Tissue Repair: Regeneration and Fibrosis Mechanisms
Tissue repair
REGENER
A
TION
&
HEALING
BY
FIBROSIS
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Definition of the tissue repair
:
restoration of tissue architecture and
function
after an injury. It occurs by two types of reactions:
1-regeneration of the injured tissue
.
2-
scar formation by the deposition of connective tissue.
1
-Regeneration
.
Some tissues are able to replace the
damaged cells and essentially
return to a normal state
this process is called regeneration.
Regeneration occurs
by
proliferation of residual (uninjured) cells that retain the capacity to divide, and by
replacement from tissue
stem cells. It is the typical response to injury in the
rapidly
dividing epithelia of the skin and intestines
, and
some parenchymal organs,
notably the liver
.
2-Scar formation
.
1-
If the injured tissues are incapable of
regeneration
2-
if the supporting structures of the tissue
are severely damaged, repair occurs by the
laying down of connective (fibrous) tissue, a process that results in scar formation.
Although the fibrous scar cannot
perform the function of lost parenchymal cells, it
provides enough structural stability that the injured tissue is usually able to function. The
term
fibrosis
is most often
used to describe the extensive deposition of collagen that
occurs in the lungs, liver, kidney, and other organs
as a consequence of chronic
inflammation, or in the
myocardium after extensive ischemic necrosis (infarction).
THE CONTROL
OF CE
L
L
PROLIFERATION
Sev
e
r
a
l
c
e
ll types
prolife
r
ate
d
u
ring tissue
r
e
pair.
These i
n
clude
1
. T
h
e
re
m
nants
of
the in
j
ured
tissue
(which
att
e
m
p
t
to re
s
to
r
e
normal
structur
e
)
2
.
V
as
c
u
l
ar
endothelial
cells
(to
cr
e
ate
new
v
e
ssels that
pro
v
ide
the
n
u
trients for
the r
e
pair
pro
c
ess)
3
.
F
ibro
b
lasts
(the
source
of
the
fi
b
rous tiss
u
e
that
fills
defe
c
ts).
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4-The
pr
o
liferatio
n
of
the
a
b
o
ve
c
e
ll
types
is
d
r
iv
e
n
by
gr
o
wth
fa
c
tor
s
.
5
-
The
normal
si
z
e
of
c
ell
p
o
p
u
lati
o
ns
in
a
ny
gi
v
en
tis
sue
is
det
e
rmined
by
a
b
ala
nce
of
c
ell
pro
l
iferat
i
on
,
c
e
ll
de
a
th
by
apop
tosis,
an
d
em
e
rgence
of
new
di
f
fer
e
n
t
ia
ted
c
e
lls
from
s
t
em
c
e
lls .
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6
Cell
nu
m
bers
can
be
alte
r
ed
by
inc
r
eased
or
dec
r
eased
rates
of stem
cell
input,
cell
death
via
apoptosis,
or
changes
in
the
rates
of
p
r
oliferation
or
dif
f
e
r
entiation.
Mechanisms
r
egula
t
ing
ce
l
l
pop
u
la
t
ions.
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Prolifer
a
tive
Capacities
of
Tis
s
ues:
The
t
iss
ues of
the
b
o
dy
are di
v
ided
in
to
three grou
p
s:
1.
Con
t
in
u
ously
Dividing
Tis
s
ues
(
l
a
bile
tis
sues):
c
e
lls
of
these
tis
sues
are
con
tin
u
o
u
s
ly
being
lo
st
an
d
r
e
pl
a
c
e
d
by
mat
urati
o
n
from
s
t
em
c
e
lls
and
by
proliferati
o
n
of
mature
c
e
lls
.
Lab
i
le
c
ells
include:
hemat
o
p
oietic
c
e
lls
in
th
e b
o
ne
mar
r
ow
and
t
he
ma
j
o
rity
of
su
rfa
ce epitheli
a.
These
tiss
ues can
readi
l
y
regenerate a
f
ter in
j
u
r
y
p
r
ovi
d
ed the
p
o
ol
of
stem
c
ells
is
p
r
eserv
e
d.
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2.
S
table
Tiss
u
es:
Cells
of
t
hese
t
i
ssues
are
quiesc
e
nt
(
i
n the
G
0
stage
of the cell
cyc
l
e)
and have on
l
y
m
i
nimal
replicative activity
in their
normal
state.
T
h
ese ce
l
ls
are
capable
of pro
l
i
f
erating
in response to injury or loss of t
i
ssue mass
.
Stable
ce
l
ls
consti
t
ute
1-
T
he
parenchy
m
a
of
m
ost
sol
i
d
tissues,
such as
l
iver
&
kidne
y
.
2-
endothelial
ce
l
ls,
f
i
broblas
t
s,
and smooth muscle
ce
l
ls;
the
p
roli
f
era
t
i
o
n
of
t
hese
ce
l
ls
is part
i
cular
l
y
i
m
portant
in
w
ound
heal
i
ng
.
With
the
except
i
on
of l
i
ver,
stable
tissues
have
a li
m
ited
capacity
to
regenerate
af
t
er
injury.
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3.
P
erm
a
nent
Tiss
u
es:
Cells
of
these
tis
sues
are
te
r
min
a
lly
di
f
fer
e
n
t
ia
ted
an
d
n
o
n
proli
f
e
r
a
t
iv
e
in
po
st
na
t
al
li
f
e
.
The
maj
o
rity
of
1-
neurons
2-
cardiac
m
uscle
cells
3- Skeletal muscle
.
Ac
c
ord
i
n
gly,
injury
to
brain
or
heart
is
i
r
r
e
versib
l
e
an
d
r
e
su
l
ts
in
a
scar.
S
k
eletal
mu
s
cle
is
usu
a
lly
clas
sif
i
ed as
a
pe
r
ma
nent
tis
su
e
.
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10
Stem ce
l
ls a
r
e charac
t
eri
z
ed by two
imp
o
rt
a
nt prop
ert
i
es:
1.
1-
S
elf-renewal
ca
p
acity
2.
2-
Asymm
e
tric
re
p
lication.
•
As
y
m
m
et
r
ic
r
e
pl
i
c
a
tion
of stem cells
means
that
aft
e
r
ea
c
h
cell
d
ivision,
some
p
ro
g
eny
enter
a d
i
ffe
r
entiation
pathwa
y
,
while
othe
r
s
r
e
main
u
n
differ
e
ntiate
d
,
r
e
taining
their
sel
f
-
renew
a
l
capa
c
ity.
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11
REPAIR
B
Y CONNECTIVE
TISSUE ( scar formation
)
He
a
l
ing
o
r
r
e
p
a
ir
by
c
o
n
ne
c
ti
v
e
tis
sue
is
encounter
e
d
if
1.
A
severe
or
pers
i
stent
(chronic)
tis
sue
in
j
ury
t
hat
r
e
su
l
t
in
d
a
m
a
ge
t
o
p
a
rench
y
mal
c
e
lls
as
w
ell
a
s
th
e
s
t
romal
frame
w
ork
2.
In
j
ury
a
f
fects
n
o
n
d
iv
id
i
ng
c
e
lls
Under
t
hese
cond
it
i
on
s,
r
e
p
a
ir
occurs
by
r
e
pl
a
c
e
me
n
t
of
th
e
n
o
n regene
r
a
t
ed
cells
w
ith conne
c
ti
v
e
tis
su
e,
o
r
by
a
comb
i
n
ati
o
n
of
r
e
generat
i
on
of
s
o
me
c
e
lls
an
d
scar
fo
rmati
on
.
Repair
be
g
ins
w
i
t
hin 24
hours
of
injury
b
y
the
emi
g
r
at
i
on
of
f
i
brobla
s
ts
and
the
i
n
duction
of
f
i
brobla
s
t
and
e
n
dot
h
eli
a
l
ce
l
l
prol
i
ferati
o
n
.
B
y
3
to
5
d
ays
,
a
s
pecia
l
i
z
ed
t
y
pe
of
t
i
ssue
that
is
characte
r
ist
i
c
of
healing,
called
gr
a
nu
l
at
i
on
tiss
ue
is
ap
p
aren
t
.
T
h
e
term
g
ranulation
t
i
ssue
de
r
i
v
es
from
the
pin
k
,
soft,
granular
gross
appearance,
su
c
h
as
that
seen
benea
t
h
the
scab
of
a
skin
w
oun
d
.
Its
microsco
p
ic
appearance
is
c
h
aracte
r
i
z
ed
b
y
prol
i
f
e
ration
of
fibro
b
la
s
ts
and
n
e
w
thin-
w
alled,
de
l
icate
cap
i
ll
a
r
ies
(angiogenes
i
s),
in a loose
EC
M.
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13
Wound
Strength
C
a
reful
l
y
sutured
w
ou
n
ds
have a
p
proximate
l
y
70
%
of
the
st
r
ength
of un
w
oun
d
ed
s
k
in,
largely
because of
the place
m
ent
of
the sutures.
When sutures a
r
e
re
m
oved,
usually
at
1
w
ee
k
,
w
ound
st
r
ength
is
approxima
t
ely
10%
of
that of un
w
oun
d
ed
s
k
in,
but
this
increases
rapidly
over the next
4
w
ee
k
s.
Collagen
synthesis
e
xceeding
degradat
i
on d
u
ring the
f
i
rst
2
months, and from structural
modif
i
cations
of
collagen
(e.g.,
cros
s
-
l
i
nking
and
i
ncreased
f
i
ber
si
z
e)
w
hen
synthesis de
c
l
i
nes
at
l
ater
t
i
mes.
Wound
st
r
ength
reaches approx
i
ma
t
ely
7
0
% to
80%
of nor
m
al
by
3
months
but us
u
ally
does not
substantially
improve
beyond
that
poin
t
.
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14
Causes of delay wound healing
•
1.
Infe
c
tio
n
is
the
s
i
ngle
most
i
m
porta
n
t
cause
of
de
l
ay
in healing
.
•
2.
N
ut
ritio
n
has p
r
o
f
ound
effects
on
w
ound
heal
i
ng;
pr
o
t
e
in de
f
i
c
i
e
ncy
&
v
i
tamin
C de
f
i
c
i
e
nc
y
,
inh
i
bits
collagen
synthesis
a
n
d ret
a
rds
healing.
•
3.
3.
Glucocorticoi
d
s
(
stero
i
d
s
)
ha
v
e
an
t
i-in
f
la
m
m
at
o
r
y ef
f
ects,
a
n
d
the
i
r
a
d
m
i
nistra
t
ion
may
resu
l
t
in
p
o
or
w
o
u
nd stren
g
th
due
to dim
i
nished
fibrosis
•
4.
M
e
chan
i
cal
v
ar
i
a
b
les
such
as
in
c
reased
local
pres
s
ureor torsion
may
cause
w
o
u
nds
to
pull
a
p
ar
t
,
or
dehisce
i.e.
o
p
en
o
u
t or
g
a
pe.
•
5.
P
o
o
r
per
f
u
sio
n
,
due
e
i
ther
to
ar
t
er
i
osc
l
er
o
sis
a
n
d
diabe
t
es or to
o
b
struc
t
ed
ven
o
us
drain
a
ge
(e.
g
.
in
v
a
r
i
cose
veins),
also i
m
p
a
i
r
s
healing
•
6.
6.
F
o
r
eign
b
o
d
i
es
such
as
fr
a
gments
of
steel,
glass,
or
e
ven b
o
ne
i
m
pede
healing.
Tissue repair involves two primary mechanisms: regeneration, where some tissues can replace damaged cells, and fibrosis, where scar tissue forms if regeneration is not possible. Cell proliferation, growth factors, and cell population control play key roles in the restoration of tissue architecture and function after injury.
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Presentation Transcript
REGENERATION & HEALING BY FIBROSIS Definition of the tissue repair: restoration of tissue architecture and function after an injury. It occurs by two types of reactions: 1-regeneration of the injured tissue . 2- scar formation by the deposition of connective tissue. 1-Regeneration. Some tissues are able to replace the damaged cells and essentially return to a normal state this process is called regeneration. Regeneration occurs by proliferation of residual (uninjured) cells that retain the capacity to divide, and by replacement from tissue stem cells. It is the typical response to injury in the rapidly dividing epithelia of the skin and intestines, and some parenchymal organs, notably the liver. Al-Madena Copy CLS 2
2-Scar formation. 1- If the injured tissues are incapable of regeneration 2- if the supporting structures of the tissue are severely damaged, repair occurs by the laying down of connective (fibrous) tissue, a process that results in scar formation. Although the fibrous scar cannot perform the function of lost parenchymal cells, it provides enough structural stability that the injured tissue is usually able to function. The term fibrosis is most often used to describe the extensive deposition of collagen that occurs in the lungs, liver, kidney, and other organs as a consequence of chronic inflammation, or in the myocardium after extensive ischemic necrosis (infarction).
THE CONTROL OF CELL PROLIFERATION Several cell types proliferate during tissue repair. These include 1. The remnants of the injured tissue (which attempt to restore normal structure) 2. Vascular endothelial cells (to create new vessels that provide the nutrients for the repair process) 3. Fibroblasts (the source of the fibrous tissue that fills defects). Al-Madena Copy CLS 5
4-The proliferation of the above cell types is driven by growth factors. 5-The normal size of cell populations in any given tissue is determined by a balance of cell proliferation, cell death by apoptosis, and emergence of new differentiated cells from stem cells . Al-Madena Copy CLS 6
Mechanisms regulating cell populations. Cell numbers can be altered by increased ordecreased rates of stem cell input, cell death via apoptosis, or changes in the rates of proliferation or differentiation. Al-Madena Copy CLS 7
Proliferative Capacities of Tissues: The tissues of the body are divided into three groups: 1. Continuously Dividing Tissues (labile tissues): cells of these tissues are continuously being lost and replaced by maturation from stem cells and by proliferation of mature cells. Labile cells include: hematopoietic cells in the bone marrow and the majority of surface epithelia. These tissues can readily regenerate after injury provided the pool of stem cells is preserved. Al-Madena Copy CLS 8
2. Stable Tissues: Cells of these tissues are quiescent (in the G0stage of the cell cycle) and have only minimal replicative activity in their normal state. These cells are capable of proliferating in response to injury or loss of tissue mass. Stable cells constitute 1- The parenchyma of most solid tissues, such as liver & kidney. 2- endothelial cells, fibroblasts, and smooth muscle cells; the proliferation of these cells is particularly important in wound healing . With the exception of liver, stable tissues have a limited capacity to regenerate after injury. Al-Madena Copy CLS 9
3. Permanent Tissues: Cells of these tissues are terminally differentiated and nonproliferative in postnatal life. The majority of 1-neurons 2- cardiac muscle cells 3- Skeletal muscle . Accordingly, injury to brain or heart is irreversible and results in a scar. Skeletal muscle is usually classified as a permanent tissue. Al-Madena Copy CLS 10
Stem cells are characterized by two important properties: 1. 1-Self-renewal capacity 2. 2- Asymmetric replication. Asymmetric replication of stem cells means that after each cell division, some progeny enter a differentiation pathway, while others remain undifferentiated, retaining their self- renewal capacity. Al-Madena Copy CLS 11
REPAIR BY CONNECTIVE TISSUE ( scar formation) Healing or repair by connective tissue is encountered if 1. A severe or persistent (chronic) tissue injury that result in damage to parenchymal cells as well as the stromal framework 2. Injury affects non dividing cells Under these conditions, repair occurs by replacement of the non regenerated cells with connective tissue, or by a combination of regeneration of some cells and scar formation.
Repair begins within 24 hours of injury by the emigration of fibroblasts and the induction of fibroblast and endothelial cell proliferation. By 3 to 5 days, a specialized type of tissue that is characteristic of healing, calledgranulation tissue is apparent. The term granulation tissue derives from the pink, soft, granular gross appearance, such as that seen beneath the scab of a skin wound. Its microscopic appearance is characterized by proliferation of fibroblasts and new thin-walled, (angiogenesis), in a loose ECM. delicate capillaries Al-Madena Copy CLS 13
Wound Strength Carefully sutured wounds have approximately 70% of the strength of unwounded skin, largely because of the placement of the sutures. When sutures are removed, usually at 1 week, wound strength is approximately 10% of that of unwounded skin, but this increases rapidly over the next 4 weeks. Collagen synthesis exceeding degradation during the first 2 months, and from structural modifications of collagen (e.g., cross- linking and increased fiber size) when synthesis declines at later times. Wound strength reaches approximately 70% to 80% of normal by 3 months but usually does not substantially improve beyond that point. Al-Madena Copy CLS 14
Causes of delay wound healing 1. Infection is the single most important cause of delay in healing. 2.Nutrition has profound effects on wound healing; protein deficiency & vitamin C deficiency, inhibits collagen synthesis and retards healing. 3. 3. Glucocorticoids (steroids) have anti-inflammatory effects, and their administration may result in poor wound strength due to diminished fibrosis 4.Mechanical variables such as increased local pressureor torsion may cause wounds to pull apart, or dehisce i.e. open out or gape. 5. Poor perfusion, due either to arteriosclerosis and diabetes or to obstructed venous drainage (e.g. in varicose veins), also impairs healing 6. 6. Foreign bodies such as fragments of steel, glass, or even bone impede healing.
