k7- poliferasi

8/13/2019 K7- Poliferasi

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Prol i ferat ion

Differentiat ion

Control of Normal Cell Proliferation

and Differentiation

Histology Department

Medical Faculty - University of Sumatera Utara


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Introduction

Cell proliferation

and differentiationare controlled atmultiple levels

Cell fate control is

key to tissueformation duringdevelopment, andits deregulation

results indevelopmentaldefects or intumorigenesis


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The four essential processes by which

a multicellular organism is made :

Cell proliferation

Cell specialization

Cell interaction

Cell movement


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As a cell differentiates, it becomes smaller, loses its

ability to proliferate, and focuses its energy instead

on performing its function

Prol i ferat ionis the

production of many

cells from a single cell

through repeatedmitosis of daughter

cells.

In general, the more

immature a cell is, thebigger it is and the

greater its ability to

proliferate.

Differentiat ionis the

process of cell

maturation.

Through differentiation,cells acquire their

ultimate functions and

the protein

characteristics requiredto perform those

functions


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Cell Proliferation


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regulation of cell

proliferation is maintainedunder strict physiologic

control. Cell proliferation is

typically initiated by theaction of growth factors.


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TISSUE-PROLIFERATIVE

ACTIVITY The cell cycle consists of :

G1(presynthetic),

S(DNA synthesis),

G2(premitotic),

M(mitotic) phases. The tissues of the body are divided into three groups on

the basis of their proliferative activity

cont inuous ly

d iv id ingt issues=

labi letissues,

cells proliferate

throughout life

Quiescent= stable, tissues

normally have a low level ofreplication; however, cells

from these tissues can

undergo rapid division in

response to stimuli and are

thus capable of reconstitutingthe tissue of origin

Nondiv id ing

=permanentt issues,contain

cells that have left

the cell cycle and

cannot undergo

mitotic division inpostnatal life


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Con t inuously div id ing t issues

(labi letissues) Cells proliferate throughout life, replacing those that are

destroyed.

These tissues include : surface epithelia, such as stratified squamous surfaces of the skin, oral

cavity, vagina, and cervix; the lining mucosa of all the excretory ducts of the glandsof the body

(e.g., salivary glands, pancreas, biliary tract);

the columnar epitheliumof the gastrointestinal tract and uterus;

the transitional epitheliumof the urinary tract,

cells of the bone marrow and hematopoietic tissues. In most of these tissues, mature cells are derived from stem

cells,which have an unlimited capacity to proliferate and whoseprogeny may undergo various streams of differentiation

Q i ( bl i )


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Quiescent(stable tissues) Normally have a low level of replication; however, cells from

these tissues can undergo rapid division in response to stimuli

and are thus capable of reconstituting the tissue of origin. They are considered to be in the G0 stage of the cell cycle butcan be stimulated to enter G1.

In this category are the parenchymal cells of liver, kidneys, and pancreas;

mesenchymal cells, such as fibroblasts and smooth muscle; vascularendothelial cells;

and resting lymphocytes and other leukocytes.

The regenerative capacity of stable cells is best exemplified bythe ability of the liver to regenerate after partial hepatectomyand after acute chemical injury.

Fibroblasts, endothelial cells, smooth muscle cells,chondrocytes, and osteocytes are quiescent in adult mammalsbut proliferate in response to injury.

Fibroblasts in particular proliferate widely, constituting theconnective tissue res onse to inflammation


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Nond iv id ing (permanent t issues) Contain cells that have left the cell cycle and cannot

undergo mitotic division in postnatal life.

To this group belong neurons,skeletal and cardiac musclecells.

If neuronsin the central nervous system are destroyed, thetissue is generally replaced by the proliferation of the centralnervous system supportive elements, the glial cells.

However, recent results demonstrate that neurogenesis fromstem cells may occur in adult brains

Although mature skeletal muscle cells do not divide, skeletalmusc ledoes have some regenerative capacity, through the

differentiation of the satel l i te cellsthat are attached to theendomysial sheaths.

Cardiac musclehas very limited, if any, regenerative capacity,and a large injury to the heart muscle, as may occur inmyocardial infarction, is followed by scar formation.


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The proliferation of endometrialcells under estrogen stimulationduring the menstrual cycle and

the thyroid-stimulatinghormone-mediated replicationof cells of the thyroid thatenlarges the gland duringpregnancy are examples of

physiologic proliferationCellProlifreration

physiologic

pathologic

Pathologic condition suchas injury, cell death, andmechanical alterations oftissues also stimulate cellproliferation


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Physiologic stimuli may become excessive, creatingpathologic conditions such as nodular prostatic hyperplasiaresulting from dihydrotestosterone stimulation and thedevelopment of nodular goiters in the thyroid as a

consequence of increased serum levels of thyroid-stimulatinghormone.

Cell proliferationis largely controlled by signals(solubleor contact-dependent) from the microenvironment : stimulate

inhibit cell proliferation An excess of stimulators or a deficiency of inhibitors leads to

net growth and, in the case of cancer, uncontrolled growth.

Although accelerated growth can be accomplished byshortening the cell cycle, the most important mechanism of

growth is the conversion of resting or quiescent cells intoproliferating cells by making the cells enter the cell cycle.

Both the recruitment of quiescent cells into the cycle and cell-cycle progression require stimulatory signals to overcome thephysiologic inhibition of cell proliferation.


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M h i


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Mechanisms

regulating cell

populations.

Cell numberscan be altered

by increased or

decreased

rates of stemcell input, by

cell death due

to apoptosis, or

by changes inthe rates of

proliferation or

differentiation.


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Cell Differentiation


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Cellular differentiation is the

process by which an immaturecell becomes a more mature cell

Differentiation changes a cell's

size, shape, membrane potential,

metabolic activity, and

responsiveness to signals orsignal pathways


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The obvious changes of cell behavior that we

see as a multicellular organism develops are the

outward signs of a complex molecularcomputation, dependent on cell memory, that

is taking place inside the cells as they receive

and process signals from their neighbours and

emit signals in return. The final pattern of differentiated cell typesis

cell specializationa program played out in the

changing patterns of expression of gene

regulatory proteins, giving one cell different

potentialities from another long before terminal

differentiation begins. .


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The mechanism by which cells in a multicellularorganism become specialized to performspecific functions in a variety of tissues and

organs. Specialized cells are the product of

differentiation.

The process can be understood only from ahistorical perspective, and the best place tostart is the fertilized egg.

Different kinds of cell behavior can be observedduring embryogenesis: cells double, change inshape, and attach at and migrate to varioussites within the embryo without any obvious

signs of differentiation.


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Embriogenesis


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Th t bl diff ti t d t t i


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The stable differentiated state is a consequence

of multicellularity.

A complex organism maintains its characteristic

form and identity because populations of

specialized cell types remain assembled in a

certain pattern.

Thus several kinds of cells make up a tissue,

and different tissues build organs.

The variable assortment of about 200 cell types

allows for an almost infinite variety of distinctorganisms.


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Cell Differentiated

Stabel Stage

Cell Cell Cell Cell Cell Cell

Tissue Tissue Tissue

Organ Organ Organ

Note : The variable assortment of about 200 cell types

allows for an almost infinite variety of distinct organisms


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Epithelia, sheets of cells of specificstructure and function, cover the outer

surface of the vertebrate body and line thelungs, gut, and vascular system.

The stable form of a vertebrate is due toits rigid skeleton built from bone andcartilage, forming cells to which theskeletal muscles adhere.

All other organs, such as liver and

pancreas, are embedded in connectivetissue that is derived from fibroblast cellswhich secrete large amounts of soft matrixmaterial


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The renewal of terminally differentiated cellsthat are unable to divideanymore, such as skinand blood cells, is carried out by stem cells.

Stem Cell is immortal and choose, as they double,whether to remain a stem cell or to embark on apath of terminal differentiation.

Most stem cells are unipotentbecause they giverise to a single differentiated cell type.

However, all cell types of the bloodare derivedfrom a single blood-forming stem cell, a pluripotentstem cell.

A fertilized eggis atotipotentstem cell giving riseto all other cell types that make up an individualorganism


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C ll diff ti ti i lti ll l


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Cell differentiation occurs in multicellular

organisms

Normal Cells


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Normal Cells

Controlled growth

Contact inhibition One organized layer

Differentiated cells

Failure of ell ycle ontrolCancer Cells

Uncontrolled growth

No contact inhibition

Disorganized,multilayered

Non-differentiated cells

Abnormal nuclei


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Stem cells were first identified as pluripotent cells in


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Stem cells were first identified as pluripotent cells inembryos, and these were called embryon ic stem cel ls. It isnow clear that stem cells are also present in many tissues inadult animals and contribute to the maintenance of tissue

homeostasis. In recent years, much effort has been devoted to the isolationand phenotypic characterization of stem cells.

Among these are: the identification of stem cells and theirniches in various tissues, including the brain, which has been

considered a permanent quiescent organ the recognition that stem cells from various tissues and

particularly from the bone marrow may have broaddevelopmental plasticity

The enthusiasm about stem cell research derives both fromdata that challenge well-established biological concepts andfrom the hope that stem cells may one day be used to repairinjury in human tissues, including heart, brain, and skeletalmuscle.


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Embryonic Stem Cells (ES)

Embryos contain pluripotent ES cells, which can give rise toall the tissues of the human body.

Such cells can be isolated from normal blastocysts, thestructures formed at about the 32-cell stage during

embryonic development. ES cells can be maintained in culture as undifferentiated celllines or induced to differentiate into many different lineages.

The pluripotency of ES cells may be related to theexpression of unique transcription factors in these cells,

such as a recently described homeobox protein calledNanog (named after Tir na n'Og, the Celtic land of theever-young).

Recent studies also implicate the Wnt--catenin signalingin maintaining pluripotency.


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ES cells may, in the future, be used torepopulate damaged organs, such as the liverafter hepatocyte necrosis and the myocardium

after infarction. The generation of some specific cell types from

cultured ES cells has already been achieved.

Insulin-producing pancreatic cells and nervecells produced in these cultures have beenimplanted, respectively, in diabetic animals andin mice with neurologic defects.

Although the effectiveness of these proceduresfor human diseases is still unknown, there is anintense debate about the ethical issuesassociated with this type of therapy, which isknown as therapeutic cloning.


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Adult Stem Cells

Many tissues in adult animals have been shownto contain reservoirs of stem cells, which arecalled adult stem cells.

Compared to ES cells, which are pluripotent,adult stem cells have a more restricteddifferentiation capacityand are usuallylineage-specific.

However, stem cell research may have come fullcircle, as stem cells with broad differentiation

potential appear to exist in adult bone marrowand, perhaps, in other tissues as well.

Stem cells located outside of the bonemarrow as generally referred to as t issue

stem cel ls.


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Stem-cell niches in various tissues

1. Epidermal stem cells located in the bulge area

of the hair follicleserve as a stem cells for the hairfollicle and the epidermis.

2. Intestinal stem cells are located at the base of acolon crypt, above Paneth cells.

3. Liver stem cells (commonly known as ovalcells) are located in the canals of Hering ( thickarrow),structures that connect bile ductules (thinarrow)with parenchymal hepatocytes (bile duct andHering canals are stained for cytokeratin ;

4. Corneal stem cells are located in the limbusregion, between the conjunctiva and thecornea. courtesy of Tania Roskams, M.D.,University of Leuven). (Courtesy of T-T Sun, New

York University, New York, NY.)


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Mesenchymal Stem Cell


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GROWTH FACTORS

There is a large number of known polypeptide

growth factors :

some of which act on many cell types

others have restricted cellular targets

In addition to stimulating cell proliferation,

growth factors may also have effects on cell

locomotion, contractility, differentiation, and

angiogenesis, activities that may be asimportant as their growth-promoting effects.

Here we review only those that have major

roles in these processes.


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Epidermal Growth Factor (EGF) and


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Epidermal Growth Factor (EGF) and

Transforming Growth Factor- (TGF-)

These two factors belong to the EGF family and share a common receptor. EGFis mitogenic for a variety of epithelial cells, hepatocytes, andfibroblasts.

It is widely distributed in tissue secretions and fluids, such as sweat,saliva, urine, and intestinal contents. In healing wounds of the skin,

EGF is produced by keratinocytes, macrophages, and other

inflammatory cellsthat migrate into the area. EGF binds to a receptor (EGFR) with intrinsic tyrosine kinase activity,

triggering the signal transduction.

TGF- was originally extracted from sarcoma virus-transformed cellsand is involved in epithelial cell proliferation in embryos and adults andmalignant transformation of normal cells to cancer.

TGF- has homology with EGF, binds to EGFR, and produces most of thebiologic activities of EGF.

The "EGF receptor" is actually a family of membrane tyrosine kinasereceptors that respond to EGF, TGF-, and other ligands of the EGF family.

The main EGFR is referred to as EGFR1, or ERB B1. The ERB B2 receptor(also known as HER-2/Neu) has received great attention because it is

overexpressed in breast cancers and is a therapeutic target


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Vascular Endothelial Growth Factor


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Vascular Endothelial Growth Factor

(VEGF)

VEGF is a family of peptides that includes VEGF-A(referred throughoutas VEGF), VEGF-B, VEGF-C, VEGF-D, and placental growth factor.

VEGF is a potent inducer of blood vessel formation in earlydevelopment (vasculogenesis)and has a central role in the growth of newblood vessels (angiogenesis)in adults.

It promotes angiogenesis in tumors, chronic inflammation, and healing

of wounds. VEGF family members signal through three tyrosine kinase receptors:

VEGFR-1, VEGFR-2, and VEGFR-3. VEGFR-2 is located in endothelialcells and is the main receptor for the vasculogenic and angiogeniceffects of VEGF.

The role of VEGFR-1 is less well understood, but it may facilitate the

mobilization of endothelial stem cells and has a role in inflammation. VEGF-C and VEGF-D bind to VEGFR-3 and act on lymphatic endothelial

cells to induce the production of lymphatic vessels (lymphangiogenesis).VEGF-B binds exclusively to VEGFR-1.

Vascular Endothelial Growth Factor (VEGF)


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Vascular Endothelial Growth Factor (VEGF)

Platelet-Derived Growth Factor


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Platelet-Derived Growth Factor

(PDGF)

PDGF is a family of several closely related proteins, each consisting of twochains designatedAand B.

All three isoforms of PDGF (AA, AB, and BB) are secreted and arebiologically active.

Recently, two new isoformsPDGF-C and PDGF-Dhave been identified.

PDGF isoforms exert their effects by binding to two cell-surface receptors,designated PDGFR and , which have different ligand specificities.

PDGF is stored in platelet granules and is released on plateletactivation.

It can also be produced by a variety of other cells, including activatedmacrophages, endothelial cells, smooth muscle cells, and many tumorcells.

PDGF causes migration and proliferation of fibroblasts, smooth musclecells, and monocytes, as demonstrated by defects in these functions inmice deficient in either the A or the B chain of PDGF.

It also participates in the activation of hepatic stellate cells in the initial stepsof liver fibrosis

Fib bl t G th F t (FGF)


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Fibroblast Growth Factor (FGF)

This is a family of growth factors containing more than 10 members, of which

acidic FGF (aFGF, or FGF-1) and basic FGF (bFGF, or FGF-2) are the bestcharacterized. FGF-1 and FGF-2 are made by a variety of cells. ReleasedFGFs associate with heparan sulfate in the ECM, which can serve as areservoir for storing inactive factors.

FGFs are recognized by a family of cell-surface receptors that have intrinsictyrosine kinase activity.

A large number of functions are attributed to FGFs, including the following: New b lood v essel format ion(angiogenesis):FGF-2, in particular, has the abilityto induce the steps necessary for new blood vessel formation both in vivo and invitro (see below)

Wound repair:FGFs participate in macrophage, fibroblast, and endothelial cellmigration in damaged tissues and migration of epithelium to form new epidermis.

Development:FGFs play a role in skeletal muscle development and in lung

maturation. For example, FGF-6 and its receptor induce myoblast proliferationand suppress myocyte differentiation, providing a supply of proliferatingmyocytes. FGF-2 is also thought to be involved in the generation of angioblastsduring embryogenesis. FGF-1 and FGF-2 are involved in the specification of theliver from endodermal cells.

Hematopoiesis:FGFs have been implicated in the differentiation of specificlineages of blood cells and development of bone marrow stroma.


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C ki


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Cytokines

Cytokines have important functions as

mediators of inflammation and immune

responses.

Some of these proteins can be placed intothe larger functional group of polypeptide

growth factors because they have growth-

promoting activities for a variety of cells.


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refferences

McGraw-Hill Concise Encyclopedia of

Bioscience. 2002 by The McGraw-Hill

Companies, Inc.

2002 by Bruce Alberts, AlexanderJohnson, Julian Lewis, Martin Raff, Keith

Roberts, and Peter Walter


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