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Tissue renewal and repairregeneration, healing, and fibrosis
C.Murtono
Dept.Pathological Anatomy
Medical Faculty UNIKA Atma Jaya
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Regeneration - healing
Regeneration: growth of cells to replace lost
structure. Tissue scaffold intact
Healing: Tissue response to wound, inflammatory
process, or to cell necrosis. Tissue scaffold
damaged.
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Control of tissue growth
Cell population determined by
- proliferation
myocytes, neuron is terminal (permanent)
hepatocytes if needed (stable tissue)
epithelial cell, always new (labile)
- differentiation-death by apoptosis
stimulated by physiologic, pathologic condition
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Stem cells
Characterized by prolonged self renewal
capacity and by asymmetric replication ( in every
cell division, one of the cells retains its self-
renewing capacity while the others enters adifferentiation pathway and converted to a mature
population)
1. first identified: embryonic stem cells(pluripotential cells)
2.adult stem cells
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Embryonic stem cells
Embryo contain pluripotent ES which can rise to
all tisue of human bodies . Can be isolated from
blastocyst (32 cell group)
ES cells be used to repopulate damaged organ
such as myocard after infarct.
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Adult stem cells
Many tisue in adult contain reservoir of stem cells
Not pluripotent, restricted differentiation
If located outside bone marrow: tissue stem cells
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Location of diverse tissue stem
cells
Epidermal stem cell: in the bulge of hair foll
Intestinal stem cells: at the base of colon crypt,
above Paneth cell
Liver stem cells (oval cells): in canal of Hering(connected the bile duct and parenchym cells)
Corneal stem cells: in limbus (between cornea andconjunctiva)
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Role of stem cells in tissue
homeostasis (I)
Liver: liver stem cells functions if hepatocyte
proliferation is blocked. After partial hepatectomy
or necrotizing injury, hepatocytes them cells
proliferate and stem cells are not activated.
In fulminant or chronic hepatitis and cirrhosis,
when hepatocytes proliferation is blocked, ovalcells proliferation is prominent
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Role of stem cells in tissue
homeostasis (II)
Skeletal and cardiac muscle: myocytes do not
generate. Regeneration of skelet muscle occur in
the form of proliferation of satellite cells, that
generate differentiated myocytes after injury.
Placed in different environment, satellite cells can
be osteogenic or adipogenic.
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Role of stem cells in tissue homeostasis (III)
Epithelial tissue: intermediate cells are highly
proliferative and terminally differentiated cells do
not divide and continously lost of the surface.
Brain: old dogma that NO neuron are generated
in adult mammals. Neural stem cells found in
olfactory bulb and in dentate gyrus ofhypocampus (protein nest in is the histologic
marker)
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Growth factors (I)
Polypeptide growth factors functions:
stimulates cell proliferation
cell locomotion
differentiation
angiogenesis
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Growth factors (II)EGF (epidermal growth factor) and TGF
alfa (transforming Growth Factor)
EGF: mitogenic for variety of epithelial cell, hepatocytes.Healing wound.
TGF-alfa: involved in proliferation of epithelial cell inembryo and adult and also malignant transformation ofnormal to malignant cells.
Fibroblast GF: angiogenesis, hematopoesis, skeletalmuscle development, wound repair
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Growth factors (III)
HGF(hepatocyte Growth factor): mitogenic effects inmost epithelial cells, incl. Hepatocytes and biliaryepithelium
VEGF (Vascular endothelial GF): potent inducer ofblood vessel formation/vasculogenesis and newblood vessel (angiogenesis)
Platelet Derived GF: migration and proliferation offibroblast, macrophages, and monocytes
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Growth factors (IV): TGF beta
Growth inhibitor for epithelial cell types and
leukocytes.
In mesenchymal cell: generally proliferation for
fibroblast and smooth muscle cell.
Potent fibrogenic
Strong anti inflammatory effect
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Signaling mechanisms in cell
growth
First: binding of signaling molecule (ligand) to cell
receptors
Based on the source of ligand and the location of
its receptor (same, adjacent, or distant cells)there are three modes of signaling: autocrine,
paracrine, and endocrine.
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Autocrine signaling
Cell respond to the signaling molecules that
themselves secrete
For examples: - liver regeneration
- proliferation of antigen-
stimulated
lymphocytes
Tumour frequently overproduces GFs and their
receptors
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Autocrine signaling
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Paracrine signaling
One cell type produce the ligand which then acts
on adjacent target cells that express the
appropriate receptors.
Common in wound healing. Factor produced by
one cell type (eg macrophage)has growth effects
on adjacent cell (*eg.fibroblast)
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Paracrine signaling
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Endocrine signaling
Hormone ia synthesized by cells of endocrine
organ and act on the target cells distant of their
sites of synthesis.
GF, eg HGF may also circulate and acts on distant
sites.
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Endocrine signaling
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Extra cellular matrix (ECM)
Macromolecule outside cells
1. fibrous structural protein
collagen, elastine
2. adhesive glycoprotein
3. proteoglycans, hyaluronic acid
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Cell adhesion molecule
(CAM) Several adhesion molecules play in part of
leucocytes migration, homing, and cell to cell
interaction.
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Repair by healing, scar formation and
fibrosis
Induction of inflammatory process
Proliferation and migration of parenchym and
connective tissue cell
Angiogenesis
Synthesis of ECM protein
Tissue remodelling
Wound contraction
Acquisition of of wound strength
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Factors that influences the repair
reaction
Tissue environment and extent of tissue damage
The intensity and duration of the stimulus
Condition that inhibit repair, as foreign body
Various diseases that inhibit repair
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Angiogenesis
In embryo: vasculogenesis, formed by endothelial
precursor cells (EPCs, angioblast)
In adult: angiogenesis (neovascularization):
-branching of adjacent blood vessel
-recruitment of angioblast from bone marrow
Critical for:-chronic inflammation
-tumour growth
-vascularization of ischaemic tissue
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Angiogenesis from Endothelial
Progenitor Cells.
Closely related with embryonal development.
2 systems: -hemangioblast, generate
hematopoetic stem cells
-angioblast proliferate, migrate to
peripher, and differentiate to endothelial cells
EPCs are stored in bone marrow and partisipate
in replacement of endothel, neovascularization of
ischemic organ.
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Angiogenesis from pre existing
vessel.
Vasodilatation and increased permeability ofvessel, degradation of ECM, migration ofendothel.
Vasodilatation in response to nitric oxide Degradation of BM by MMP
Migration of endothel by angiogenic stimulus
Proliferation and maturation of endothel Recruitment of pericytes and smooth muscle
cells
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Which GFs involved
VEGF, stimulates the mobilization of ECP from bonemarrow. Proliferation and differentiation in the site ofangiogenesis
PDGF, TGF-beta:stabilize the new vessel viaformation of ECM
cytokines
Hypoxia.
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Scar formation (I)
Fibroblast emigration and proliferation, which is
triggered by GFs TGF-beta, PDGF, FGF, EGF,
cytokines IL-1 and TNF.The source of this GFs is
inflammatory cells.
Incresed synthesis of collagen, decreased of
ECM by MMP.
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Cutaneous wound healing
3 phases: - inflamation
-granulation tissue
-wound contraction
2 types: healing by first intention, in uninfected
surgical wound
healing by second intention
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Process of wound healing
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