Tissue Repair Mechanisms: Regeneration and Fibrosis
Tissue Repair
Stimuli
that induce death in some cells can
trigger
the activation of
replication pathways in others; recruited inflammatory cells not only clean up
the necrotic debris
but
also
elaborate
mediators that
drive
the synthesis of
new extracellular matrix (
ECM
).
-Regeneration
of injured tissue by parenchymal cells of the same type.
-Replacement
by connective tissue (fibrosis), resulting in a scar.
- Regeneration and scarring involve essentially similar mechanisms including
cell
migration
,
proliferation
, and
differentiation
, as well as
matrix
synthesis
.
- Regeneration of epithelium
requires
an intact
basement membrane
(BM)
matrix.
Mechanisms of tissue repair. In this example, injury to the liver is repaired by regeneration if only the hepatocytes
are damaged, or by laying down of fibrous tissue if the matrix is also injured.
The cells of the body are divided into
three groups
on the
basis
of their
regenerative capacity
:
1-Labile cells:
These are
continuously
dividing
(and continuously
dying
) and include:
-The
Hematopoietic
cells in the bone marrow.
-The
stratified squamous
surfaces of the
skin
,
oral
cavity,
vagina
, and
cervix.
-The
cuboidal epithelia
of the ducts draining exocrine organs (e.g.,
salivary
glands,
pancreas
,
biliary
tract).
-The
columnar epithelium
of the
gastrointestinal
tract,
uterus
, and
fallopian
tubes.
-The
transitional epithelium
of the
urinary
tract.
2-Stable cells:
quiescent
in their
normal
state, but are capable of undergoing rapid
division
in
response to
injury
. These include:
-The
parenchyma
of
most
solid
glandular
tissues, including
liver
,
kidney,
and
pancreas.
-The
Endothelial
cells lining blood vessels, and the
fibroblast
and
smooth muscle
connective tissue
(
mesenchymal
) cells.
3-Permanent cells
:
Terminally
differentiated and
nonproliferative
in
postnatal
life. The
majority
of
neurons
and
cardiac muscle
cells belong to this category.
Extracellular signaling via soluble mediators occurs in four different forms:
1-Autocrine signaling
,
in which a soluble mediator acts the
cell
that
secretes it
. This pathway is important in the
immune response
(cytokines) and in compensatory
epithelial hyperplasia
(e.g., liver regeneration).
2-Paracrine signaling:
mediators affect cells only in the
immediate vicinity
. This pathway is important for
recruiting
inflammatory
cells
to the site of
infection
and for the controlled process of
wound healing
.
3-Synaptic:
activated
neural
tissue secretes
neurotransmitters
at a specialized cell junction (
synapse
) onto target cells
such as other
nerves
or
muscle.
4-Endocrine,
in which a
regulatory
substance, such as a
hormone
, is released into the
bloodstream
and acts on
target
cells at a
distance
.
General components of repair process:
-Formation
of new blood vessels (
angiogenesis
).
-Migration
and proliferation of fibroblasts.
-Deposition
of ECM.
-Maturation
and reorganization of the fibrous tissue (
remodeling
).
Blood vessels are assembled by two processes:
-Vasculogenesis: in
embryonic
development occure by
angioblasts
(endothelial cell
precursors).
-Angiogenesis (neovascularization
)
by which preexisting vessels
send out
capillary
sprouts
to
produce new vessels.
Four general steps occur in the development of a new capillary vessel:
-Proteolytic degradation
of the parent vessel BM to form of a capillary sprout.
-Migration of endothelial
cells from the original capillary toward an angiogenic stimulus.
-Proliferation of the endothelial
cells.
-Maturation of endothelial:
this includes recruitment and proliferation of
pericytes
(for
capillaries
)
and
smooth
muscle cells (for
larger
vessels) to support the endothelial tube and provide accessory
functions.
Fibrosis (Scar Formation)
Fibrosis
, or scar formation, builds on the
granulation
tissue framework of new
vessels
and loose
ECM
that develop early at the repair
site
.
The process of fibrosis occurs in two steps:
(1)
Emigration
and
proliferation
of fibroblasts into the site of injury.
(2) Deposition
of
ECM
by these cells.
The recruitment and stimulation of fibroblasts is driven by many of the growth factors, including
platelet-derived growth factor (
PDGF
),
FGF
, and
TGF-β
.
The main source of these factores are activated
Endothelium
and
Macrophages
.
Scar Remodeling
Shifts
in the composition of the
ECM
; even after its synthesis and deposition, scar ECM continues to
be
modified
and
remodeled.
Degradation of
collagens
and other
ECM
components performed by
metalloproteinases
(zinc ions
for their activity).
These enzymes are produced by (
fibroblasts
,
macrophages
,
neutrophils,
synovial cells
, and some
epithelial cells
)
Angiogenesis
resulting from,
A,
the mobilization of bone marrow endothelial precursor cells (
EPCs
), and,
B,
from preexisting vessels
at the site of injury.
EPCs
can be
mobilized
from the bone marrow and
migrate
to a site of injury and
differentiate
and form a mature
network by linking with preexisting vessels. Endothelial cells from preexisting vessels become
motile
and
proliferate
to form capillary
sprouts
.
Regardless
of the
mechanism
of angiogenesis, vessel maturation
requires
the recruitment of
pericytes
and
smooth muscle
cells
to form the
periendothelial
layer.
Phases
Wound healing: include:
1-Inflammatory
phase by the
initial
injury. (First 48 hours- 6 days).
2-proliferative phase
(
7
days to
6
weeks):
-
Parenchymal
cell regeneration (where
possible
).
-
Migration
and
proliferation
of both
parenchymal
and
connective tissue
cells
-
Synthesis
of ECM proteins.
3-Remodeling phase
(
Maturation phase
) (Day
8
through
years
).
-
For
parenchymal elements to restore tissue
function.
-
For
connective tissue to achieve wound
strength
.
Types of healing:
1-Healing by First Intention
Healing of a
clean
,
uninfected
surgical incision
approximated by surgical
sutures.
This is
referred to as
primary union
, or healing by
first intention.
-Causes
only
focal
disruption of
epithelial basement membrane.
-Death
of a relatively few
epithelial
and
connective
tissue cells.
-Epithelial
regeneration.
Wounds during
inflammatory Phase
Wound during Inflammatory
Phase
Wounds during p
roliferative
phase
Remodeling (Maturation)
Phase
Healing by Second Intention
When cell or tissue loss is
more extensive
, as in
infarction
, inflammatory
ulceration
,
abscess
formation, or even just
large wounds.
-Regeneration of
parenchymal
cells
alone
cannot
restore the original
architecture
.
-E
xtensive
ingrowth of
granulation
tissue from the wound
margin
,
-Accumulation of
ECM
and
scarring.
This form of healing is referred to as
secondary union
, or healing by
second intention
.
Secondary healing differs from primary healing in several respects:
1-Large
tissue defects i
ntrinsically
have a
greater
volume of
necrotic debris
,
exudate
, and
fibrin
that
must
be
removed.
2-Much larger
amounts of
granulation
tissue are
formed.
3-Secondary
healing
exhibits
wound (
contraction):
Within
6 weeks
, large
skin
defects may be
reduced to
5%
to
10%
of their original size, largely by
contraction
. This may due to modified of
fibroblasts
to
contractible
myofibroblasts
.
-
The accumulation of
exuberant
amounts of
collagen
can give rise to
prominent
,
raised scars
known
as keloids
.
Steps in wound healing by first intention (left) and second intention (right). In the latter, note the large amount of
granulation tissue and wound contraction.
Secondary Wound Healing
Wound
contraction
Healing of skin ulcers. A,
Pressure ulcer
of the skin, commonly found in diabetic patients.
B, A
skin ulcer with a
large gap
between the edges of the lesion.
C,
A thin layer of epidermal
re-epithelialization
, and extensive
granulation tissue formation in the dermis.
D,
Continuing
re-epithelialization of the epidermis and wound
contraction.
Keloid. A, Excess collagen deposition in the skin forming a raised scar known as a keloid. B, Thick connective
tissue deposition in the dermis.
Keloid
Keloid Scar
Healed wound (scar)
Tissue repair involves complex mechanisms like regeneration by parenchymal cells or fibrosis leading to scar formation. Inflammatory cells play a crucial role in tissue repair, along with processes like ECM synthesis and cell migration. Different types of cells in the body have varying regenerative capacities, from labile continuously dividing cells to permanent non-proliferative cells. Extracellular signaling via soluble mediators occurs through autocrine, paracrine, synaptic, and endocrine pathways. The repair process includes angiogenesis, fibroblast migration and proliferation, ECM deposition, and tissue remodeling.
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Presentation Transcript
Tissue Repair Stimuli that induce death in some cells can trigger the activation of replication pathways in others; recruited inflammatory cells not only clean up the necrotic debris but also elaborate mediators that drive the synthesis of new extracellular matrix (ECM). -Regeneration of injured tissue by parenchymal cells of the same type. -Replacement by connective tissue (fibrosis), resulting in a scar. - Regeneration and scarring involve essentially similar mechanisms including cell migration, proliferation, and differentiation, as well as matrix synthesis. - Regeneration of epithelium requires an intact basement membrane (BM) matrix.
Mechanisms of tissue repair. In this example, injury to the liver is repaired by regeneration if only the hepatocytes are damaged, or by laying down of fibrous tissue if the matrix is also injured.
The cells of the body are divided into three groups on the basis of their regenerative capacity: 1-Labile cells: These are continuouslydividing (and continuously dying) and include: -The Hematopoietic cells in the bone marrow. -The stratified squamous surfaces of the skin, oral cavity, vagina, and cervix. -The cuboidal epithelia of the ducts draining exocrine organs (e.g., salivary glands, pancreas, biliary tract). -The columnar epithelium of the gastrointestinal tract, uterus, and fallopian tubes. -The transitional epithelium of the urinary tract. 2-Stable cells:quiescent in their normal state, but are capable of undergoing rapid division in response to injury. These include: -The parenchyma of most solid glandular tissues, including liver, kidney, and pancreas. -The Endothelial cells lining blood vessels, and the fibroblast and smooth muscle connective tissue (mesenchymal) cells. 3-Permanent cells: Terminally differentiated and nonproliferative in postnatal life. The majority of neurons and cardiac muscle cells belong to this category.
Extracellular signaling via soluble mediators occurs in four different forms: 1-Autocrine signaling, in which a soluble mediator acts the cell that secretes it. This pathway is important in the immune response (cytokines) and in compensatory epithelial hyperplasia (e.g., liver regeneration). 2-Paracrine signaling: mediators affect cells only in the immediate vicinity. This pathway is important for recruiting inflammatory cells to the site of infection and for the controlled process of wound healing. 3-Synaptic: activated neural tissue secretes neurotransmitters at a specialized cell junction (synapse) onto target cells such as other nerves or muscle. 4-Endocrine, in which a regulatory substance, such as a hormone, is released into the bloodstream and acts on target cells at a distance.
General components of repair process: -Formation of new blood vessels (angiogenesis). -Migration and proliferation of fibroblasts. -Deposition of ECM. -Maturation and reorganization of the fibrous tissue (remodeling). Blood vessels are assembled by two processes: -Vasculogenesis: in embryonic development occure by angioblasts (endothelial cell precursors). -Angiogenesis (neovascularization) by which preexisting vessels send out capillary sprouts to produce new vessels. Four general steps occur in the development of a new capillary vessel: -Proteolytic degradation of the parent vessel BM to form of a capillary sprout. -Migration of endothelial cells from the original capillary toward an angiogenic stimulus. -Proliferation of the endothelial cells. -Maturation of endothelial: this includes recruitment and proliferation of pericytes (for capillaries) and smooth muscle cells (for larger vessels) to support the endothelial tube and provide accessory functions.
Fibrosis (Scar Formation) Fibrosis, or scar formation, builds on the granulation tissue framework of new vessels and loose ECM that develop early at the repair site. The process of fibrosis occurs in two steps: (1) Emigration and proliferation of fibroblasts into the site of injury. (2) Deposition of ECM by these cells. The recruitment and stimulation of fibroblasts is driven by many of the growth factors, including platelet-derived growth factor (PDGF), FGF, and TGF- . The main source of these factores are activated Endothelium and Macrophages. Scar Remodeling Shifts in the composition of the ECM; even after its synthesis and deposition, scar ECM continues to be modified and remodeled. Degradation of collagens and other ECM components performed by metalloproteinases (zinc ions for their activity). These enzymes are produced by (fibroblasts, macrophages, neutrophils,synovial cells, and some epithelial cells)
Angiogenesis resulting from, A, the mobilization of bone marrow endothelial precursor cells (EPCs), and, B, from preexisting vessels at the site of injury. EPCs can be mobilized from the bone marrow and migrate to a site of injury and differentiate and form a mature network by linking with preexisting vessels. Endothelial cells from preexisting vessels become motile and proliferate to form capillary sprouts. Regardless of the mechanism of angiogenesis, vessel maturation requires the recruitment of pericytes and smooth muscle cells to form the periendothelial layer.
Phases Wound healing: include: 1-Inflammatory phase by the initial injury. (First 48 hours- 6 days). 2-proliferative phase (7 days to 6 weeks): -Parenchymal cell regeneration (where possible). -Migration and proliferation of both parenchymal and connective tissue cells -Synthesis of ECM proteins. 3-Remodeling phase (Maturation phase) (Day 8 through years). -For parenchymal elements to restore tissue function. -For connective tissue to achieve wound strength. Types of healing: 1-Healing by First Intention Healing of a clean, uninfectedsurgical incision approximated by surgical sutures. This is referred to as primary union, or healing by first intention. -Causes only focal disruption of epithelial basement membrane. -Death of a relatively few epithelial and connective tissue cells. -Epithelial regeneration.
Wounds during inflammatory Phase
Healing by Second Intention When cell or tissue loss is more extensive, as in infarction, inflammatory ulceration, abscess formation, or even just large wounds. -Regeneration of parenchymal cells alone cannot restore the original architecture. -Extensive ingrowth of granulation tissue from the wound margin, -Accumulation of ECM and scarring. This form of healing is referred to as secondary union, or healing by second intention. Secondary healing differs from primary healing in several respects: 1-Large tissue defects intrinsically have a greater volume of necrotic debris, exudate, and fibrin that must be removed. 2-Much larger amounts of granulation tissue are formed. 3-Secondary healing exhibits wound (contraction): Within 6 weeks, large skin defects may be reduced to 5% to 10% of their original size, largely by contraction. This may due to modified of fibroblasts to contractiblemyofibroblasts. -The accumulation of exuberant amounts of collagen can give rise to prominent, raised scars known as keloids.
Steps in wound healing by first intention (left) and second intention (right). In the latter, note the large amount of granulation tissue and wound contraction.
Secondary Wound Healing Wound contraction
Healing of skin ulcers. A, Pressure ulcer of the skin, commonly found in diabetic patients. B, A skin ulcer with a large gap between the edges of the lesion. C, A thin layer of epidermal re-epithelialization, and extensive granulation tissue formation in the dermis. D, Continuing re-epithelialization of the epidermis and wound contraction.
Keloid. A, Excess collagen deposition in the skin forming a raised scar known as a keloid. B, Thick connective tissue deposition in the dermis.
Keloid Scar Keloid
