d.
liver nonparenchymal cells
produced as inactive single-chain form activated by serine
protease
c-Met
o
receptor for HGF
4.
5.
6.
CHAPTER 3
TISSUE RENEWAL, REGENERATION, and REPAIR
a.
b.
c.
a.
platelets
b.
EC
c.
lymphocytes
d.
macrophages
Native TGF- is synthesized as precursor protein
secreted proteolytically cleaved to yield:
a.
active TGF-
o
binds to 2 cell surface receptors with
serine threonine kinase activity
triggers
the
phosphorylated
of
cytoplasmic transcription factor called
Smads
o
Smads
collagen
fibronectin, and
proteoglycans.
o
inhibits collagen degradation by
increasing
protease
inhibitor
activities.
o
involved in the development of fibrosis in a
variety of chronic inflammatory conditions
particularly in the lungs, kidney, and liver.
o
High TGF- expression also occurs in
hypertrophic scars, systemic sclerosis , and
the Marfan syndrome.
TGF- has a strong anti-inflammatory effect but may
enhance some immune functions
Cytokines
a.
b.
a.
b.
c.
d.
ECM
a.
b.
c.
d.
e.
f.
COLLAGEN
CHAPTER 3
TISSUE RENEWAL, REGENERATION, and REPAIR
-
Collagen
Type
Tissue Distribution
i.
ii.
iii.
iv.
Genetic Disorders
FIBRILLAR COLLAGENS
I
II
Cartilage,
intervertebral disk,
vitreous
III
IX
Cartilage, vitreous
Stickler syndrome
Basement membranes
Alport syndrome
OTHER COLLAGENS
VI
Ubiquitous in
microfibrils
Bethlem myopathy
VII
Anchoring fibrils at
dermal-epidermal
junctions
IX
Cartilage,
intervertebral disks
XVII
Transmembrane
collagen in epidermal
cells
XV and
XVIII
Endostatin-forming
collagens, endothelial
cells
CAMS
cell adhesion molecules
four main families
sometimes
stored
in
cytoplasm
provide interaction between the same cells or different
cell types (homotypic and heterotypic respectively)
Integrins
o
bind to ECM proteins such as
fibronectin
laminin, and
osteopontin
o
providing a connection between cells and ECM,
and also to adhesive proteins in other cells,
establishing cell-to-cell contact.
Fibronectin
o
is a large protein that binds to many molecules,
such as collagen, fibrin, proteoglycans, and cell
surface receptors.
o
It consists of two glycoprotein chains, held
together by disulfide bonds.
o
Fibronectin messenger RNA has two splice forms,
giving rise to tissue fibronectin and plasma
fibronectin.
o
The plasma form binds to fibrin, helping to
stabilize the blood clot that fills the gaps created
by wounds, and serves as a substratum for ECM
deposition and formation of the provisional matrix
during wound healing
Laminin
o
is the most abundant glycoprotein in the
basement membrane and has binding domains for
both ECM and cell surface receptors.
o
In the basement membrane, polymers of laminin
and collagen type IV form tightly bound networks.
o
Laminin can also mediate the attachment of cells
to connective tissue substrates.
cadherin
o
calcium-dependent adherence protein.
o
participate in interactions between cells of the
same type.
o
These interactions connect the plasma membrane
of adjacent cells, forming two types of cell
junctions called
a.
zonula adherens
small
spotlike junctions
stronger
and more extensive
junctions
CHAPTER 3
TISSUE RENEWAL, REGENERATION, and REPAIR
MECHANISMS OF ANGIOGENESIS
SPARC
o
o
o
GLYCOSAMINOGLYCANS
GAGs
o
VEGF
o
o
VEGFR-2
CHAPTER 3
TISSUE RENEWAL, REGENERATION, and REPAIR
VEGF functions:
a.
induces migration of EPCs in the none marrow
b.
enhances proliferation and differentiation of cells at
sites of angiogenesis
In angiogenesis from preexisting local vessels, VEGF:
a.
stumlates the survival of endothelial cells, proliferation,
motility
b.
initiating the sprouting of new capillaries
Notch Pathway
mechanism for modulation of vasculogenesis
promtes proper branching of new vessels
prevents excessive angiogenesis by decreasing the
responsiveness to VEGF
o
o
o
o
o
o
o
Healing by secondary
o
o
o
o
1.
1.
Inflammation
o
o
2.
Proliferation
o
o
2.
3.
o
Maturation
o
ECM deposition
o
tissue remodeling
o
wound contraction
3.
CHAPTER 3
TISSUE RENEWAL, REGENERATION, and REPAIR
clearing extracellular debris, fibrin, and other
foreign material at the site of repair, and
o
promoting angiogenesis and ECM deposition
Migration of fibroblasts to the site of injury is driven by
chemokines
a.
TNF
b.
PDGF
c.
TGF-b
d.
FGF
Macrophages are main source of these
factors
Collagen fibers are now present at the margins of the
incision (vertically oriented and do not bridge the incision)
24 to 48 hours
o
spurs of epithelial cells move from the wound edge
along the cut margins of the dermis deposit
basement membrane components as they move
fuse in the midline beneath the surface scab
producing a thin, continuous epithelial layer that
closes the wound
o
full epithelialization of the wound surface is much
slower in healing by secondary union because the
gap to be bridged is much greater
Macrophages stimulate fibroblast to produce:
a.
FGF-7 (Keratinocyte growth factor)
b.
IL 6 - enhance keratocyte migration and proliferation
HGF and HB-EGF
CXCR-3 - promotes skin reepithelialization
TGF
most important fibrogenic agent
produced by most cells in granulation tissue
causes
a.
fibroblast migration proliferation
b.
increased synthesis of collagen and fibronection
c.
decreased
degradation
of
ECM
by
metaloproteinases
a.
b.
c.
d.
-
5.
6.
Scar Formation
2nd week - leukocytic infiltrate, edema and increased
vascularity disappear.
Blanching begins
blanching is accomplished by:
a.
increased accumulation of collagen within the
wound area
b.
regression of vascular channles
Original granulation tissue scaffolding is converted into a
pale, avascular scar, composed of:
a.
spindle shaped fibroblasts
b.
dense collagen
c.
fragments of elastic tissue
d.
other ECM components
Dermal appendages have been destroyed in the line of the
incision are permanently lost
By the end of first month, the scar is made up of acellular
connective tissue devoid of inflammatory infiltrate, covered
by intact epidermis
Wound Contraction
Wound contraction generally occurs in large surface wounds
Contraction helps to close the wound by:
a.
decreasing the gap between its dermal edges
b.
reducing the wound surface area
contraction is an important feature in healing by secondary
union
Initial steps of wound contraction involves the formation of
myofibroblasts at the edge of the wound.
Myofibroblasts
expresse smooth mucle -actin and vimentin
Ultrastructural characteristics of a smooth muscle cell
contract in the wound tissue
7.
released by macrophages at
the wound site
GF (PDGF, FGF)
phagocytosis in macrophages
secretion is inhibited by
TGF-
steroids
Collagenase
o
cleave collagen under physiologic conditions.
o
synthesized as a latent precursors
o
activated by chemicals
ADAM
o
disintegrin and metalloproteinase-domain
family
o
anchored by a single transmembrane domain
to cell surface
o
ADAM-17
cleaves
the
membrane-bound
precursor forms of TNF and TGF-
CHAPTER 3
TISSUE RENEWAL, REGENERATION, and REPAIR
-
Systemic Factors:
Nutrition
protein deficiency
vitamin C deficiency -inhibit collagen synthesis and
retard healing
Metabolic Status
change wound healing
DM - associated with delated wound healing
(consequence of microangiopathy)
Circulatory Status
modulate wound healing
inadequate blood supply (caused by arterioscelorosis)
or venous abnormalities that retard venous drainaige,
also impairs healing
Hormones
glucocorticoids
o
anti inflammatory effects
o
influence components of inflammation
o
inhibits collagen synthesis
B.
Local Factors
Infection
most important cause of delay in healing
it results in persistent tissue injury and inflammation
Mechanical Factors
e.g. early motion of wounds
delay healing by compressing blood vessels and
separating edges of the wounds
Foreign bodies
unnecessary sutures or fragments of steel, glass or
bone
Size, location and type of wound
wounds in richly vascularized areas (e.g. face) - heal faster
than poorly vascularized area (foot)
4.
Hypertrophic Scars
o
accumulation of excessive amounts of collagen
o
raised scar
o
generally develop after thermal or traumatic injury
that involves the deep layer of the dermis
Keloid
Desmoids
Contractions
Contractures
exaggeration in the contraction of the size of the wound
Note that:
a.
the initial wave of the host response to external
invaders and tissue injury generates classically
activated macrophages
effective in ingesting and destroying microbes and dead
tissues
b.
alternatively activated macrophages
suppress the microbicidal activities
remodel tissues
promote angionesis and scar formation
TGF-b is always involved as an important fibrogenic agent
Osteopontin
impt role in healing and fibrosis
strongly expressed in the fibrosis of heart, lung, liver,
kidney and some other tissues
CHAPTER 3
TISSUE RENEWAL, REGENERATION, and REPAIR
e.
f.
SUMMARY
glomerulonephritis
constrictive pericarditis
10