2. •Regeneration
to replace the damaged components and return
to a normal state
•Healing : if the supporting structures of
the tissue are severely damaged, repair
occurs by laying down of connective
(fibrous) tissue lead to scar formation.
•fibrosis: extensive deposition of collagen that
occurs in the lungs , liver , kidney, and other
organs as a consequence of chronic inflammation
3.
4.
5. The cell cycle
•G1: the presynthetic growth phase1
•S: the DN synthesis phase .
•G2: the premitotic growth phase 2
•M: the mitotic phase.
•* Non-dividing cells are either in cell cycle
arrest in G1 or they exit the cycle to enter
phase called Go.
6. •* Checkpoint controls: prevent DNA
replication or mitosis of damaged cells
•-stop the cell cycle to allow for DNA repair
•-eliminate irreversibly damaged cells by
apoptosis.
•* cyclin-dependent kinases (CDKs) :
promoting DNA replication and various aspects of
the mitotic process and are required for cell cycle
progression
•-CDKs are suppressed during G1
7.
8. Proliferative Capacities of Tissues
•Labile cells (continuously dividing & continuously dying)
-Stem cells divide: self renewal and differentiation
•-Examples:
-Skin epidermis
•-GIT epithelium
•-Bone marrow cells
• Stable cells (cell are quiescent in the G1 stage)
-capable to proliferate in response to injury
•-Examples:
•-parenchymaofmostsolidtissue(Liver,
kidney and pancreas )
•-endothelialcell,fibroblastandSmooth
muscles.
10. Stem cells
•Self renewal capacity
••Asymmetric replication
••Capacity to develop into multiple lineages
••Extensive proliferative potential
•-Embryonic stem cells: Pluripotent cells that can
give rise to all tissues of the body
•-Adult stem cells: tissue stem cells
•*stem cells capable of regenerating multiple cell
lineage.
11. Examples of Adult Stem Cells
•Bone marrow Hematopoietic stem
cells
•Liver Hering canal
•Skeletal muscle Satellite cells
•Intestine Base of crypts
•Skin Hair follicle bulge
14. Growth factors
•proteins that affect cell growth by binding to
specific receptors on the cell surface or
intracellularly . They are the most important
mediators affecting cell growth
•have pleiotropic effects; proliferation, cell
migration, differentiation, tissue remodeling
•Regulate growth of cells by controlling expression
of genes that regulate cell proliferation (proto-
oncogenes)
*mutation in this genes lead to cancer
•growth factor have opposite effects on the same
cell depending on its concentration.
15.
16. Signaling mechanisms of growth
factor receptors
•1-Autocaine signaling : acts on the cell that
secretes it.
2-Paracaine signaling: affects cells in the immediate
vicinity of the cell that released the agent. This
pathway is important for recruiting inflammatory
cells to the site of infection and for wound
healing.
•3-Endocrine signaling: a regulatory sub-stance,
such as a hormone, is released into the blood-
stream and acts on target cells at a distance.
17.
18. Type of receptors:
•There are three type of growth factor receptor:
•1-: receptors with tyrosine kinase activity:
•These are usually dimeric transmembrane molecules with an
extracellular ligand-binding domain;
•
•-Growth factors such as epidermal growth factor (EGF) and
hepatocyte growth factor (HGF) bind to receptors with
intrinsic kinase activity phosphorylating events through
MAP kinases, transcription factor activation and DNA
replication
19. •2- G-protein—coupled receptors
•. -These receptor contain seven transmembrane
a-helix segments.
•*after ligand binding receptor binding with
G protein exchange of GDP to GTP
activation of (cAMP) and (IP3)
•*this receptors constitute the largest family of
plasma membrane receptors and include those
for epinephrine, vasopressin, serotonin,
histamine, and glucagon, as well as the
chemokines
20. 3-Receptors without intrinsic
enzymatic activity
•These are usually monomeric transmembrane
molecules with an extracellular ligand-binding
domain.
•ligand interaction induces an intracellular
conformational change that allows association
with intracellular protein kinases called Janus
kinases (JAKs)
•. Ligands for these receptors include many
cytokines, the interferon's, colony-stimulating
factors, growth hormone, and erythropoietin.
21.
22. EXTRACELLULAR MATRIX (ECM) AND
CELL-MATRIX INTERACTIONS
•- ECM regulates the proliferation, movement,
and
differentiation of the cells living within it.
• An intact ECM is required for tissue
regeneration, and if the ECM is damaged,
repair can only be accomplished by scar
formation.
23. -have to basic forms:
1-Interstitial Matrix: present in the spaces
between cells in connective tissue, and between
epithelium and supportive vascular and smooth
muscle structures.
- it is synthesized by mesenchymal cells (e.g.,
fibroblasts)
-Its contains:
*fibrillar and nonfibrillar collagens
*fibronectin
*elastin
*proteoglycans
*hyaluronate.
24. 2-Basement Membrane: random array of
interstitial matrix in connective tissues
becomes highly organized around epithelial
cells, endothelial cells, and smooth muscle
cells.
-It contains:
•Type IV collagen
•Adhesive glycoproteins
•Laminin
•.
25. Roles of the Extracellular Matrix
•• Mechanical support for cells and cell
migration
•• Control of cell growth
•• Maintenance of cell differentiation
• Scaffolding for tissue renewal: injury to the
tissues results in restitution of the normal
structure only if the ECM is not damaged.
Disruption of these structures leads to
collagen deposition and scar formation.
26. •• Establishment of tissue
microenvironments. Basement membrane
acts as a boundary between epithelium and
underlying connective tissue.
•. • Storage and presentation of regulatory
molecules. For example, growth factors like
FGF and HGF are excreted and stored in the
ECM in some tissues.
27. Components of the Extracellular
Matrix
•(1) fibrous structural proteins such as
collagens and elastins, which confer tensile
strength and recoil
•(2) water-hydrated gels such as
proteoglycans and hyaluronan, which permit
resilience and lubrication
•(3) adhesive glycoproteins that connect the
matrix elements to one another and to cells
28.
29. collagen
•• The most common protein in animals
•• are composed of three separate polypeptide
chains with triple helix
••Fibrillar & nonfibrillar
••Hydroxylation, mediated by vit C, provides
strength
••Fibrillar collagens form most of CT in wounds &
scars
••Non-fibrillar (type IV) main component of BM
30. elastin
-Provides elasticity
-Its important in large vessels, uterus, skin, and
ligaments.
Proteoglycans and Hyaluronan:
-provide resilience and lubrication (such as in
the cartilage in joints)
-serve as reservoirs for growth factors secreted
into the ECM (e.g., FGF and HGF).
31. .4-Adhesive Glycoproteins and
Adhesion Receptors:
Involve in cell-to-cell adhesion, the linkage between cells
and ECM, and binding between ECM components.
The adhesive glycoproteins:
1-fibronectin (major component of the interstitial
ECM), synthesized by a variety of cells, including
fibroblasts, monocytes, and endothelium.
*Tissue fibronectin forms fibrillar aggregates at wound
healing sites.
*plasma fibronectin binds to fibrin to form the
provisional blood clot of a wound,
32. •2- laminin (major component of basement
membrane).
is the most abundant glycoprotein in basement
membrane, its connects cells to collagen and
heparan sulfate.
33. Adhesion Receptors
•Intergins:
main cellular receptors for ECM components,
such fibronectins and laminins,
Example:
itergrins as leukocyte surface molecules that
mediate firm adhesion and transmigration
across endothelium at sit of inflammation.
34. Cell and tissue regeneration
•Replacing injured tissue by same type of original tissue
cells.
••Labile & stable cells
••Involves two tissue components:
••Cellular proliferation, regulated by growth factors &
growth inhibitors.
••Extracellular matrix (ECM) & cell-matrix interaction
••An intact basement membrane directs epithelial cell
polarity & is essential for its orderly regeneration
•
35. Repair by connective tissue
•*If tissue injury is severe or chronic, and
results in damage to parenchymal cells and
epithelia as well as the stroma framework, or
if nondividing cells are injured, repair cannot
be accomplished by regeneration alone. In
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.
36. *With in 24 hours emigration of
fibroblasts and the induction of fibroblast
and endothelial cell proliferation.
*By 3 to 5 days granulation tissue( pink
,soft , granular gross appearance ) with
proliferation of fibroblast and new thin-
walled capillaries in a loose ECM.
* Then granulation tissue accumulate
connective tissue matrix result in a scar
formation.
37.
38. Repair by connective tissue deposition
consists of four sequential processes:
• Formation of new blood vessels
(angiogenesis)
• Migration and proliferation of fibroblasts
• Deposition of ECM (scar formation)
• Maturation and reorganization of the
fibrous tissue (remodeling)
40. Growth factor involve in angiogenesis
-VEGF effect on endothelial cells :
migration
proliferation
differentiation
permeability
-Angiopoietins 1 and 2 ,PDGF and TGF-B
stabilize the newly formed vessels.
41. Angiogenesis from endothelial
precursor cells(EPCs)
•-hematopoietic stem cells and angioblasts
(EPCs)
•-are stored in bone marrow
•-migrate from the bone marrow to areas of
injury and participate in angiogenesis at these
sites.
•-(EPCs) play a role in neovascularization ,
replacement of endothelial cells ,
re-endothelialization of vascular implants.
42.
43. Angiogenesis from pre-existing
vessels
•-a parent vessel sends out capillary sprouts to produce
new vessels.
•-steps involved:
•1-vasodilation in response in nitric oxide __increase
permeability of the pre-existing vessel .
•2-migeration of endothelial cells toward the area of
tissue injury
•3-Proliferation of endothelial cells
•4-Inhibition of endothelial cell proliferation and
remodeling into capillary tubes.
•5- Recruitment of periendothelial cells to form the
mature vessel
•
44.
45. Emigration and proliferation of
fibroblasts
•Growth factors: PDGF, FGF, EGF, TGF-b
Deposition of ECM
•Growth factors: PDGF, FGF, TGF-b and cytokines
(IL-1 &TNF)
46. ECM and tissue remodeling
•Shift and change of the composition of the ECM of the
scar as a result of synthesis and degradation
•Metalloproteinases: Enzymes produced by many
cells and capable of degrading different ECM
constituents
•Interstitial collagenases
•Gelatinases
•Stromelysins
•Metalloproteinases (Zn dependent) activated by
proteases (plasmin). Inactivated by tissue inhibitors of
metalloproteinases (TIMP) and steroids.
47. Cutaneous wound healing
Has three man phases:
1. inflammation
2. formation of granulation tissue
3. ECM deposition and remodeling
Based on the nature of the wound, the
healing can be by:
1. first intention
2. second intention
48. Healing by First intention:
•like in the healing of a clean , uninfected
surgical incision approximated by surgical
sutures.
* in this type epithelial regeneration
predominant over fibrosis , a small scar is
formed but there is minimal wound
contraction.
49. ** Within 24 hours , neutrophils are seen at the
incision margin migrating toward the fibrin clot.
** Within 24-48 hours, epithelial cells from the
edges have begun to migrate and proliferate
along the dermis, yielding a thin continuous
epithelial layer.
**By day 3 , neutrophil have been replaced by
macrophages and granulation tissue invade in
incision space , and fibers are predominant at the
incision's margins but don’t bridge the incision ,
epithelial proliferate more forming a thick
epidermal layer.
50. •**By day 5, neovascularization reaches it peak as
granulation tissue fill the incision space , more
collagen are formed and begin to bridge the
incision . Differentiation of surface cells yields a
mature epidermal architecture with surface
keratinization.
•**During the 2nd week , more collagen and
fibroblast are formed. The leukocyte infiltrate,
edema and increased vascularity are substantially
diminished. The long blanching begins by
increase collagen deposition and regression of
vascularity.
•**By the end of 1st month, the scar are devoid of
inflammatory cells and are covered by normal
epidermis.
51.
52. Healing by second intention
•Such as in large wounds, abscess formation,
ulceration, after infarction in parenchymal organs.
•*Secondary healing differs from primary healing
in several respects:
•1. a larger clot rich in fibrin or fibronectin forms at
the surface of the wound.
•2. inflammation is more intense
•3. much larger amounts of granulation tissue are
formed, results in greater amount of scar tissue.
•4. secondary healing involves wound contraction (
due to presence of myofibroblasts.
53. Wound strength
•carefully sutured wound have 70% of the
strength of unwounded skin.
•When sutures are removed at 1 week, wound
strength is approximately 10% of that of
unwounded skin.
•Wound strength reaches proximately 70-80%
of normal by 3 months but usually doesn’t
improved beyond that point.
54. Pathologic aspects of repair
•Multiple variables might affect wound healing, like:
•**infection: the most important cause of delay in
healing
•.** nutrition: protein deficiency and vitamin C
deficiency inhibit collagen synthesis and retard healing.
•**Glucocorticoids ( steroids) have well documented
anti-inflammatory effect. And their administration
result in poor wound strength due to diminished
fibrosis.
•** mechanical variables such as increased local
pressure and torsion may cause wounds to pull apart .
•**poor perfusion due to arteriosclerosis, diabetes, or
obstructed venous drainage impairs healing
55. •**foreign bodies such as fragments of steel,
glass, or bones impede healing.
•**the type and volume of tissue injured are
critical, complete restoration occurs only in
stable and labile cells. Injury to the tissues
composed of permanent cells must inevitably
result in scarring.
•**the location of injury and the character of
injured tissues are also important.( e.g
inflammation in pleural and synovial cavities
develops extensive exudate) .
56. •**Keloids : prominent, raised scars , more
common in blacks ,result from accumulation
of exuberant amount of collagen .
•Exuberant granulation ( proud flesh ) :
excessive granulation tissue that protrudes
above the level of surrounding skin and
hinders Re-epithelization. The treatment is by
cautery or surgical resection of granulation
tissue.
