The regeneration of injured cells and tissues involves cell proliferation, which is driven by growth factors and is critically dependent on the integrity of the extracellular matrix, and by the development of mature cells from stem cells” Regeneration: Returning to normal state Cells having capacity to proliferate E.g., epithelial cells of skin and intestine Liver Scar formation: Incapable of complete restitution Supporting tissue severely injured Fibrosis >> scar formation “ Acellular connective tissue devoid of inflammatory infiltrate covered by intact epithelium is called scar”

1. Wound Healing & Repair

2.  Repair/Healing : restoration of tissue
architecture and function after an injury.
 Repair: parenchymal & connective tissue
 Healing: epithelial tissue.

3. Cell & tissue regeneration
“The regeneration of injured cells and tissues
involves cell proliferation, which is driven by
growth factors and is critically dependent on the
integrity of the extracellular matrix, and by the
development of mature cells from stem cells”

4.  Repair of damaged tissues occurs by two
processes:
 Regeneration, which restores normal cells,
and
 Scarring, the deposition of connective tissue

6.  Regeneration
 Some tissues are able to replace the damaged
components and essentially return to a normal
state; this process is called regeneration.
 Hepatocytes in the liver, epithelia of the skin
and intestines.

7.  Connective tissue deposition (scar
formation).
 If the injured tissues are incapable of
regeneration, or if the supporting structures
of the tissue are too severely damaged, repair
occurs by the laying down of connective
(fibrous) tissue, a process that may result in
scar formation.

9. Tissues of body
 3 types:
Labile tissues
Stable tissues
Permanent tissues

10.  Labile (continuously dividing)
tissues.
 Cells of these tissues are continuously being
lost and replaced by maturation from tissue
stem cells and by proliferation of mature cells.
 Include hematopoietic cells in the bone
marrow,
 Surface epithelia, such as the stratified
squamous epithelia of the skin, oral cavity,
vagina, and cervix

11.  Cuboidal epithelia of the ducts draining
exocrine organs (e.g., salivary glands, pancreas,
biliary tract);
 Columnar epithelium of the gastrointestinal
tract, uterus, and fallopian tubes; and
 Transitional epithelium of the urinary tract.
These tissues can readily regenerate after
injury as long as the pool of stem cells is
preserved.

12.  Stable tissues.
 Cells are quiescent (in the G0 stage of the cell
cycle) and have only minimal proliferative
activity in their normal state.
 However, these cells are capable of dividing in
response to injury or loss of tissue mass.
 Parenchyma of most solid tissues, such as liver,
kidney, and pancreas.

13.  Endothelial cells, fibroblasts, and smooth
muscle cells.
 With the exception of liver, stable tissues
have a limited capacity to regenerate after
injury.

14.  Permanent tissues.
 The cells are considered to be terminally
differentiated and nonproliferative in
postnatal life.
 The majority of neurons and cardiac muscle
cells belong to this category. Thus, injury to
the brain or heart is irreversible and results in
a scar because neurons and cardiac myocytes
cannot regenerate

15.  Skeletal muscle is usually classified as a
permanent tissue, but satellite cells attached
to the endomysial sheath provide some
regenerative capacity for muscle.
 In permanent tissues, repair is typically
dominated by scar formation.

16. Cell signaling
 Damage to neighboring cells and pathogens (danger signals)
 Contact with neighboring cells (gap junction signaling)
 Contact with ECM
 Secreted molecules (growth factors, cytokines, hormones)

17. Extracellular cell-cell signaling
pathways
 Paracrine signaling
 Autocrine signaling
 Synaptic signaling
 Endocrine signaling

18. Receptors
 Intracellular receptors
 Vitamin D & steroids
 Cell surface receptors
 Open ion channels
 GTP binding regulatory protein (G protein)
 Endo or exogenous enzymes (Tyrosine kinase)
 Proteolytic events

19. Signal transduction
pathways

21. Growth Factor & receptors
 Stimulate the activity of genes that are
required for cell growth and cell division
 Promote entry of cells into the cell cycle
 Relieve blocks on cell cycle progression
 Prevent apoptosis
 Enhance biosynthesis of cellular components

24. Extracellular matrix (ECM)
 Two forms:
 Interstitial matrix (fibroblasts)
 Fibrillar and non-fibrillar collagens
 Fibronectin, elastin, proteogylcans, hyaluronate
 Basement membrane

25. ECM components
1. Fibrous structural proteins
 Collagen and Elastin
2. Water hydrated gels:
 Proteoglycans and Hyaluronan
3. Adhesive glycoproteins
 Fibronectin, Laminin, Integrins

27. Interaction of Extracellular Matrix

28.  Mechanical support
 Control of cell proliferation
 Scaffolding for tissue renewal
 Establishment of tissue micro-environment

29. Cell cycle
Maintaining cell population

31. Stem cells
 Self-renewal properties and by their capacity to
generate differentiated cell lineages
 Obligatory asymmetric replication

32. Regenerative
medicine

35. Cell and tissue regeneration

36. Cell & tissue regeneration
“The regeneration of injured cells and tissues
involves cell proliferation, which is driven by growth
factors and is critically dependent on the integrity
of the extracellular matrix, and by the development
of mature cells from stem cells”

37.  Cell proliferation: signals and control mechanisms
 Mechanism of tissue regeneration

38.  Regeneration:
 Returning to normal state
 Cells having capacity to proliferate
 E.g., epithelial cells of skin and intestine
o Liver
 Scar formation:
 Incapable of complete restitution
 Supporting tissue severely injured
 Fibrosis >> scar formation
 “ Acellular connective tissue devoid of inflammatory infiltrate
covered by intact epithelium is called scar”

39. Fibrosis
 Extensive deposition of collagen that occurs in
the lungs, liver, kidney and other organs:
 Chronic inflammation
 Myocardium infarction
 Fibrosis in inflammatory exudate: Organization
 Organizing pneumonia

41. Restoration
 Residual tissue is structurally intact
 Partial surgical resection
 Entire tissue is damaged (infection or
inflammation)
 Incomplete regeneration and scarring

42. Hepatic regeneration

43. Steps in Scar Formation
 Angiogenesis
 Formation of granulation tissue
 Remodeling of connective tissue

45. Angiogenesis
 Formation of new blood vessels
 VEGF causes angiogenesis.
 Increases vascular permeability.

46. Granulation tissue
 Pink, soft, granular gross appearance
Histologically:
Proliferation of fibroblasts and new thin-
walled, delicate capillaries (angiogenesis), in a loose
ECM, often with admixed inflammatory cells, mainly
macrophages

48.  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, the specialized granulation tissue
that is characteristic of healing is apparent.

49. 1
2
3
5
4
Suppression of
proliferation

50. Components of Angiogenesis
 Growth factors:
 VEGF
 FGFs
 Angiopoietins 1 & 2
 PDGF & TGF-β
 Notch Signaling
 ECM proteins
 Enzymes: MMP

51. Deposition of Connective Tissue
(1) Migration and proliferation of fibroblasts into the
site of injury
(2) Deposition of ECM proteins produced by
fibroblasts
(3) TGF-B is the most important cytokine for
synthesis and deposition of connective tissue
protein.

52.  Cells: Macrophages
 Growth factors: PDGF, FGF-2, TGF-β
 Myofibroblasts

53. TGF-β
 Stimulates fibroblast migration and proliferation
 Increased synthesis of collagen and fibronectin
 Decreased degradation of ECM d/t inhibition of
metalloproteinases
 Anti-inflammatory cytokines
 Inhibit lymphocyte proliferation and activity of other
leukocytes

54. Remodeling of Connective tissue
 Outcome of repair process: balance between
synthesis and degradation of ECM proteins
 Matrix metalloproteinases (MMPs)

55. Matrix metalloproteinases (MMPs)
 Produced by:
 Fibroblasts, macrophages, neutrophils, synovial cells & some
epithelial cells
 Interstitial collagenase:
 Cleaves fibrillar collagen
 Gelatinases:
 Degrades amorphous collagen, fibronectin, stromolyseins
 Tissue Inhibitors of metalloproteinases (TIMPs)

56. Factors That Influence Tissue
Repair

57.  Infection
 Diabetes
 Nutritional status
 Glucocorticoids (steroids)
 Mechanical factors

58.  Poor perfusion
 Foreign bodies
 The type and extent of tissue injury
 Location of the injury & character of the tissue

59. Healing of Skin Wounds
 Process that involves both epithelial
regeneration and the formation of connective
tissue scar
 Based on nature and size of the wound:
 Healing by first intention
 Healing by second intention

60. Healing by First Intention
 When the injury involves only the epithelial layer,
the principal mechanism of repair is epithelial
regeneration, also called primary union
 Example:
Clean, uninfected surgical incision
approximated by surgical sutures.

61.  3 interconnected processes:
 Inflammation,
 Cellular proliferation of epithelial and other
cells,
 Maturation of the connective tissue scar

62. Primary union
 Clot followed by scab formation
 Day 1: neutrophils
 Day 2: epithelial cell migration and basement membrane
deposition
 Day 3: macrophages, granulation tissue

63.  Day 5: neovascularization and granulation
tissue, migration of fibroblasts, complete
epithelial restoration
 2nd week: collagen accumulation, fibroblast
proliferation, scar formation begins
 First month: Scar formation, appendages
lost, strength of tissue goes on….
 6 weeks: 5-10 % of tissue strength is
attained
 Max: 70-80 % by end of 3 months

65. Healing by Second Intention
When cell or tissue loss is more extensive, such as in
large wounds, abscesses, ulceration, and ischemic necrosis
(infarction) in parenchymal organs, the repair process
involves a combination of regeneration and scarring.

66. Difference b/t secondary & primary union
Primary union Secondary union
Fibrin clot Less Larger
Exudate & necrotic
debris
Less More
Inflammation Less intense More intense
Granulation tissue Less More
Scar tissue Lesser mass Greater mass
Appendages -- Permanently lost
Wound contraction Absent Present

67. Fibrosis in
parenchymal organs

68. Fibrotic disorders
 Liver cirrhosis
 Systemic sclerosis (scleroderma)
 Fibrosing diseases of the lung
 End-stage kidney disease
 Constrictive pericarditis

69. Complication of wound healing
 Wound dehiscence and ulceration
 Increase abdominal pressure
 Atherosclerotic peripheral vascular disease
 Diabetic peripheral nephropathy
 Hypertrophic scars and keloids
 Keloid: African Americans
 H. scar: thermal and traumatic injury (deep
layers involved)

70.  Exuberant granulation
 Proud flesh
 Desmoid tumour/ aggressive fibromatosis
 Contracture

72. Keloid:
 Wide bands of collagen with large, brightly
eosinophilic, glassy fibers
 Also parallel fibroblasts and myofibroblasts
Hypertrophic scar:
 Replacement of the papillary and reticular
dermis by scar tissue with prominent vertically
oriented blood vessels.

74. Thankyou
Questions??