Gives detailed information on how the wound heals either through scar formation or complete regeneration

1. HEALING & REPAIR
‫الرحيم‬‫الرحمن‬‫هللا‬‫بسم‬
Dr: Omer Eltahir

2. • The inflammatory response sets into motion the process
of repair.
• It occurs by two types :

3. • 1-Regeneration:
• replace the damaged components
• return to a normal state;
2- Healing by fibrosis: scar formation.
• If the injured tissues are: incapable of complete restitution,
• repair occurs by laying down of connective (fibrous) tissue,
• Although the fibrous scar is not normal, it provides enough
structural stability
both regeneration and scar formation
contribute in varying degrees to the
ultimate repair.

4. • Repair involves :
• 1- the proliferation of various
cells, and
• 2- close interactions between
cells and the extracellular
matrix (ECM).

5. 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.

6. 1- THE CONTROL OF
CELL PROLIFERATION

7. • , several cell types proliferate during tissue repair.
• 1- the remnants of the injured tissue
• 2- vascular endothelial cells (to create new vessels
• 3- fibroblasts
• The proliferation of these cell types is
driven by growth factors.
•

8. • labile tissues:
• 1- hematopoietic cells in the bone marrow
• 2- epithelia,
• Stable Tissues
• quiescent
• capable of proliferating in response to injury or loss of tissue mass.
• 1- the parenchyma of most solid tissues, such as liver, kidney, and pancreas.
• 2- endothelial cells, fibroblasts, and smooth muscle cells;
• Permanent Tissues
• neurons and cardiac muscle cells
• Skeletal muscle ???
• repair is dominated by scar formation.

9. • Regeneration of human
liver. Computed
tomography scans of the
donor liver in living-donor
liver transplantation. A,
The liver of the donor
before the operation. Note
the right lobe (outline),
which will be resected and
used as a transplant. B,
Scan of the same liver 1
week after resection of
the right lobe; note the
enlargement of the left
lobe (outline) without
regrowth of the right lobe

10. Stem Cells
• Stem cells are characterized by two important
properties:
1. self-renewal capacity and asymmetric replication.
2. Asymmetric replication of stem cells

11. GROWTH FACTORS
THE NATURE AND MECHANISMS OF ACTION

12. • There is a huge (and ever-increasing) list of known growth
factors.
• growth factors produced by :
• leukocytes
• parenchymal cells .
• the stromal (connective tissue)

13. Growth Factors and Cytokines Involved in Regeneration and Wound Healing
Cytokine Symbol Source Functions
1- Epidermal
growth factor
EGF Activated
macrophages,
salivary glands,
keratinocytes,
and many other
cells
Mitogenic for keratinocytes
and fibroblasts; stimulates
keratinocyte migration and
granulation tissue
formation
2- Transforming
growth factor α
TGF-α Activated
macrophages, T
lymphocytes,
keratinocytes,
and many other
cells
Similar to EGF; stimulates
replication of hepatocytes
and many epithelial cells

14. 3-
Hepatocyte
growth
factor
(scatter
factor)
HGF Mesenchymal
cells
Enhances
proliferation of
epithelial and
endothelial cells, and
of hepatocytes;
increases cell motility
4- Vascular
endothelial
cell growth
factor
(isoforms A,
B, C, D)
VEGF Mesenchymal
cells
Increases vascular
permeability;
mitogenic for
endothelial cells (see
text)

15. 5- Platelet-derived
growth factor
(isoforms A, B, C, D)
PDGF Platelets,
macrophages,
endothelial
cells,
keratinocytes,
smooth
muscle cells
Chemotactic for PMNs, macrophages,
fibroblasts, and smooth muscle cells;
activates PMNs, macrophages, and
fibroblasts; mitogenic for fibroblasts,
endothelial cells, and smooth muscles
cells; stimulates production of MMPs,
fibronectin, and HA; stimulates
angiogenesis and wound remodeling;
regulates integrin expression
6- Fibroblast growth
factor 1 (acidic), -2
(basic), and family
FGF-1,
-2
Macrophages,
mast cells, T
lymphocytes,
endothelial
cells,
fibroblasts,
and many
tissues
Chemotactic for fibroblasts; mitogenic
for fibroblasts and keratinocytes;
stimulates keratinocyte migration,
angiogenesis, wound contraction, and
matrix deposition

16. 7- Transforming
growth factor
β(isoforms 1, 2,
3)
TGF-β Platelets, T
lymphocytes,
macrophages,
endothelial cells,
keratinocytes,
smooth muscle
cells, fibroblasts
Chemotactic for PMNs,
macrophages, lymphocytes,
fibroblasts, and smooth
muscle cells; stimulates
TIMP synthesis,
angiogenesis, and
fibroplasia; inhibits
production of MMPs and
keratinocyte proliferation;
regulates integrin
expression and other
cytokines
8- Keratinocyte
growth factor
(FGF-7)
KGF Fibroblasts Stimulates keratinocyte
migration, proliferation, and
differentiation

17. Patterns of
extracellular
signaling,
demonstrating
autocrine,
paracrine, and
endocrine
signaling

18. EXTRACELLULAR
MATRIX (ECM) AND
CELL-MATRIX
INTERACTIONS

19. ECM occurs in two basic forms: interstitial
matrix and basement membrane
• Interstitial Matrix
• This is present in the spaces between cells
• synthesized by mesenchymal cells (e.g., fibroblasts)
• Its major constituents are :
• fibrillar and nonfibrillar collagens,
• fibronectin,
• elastin,
• proteoglycans,
• hyaluronate, and
• other elements

20. Basement Membrane
• interstitial matrix in connective tissues becomes highly organized
around epithelial cells, endothelial cells, and smooth muscle cells,
forming the specialized basement membrane.
• nonfibrillar type IV collagen and laminin

21. The major components of the extracellular matrix (ECM), including collagens, proteoglycans, and adhesive
glycoproteins. Note that although there are some overlaps in their constituents, basement membrane and
interstitial ECM have different general compositions and architecture. Both epithelial and mesenchymal cells
(e.g., fibroblasts) interact with ECM via integrins. For the sake of simplification, many ECM components have
been left out (e.g., elastin, fibrillin, hyaluronan, syndecan).

22. REPAIR BY
CONNECTIVE
TISSUE

23. • If tissue injury is severe or chronic,
• and results in damage to parenchymal cells
and epithelia as well as the stromal
framework,
• or if nondividing cells are injured,
• replacement of the nonregenerated cells with
connective tissue, or by a combination of
regeneration of some cells and scar
formation.

24. granulation tissue
• within 24 hours of injury :
1. emigration of fibroblasts and
2. fibroblast and endothelial cell proliferation.
• 3 to 5 days:
• granulation tissue, is formed
• pink, soft, granular gross appearance

25. Granulation tissue is characterized by
1. proliferation of fibroblasts
2. (angiogenesis),
3. a loose ECM
4. eventually resulting in the formation of a scar

26. Repair by connective tissue deposition
consists of four sequential processes:
1. Formation of new blood vessels(angiogenesis)
2. Migration and proliferation of fibroblasts
3. Deposition of ECM (scar formation)
4. Maturation and reorganization of the fibrous
tissue (remodeling)

27. 1- Angiogenesis
Neovascularization: vessels send out capillary sprouts to produce
new vessels
steps
1. Vasodilation :nitric oxide
2. increased permeability by (VEGF)
3. Migration of endothelial cells
4. Proliferation of endothelial cells
5. Inhibition of endothelial cell proliferation and remodeling into
capillary tubes
6. Recruitment of periendothelial cells (pericytes for small
capillaries and smooth muscle cells for larger vessels) to form
the mature vessel

28. 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 or
tumor growth. At these sites EPCs differentiate and form a mature network by linking with preexisting vessels. In
angiogenesis from preexisting vessels, endothelial cells from these 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

29. 2- Migration of Fibroblasts and ECM
Deposition (Scar Formation)
• . It occurs in two steps:
• (1) migration and proliferation of fibroblasts into
the site of injury
• (2) deposition of ECM by these cells.
• growth factors, :
• PDGF,
• FGF-2
• TGF-β.

30. 4- Maturation and reorganization of
the fibrous tissue (remodeling)
• Occur by : avascularaization