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Tissue renewal and repair

regeneration, healing, and fibrosis

C.Murtono Dept.Pathological Anatomy Medical Faculty UNIKA Atma Jaya

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.

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

Stem cells

Characterized by prolonged self renewal capacity and by asymmetric replication ( in every cell division, one of the cells retains its selfrenewing capacity while the others enters a differentiation pathway and converted to a mature population) 1. first identified: embryonic stem cells (pluripotential cells) 2.adult stem cells

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.

Adult stem cells


Many tisue in adult contain reservoir of stem cells
Not pluripotent, restricted differentiation If located outside bone marrow: tissue stem cells

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 and conjunctiva)

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, oval cells proliferation is prominent

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.

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 of hypocampus (protein nest in is the histologic marker)

Growth factors (I)

Polypeptide growth factors functions: stimulates cell proliferation cell locomotion differentiation angiogenesis

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 in embryo and adult and also malignant transformation of normal to malignant cells. Fibroblast GF: angiogenesis, hematopoesis, skeletal muscle development, wound repair

Growth factors (III)

HGF(hepatocyte Growth factor): mitogenic effects in most epithelial cells, incl. Hepatocytes and biliary epithelium VEGF (Vascular endothelial GF): potent inducer of blood vessel formation/vasculogenesis and new blood vessel (angiogenesis)

Platelet Derived GF: migration and proliferation of fibroblast, macrophages, and monocytes

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

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.

Autocrine signaling
Cell respond to the signaling molecules that themselves secrete For examples: - liver regeneration - proliferation of antigenstimulated lymphocytes Tumour frequently overproduces GFs and their receptors

Autocrine signaling

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)

Paracrine signaling

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.

Endocrine signaling

Extra cellular matrix (ECM)

Macromolecule outside cells 1. fibrous structural protein collagen, elastine 2. adhesive glycoprotein 3. proteoglycans, hyaluronic acid

Cell adhesion molecule (CAM)

Several adhesion molecules play in part of leucocytes migration, homing, and cell to cell interaction.

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

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

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

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.

Angiogenesis from pre existing vessel.


Vasodilatation and increased permeability of vessel, degradation of ECM, migration of endothel. 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

Which GFs involved

VEGF, stimulates the mobilization of ECP from bone marrow. Proliferation and differentiation in the site of angiogenesis PDGF, TGF-beta:stabilize the new vessel via formation of ECM cytokines Hypoxia.

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.

Cutaneous wound healing


3 phases: - inflamation -granulation tissue -wound contraction 2 types: healing by first intention, in uninfected surgical wound healing by second intention

Process of wound healing