Cardiac system S.

Dimmeter et al , 2007

. Ischemic necrotic tissue may provide and entry different enviorment to dictated cell fate .,major types of cells to consider to use ofr heart therapy , slkeltal ,myoblast , bone marrow and stem cells from other tissues world . quality of life imparment S.Dimmeter et al , 2007 Ischemic disease , major causes for morbidty and mortality in industrialized

End stage patient snot eligible f or revascularization E.C.Pesen , 2006 stem cell differ in th eri inherent electrophysiologic properties and their ability to couple elecetro mechanically both among themselves and host cardio myocyes . limited clinical data available , futire pre clinical and clinacl studies will determine the most effectiuve safe cell type fro myocardial repair , clinical dignificane of cells(rr,marker,2003) . in aging failig heart a sub poluation of myp ctes undergoes DNA replication and mitosos and another undergoes huper trophy and another cel death , small myocyres are the only myocytes capable of replicating DNA. oxidstive damage ,(d,tosella)

Consequence of aging in caridiac stem cells growth and senescence was evaluated , gene products implicated in growth arrest and senescence such as p27,p53,p16 etc were detected n myocytes of young mt mice and their expression increase with age , acceoted but never proven tht paradignis that heart is a post mitotic organ characterized by a predetermined number of myocytes which is defined shortly after birth is preserved throughout life till death of the organism(d,tosella et al,2004)

. myocytes age at same pace , homogenous population , myocardial ageing interacts with ischemic hert diseass , hypertension , diabetes and other pathological conditions which together define clinical phenotype . cellular agiing is characterized by expression of nuclear proteins involved in cell cyle inhibiting ans irreversible growth arrest(d tosella , 2004)

Types of injury /diseases . myocardicac Injury leads to cardio Vascular myocyte loss , ventricular remodeling and consequent imparement of myocardicl function , mitotic capacity of cardiomyoctes is too limited to supportadequate myo cardical regeneration(D.M.Hodgson et al , 2003

Embryonic , A.Minobus and K.Guan, 1998 A. Cardio genic differncaitioni s impaired with loss of b intergin function. Study of differentiation of generally alter des cells by homologous receombination loss of b1 intergin function restricted in embryonic death shortly aftyer implantation by using es celkls differnciation approach . Check e savers.et al

A.Minobus and K.Guan, 1998 A.

protein found at only terminal differenciation stages chefck gautel et al 1995 .during in vitro differenciation of es cells in ot cardiomyocytes a developmentally c ontrolled expression pattern of tissue specific genes , actions potential s ion channels receptors where foundEffective differenciation factor RA influences differnciation of es carcinoma cells , es into neurogneic , mogenic , cardiogeneic . lineages in true co re deppemdent mananer. ventricular development was also evident by in activation of nearly all ra receptor subunits by homologous recombination and transgeneic experiment s in mice dramamtic abnormalitites obtained in embryonic develpmet especially combiig mouse strains with mutants rar and rxr sub types .

es cardiac cell occur under the direction of host paracrine signaling that supports cardiac specific differenciation(D.M.Hodgson et al , 2003 T.Minamino et al , 1999

Initro embryonic stem cells differenciation and targeted genen disruption has defined complex regulation events underlying oxidative stress induced cardiac apotosis . A Model of post ischemics reperfusion injury of myocardium . es cells derived cardidac myocytes (escm)having targeted disruotion of the mekkl gene was extreamlly sensitive relative t o wild type escm to hydrogen peroxide induced apotosis in response to oxidative stress mekki escm failed to activate a jun kinase (jnk)but did activate p38 kinase similar to observe wild type . reprogramming of ischeimic myo caardium results intra cellular injury which involves apotosisi and necrosisi , mediated in parts by ros dmage and myocardium directly oxidizing cell protein=s indirectly by stimulating the production of inflammation or cyto kines such as tumor receptors factor in cardiac myocytes . repefusion of ischemic cardiac time has been shown to induce changes in cardiac cto slkeleton demonstrate a protective role of mekkl in cardio myocyte responsiveness . cariaic myocytes can produce cyto kines including TNF in response to ischemia and reperfusion and oxidative stress .check paper for diagram. Check pparer online , A.Minobus and K.Guan, 1998 A. Quality of fetal calf serum , time of plating the eb . different cell linies exhibit dififferent development capapcitites in vitro (wobus)disadvantage variations in these conditions in fluence efficiency of cardiogenic differnciation and gne expression and may result in a synchronization of cardiac development .

Adult 2007 S.Dimmeter et al , 2007

Cardiac stem cells offer of potential for in vivo induction of proliferation and differenciation of these cells . Primed to acquire a cardiac phenotype might be optimally suited for carduiac repair . Different populations characterized including c-kit + cells , sca1+ cells side populations (sp)cells expressing protein islet detectd only in neonatal heart . cardio spheres form sub culture of human biopsy specimens. Cardio sphere derived cardiac stem cells are capable of long term self renew al and can differentiate inot the major specilaized cell types of the heart6 exact mechanism , maintains of this different populations in the heart is unknown later studies on bone maroe cell transplanted inishchemic myo cardial adopted hematopoietic fates rather than trans differentiating into myocardial cells(a,j,boyle /s. dimmeter) . use of adult stemc ells for organogeneisisi appear to be rather limited . adult stem cells lineage specific . bone marrow (has , hsc , msp ,side progenitor cells ,multipotential adult progenitor cells )derived cells are the best charcatereized cells used in may trials . distict role n salvage of dmaged tissue . Hematopoietic cell markers CD133+,CD34+..CD34+,CD133+ do not differentiate to endothelial cells Bm mn target popultuion cardiospheres, c-kit we can use mononuclear cells which can be easily separated or endothelial precursor cells CD34 , AC133 ,or use stromal cells , generally talking about autologous cells but this allogenically just as blood transfusions , immune genicicyty issue has been resolved E.C.Pesen , 2006 Transplantation of both skeletal myoblasts stem celsl into the region of infarted myocardium resultsi n improved myocardical results in improved myocardial function in both mouse and procrine infarct models(rrmarker,2003)

c kit cannot divide symmetrically or asymmetrically amd maintin the cardia stemce ll pool increase in c kit pos cells under going senescence and death interfered with the need for myocyte repolace ment in the old heart . the deficiency promotes differenciation of remiang p16 negative cells and c- kiti cells int amplifying myo cytes higher fractions of cardiac stemc ells ndergoing myocyte commitment is inconsistent with the brdu labeling of wilt typr myocytes with age .cardiac stmcell senscee and differnciation leads to progressive depletion of groeth reserve of the heart , cardiac agiing is a time depedentn process that constitituvely attenuate myocyte turn over mediated by growth limintation at the evel of co nroling cell .

D.Tosella et al , 2004

objectiveof study to establish whether aging of the heart laeds to omolecular modifications off myocytes that profoundly alter the characteristics and performance of fold hart resulting ina filing myopathy by senescence of cardiac stem cells linage able to divide and form new functional myocytes , cardia agiing may be viewd as alimtation in the replication ans commitment of cardiac stemcell that affects the tumor over of myocytes amog cell loss and the accumulation of old poory contracting cells . this cells cannot be replaced by new amplifying myocytes undergoing call division and maturation in order to meet functional needs of aged heart . repeated oxidative stress in myocytes in which cell replication is already lost. Ageing leads to a block in the capacity of hypertrophy , myocyte mechanics ca3 + transient to altered indicating that the system regulating activation conctraction relaxion are defective . ageing epression of p16 and telomeric shortening because the cdk inhibitor a large number of calcification might be xplained by enrichment of mononuclear cells by density gradient centrifugation used in mandatory clinical studied . source factors released epc stimulate migration cardiac stenm cells invitro , dysregulated in flamation in the hert after M1 consdered t obe normal part of healing process after which ischemic injury which might be modulated by administered cell therapy .(null) null Meschymal stem cells shown to direcetly attenuate cardio fibrovlast proliferation and collagen synthesis via release of paprcrine factors inviro , stem cell require a stimulus to differnciate into cardiac stem cells , local micro enviromet plays a important role to induce cell fate changes by physical cellto cell interaction or by providing paracrine factors . Ips cells (L.Ziwi and collegues in 2009) demonstrated the differentiation potential of human ips cardiomyocyes induced via embriod bodies differentiation system to work in therapy. characterizing of electro physiological proprrerties and presence of cardiac secifif poroteins by immune staing ,peace maker ACTIVITty and synchronized action potential Property of cardiac tissue physiology i

eb. differenciation o is characterized by continuous decreas in the eperession of pluripoten markers (oct 4 and nanaog )coupled with increased in cardio mesoderm markersd mespi and brachyury . (L.Ziwi and collegues in 2009)

mechanism

paracrine mechanism support for this mechanism is increasing . hypotoxic stress lead rto increased production of cytokines growth factors cm from bm . mncs into actually infarted heart and observed infart size improved cardiac function mono nuclear cell from bovi ne bone marrow into infart zone . improvement ecto diograph showed increased numbers of capillaries increased coro0nary collateral circulation on angiography . stemc ell would repair a damaged heart via active myocardial regeneration resulting from transdifferncation of ther administered stem cells(null) demonstration of endogenous replacemmenet of cardio myocytes only occurs after injury , subset of higher cell with capcity to diffeernciate not cardia myocytes enhancement of cardiac differnciation by interfering with path ways is the imporove e ment seen after therapy maintained fro prolonged time(null) Stemc ells derived from cardio myocytes integrate with host myocardium es therapy staple favourable iimpact , stem cel integrratd host myocardial hv been shown to secret cardio myogenic growth factors that interact in paracrinne fashion with receptors on stem cells(D.M.Hodgson et al , 2003) proposed mechanism of cellular therapy is angiogenesis idea that bone marrow stem cell secreat multiple potentially angegenic substances as well as transdiffrenciate into cell that create neew blood vessels is fairly well established in pre clinical studies , we kno w that they may be detected precursors of cardio myocyes in myocaridium . trying to determine if transplanted cells differnciate or if paracrine effects from transplanted cells stimulate stem cells alredy residen in th heart to differnciate or if both factors are at work E.C.Pesen , 2006 E.Chavakes et sal , 2008

Homing of cells to target tissue uptake totother organ and tissues where therer may exhibit un wanted exhibit unwanted side effects non invasive imaging performed by diret labelling of the cells with trhwt pat5icular paRICLE FOR mri in rat . in heat aftrer radio active . engraf ment of mesechymal stem ewl ls size of cell bigger and not yet adapted fo to circul ation in blood so have been injected initra musculary expertimental studies . injection of allogenic msc surprinsingly redistribution iof ifused cells from initial lu ng homing to no target v organs like liover and spleen and salso infracted heart . up take of cells appear rather low in dependent in used cell type or the route of delivery higher in cioi operation when

using CD324+ cells . increase in experession of anti apoptotic gebnes to promote survival of injected or infused cells . molecules also increase adhesion migration of cells vegf, sdf1,cr4.mecahnism of homing . homing is a prerequisite for all cell types to exhibit anay tyope of activity in t arget tissue particularly when cells are infused via vascular route . homing of progenitor cells to ischemia utilize adhension molecules for homing to sites of nerovascularization . SDF1- stimulate hematropoetic stem cell engrafment and also recruitment of progenitor cells to ischemic time regulation of spf1 v is up regulated during ischeamia . stratergies to increase homing and engraftment of cells . over expression of sdf1 enhanced stem cell homijng and in coorporationinto ischemic ti. homing of progenitor cells to ischemia utilize adhension molecules for homing to sites of nerovascularization . SDF1- stimulate hematropoetic stem cell engrafment and also recruitment of progenitor cells to ischemic time regulation of spf1 v is up regulated during ischeamia . stratergies to increase homing and engraftment of cells . over expression of sdf1 enhanced stem cell homijng and in coorporationinto ischemic tissues

Delivery /therapy , S.Dimmeter et al ,

micro environment after myocardial infarction . changes during the fiorst wek after reperfusion modulati9ng homing or subsequent functional activity of the cells . ischemia repefusion induces a transient change in expression of chermo attractive factors such as VEGF and SDF-1 known to essentially stimulate the recruitment nad retention of cells in the tissue . initial edema for matuion is followed by a transient invasion of different waves of cellsd . cell hominmg might bhe sent after a few days rather than immediately after reperfusion Study suggesting single clonally purified msc most efficient to cardiac repair. isolated bone marrow derived cells are injected into the heart without further ex vivov expansion haematopoietic progenitor cells resultsd of clinical tri9als of particular insuite acute myo ardial infarction . I n ter conoray infusion of autologous bone marrow cells is sfe and feasible in patients with acute cardiac infarction Patients with chronic ischemic cardio myopathy are unlikely to release signals from damaged myocardium to induce stem cells homing ,. Alternative approach to inter cononary infusion of cells in this setting is the endo myo cardial injection o0f cells to deliver them to the exact location where therir effect is required ,. Either by direct I n jecgtion

into the peri infracted rim of the function myo carduim or by using chemo attractant cyto kines to mobilize cells fgriom the bone marrow in cons tract to kim c + cells studied murray and clooegues and balam(a jboyle)

K.E.A.V.Dbogt6 et al , 2008 .muller etinsen and collegues where able to show htta post mortem taq man pcr based quantification of sry locus on do nr y chriomosome in the female receipent tissue can be used to quantify cell survival in heart

Minobus and K.Guan ,1998 epithelial differenciation and invitro formation of spontaneously contracting vascular smoth mzl cells . development pattern of es cells can be modulated invitro by differenciation factors eg retinoic acid . wobus et la ,or gentic means such as targeted in activation of the genens or constructive expression of the genes . loss of function approach to mimck differenciation of cells es cells cultivated as ebs cells in hanging drops of differenciation medium 2 3 days after transfer to bacteriological plates in suspension scanning electron microscope show morphological differnciation ebs plated in gelatin coated tissue cultures attach to substrate and differeinciate into many cellular phenotypes including cardio myocytes . cardio myocytes diffrenciation . check wobus et al 1991. Check paper foro th rst of ther referncen .

autologous bine marrow cells can be injected surgically or diverted with a catherter in the acute settings after myocardical in farction or in chronic setting of heart failure or refactory angina, autologous bone marrow can also be infused down the conoary artries in the acute setting of myocardial infarction E.C.Pesen , 2006

(D.M.Hodgson et al , 2003)cell fusion afer grafting , mechanism likely multi factorial no evidence of rejection of transplanted cell depite xeno transplant ation of mouse embryonic stem cells inot rat heart ,lack of host vs graft reaction may be graft or host are depent on one another as a result of low expression f immunogenic antoigens , stem cells generation of mixed chimerism , down regulation of host cell immune response or Induction of Improved tolerance , we did not observe disorganization diffrenciation leaadign to tumor formation although pluripoten stem cells carry this risk(D.M.Hodgson et al , 2003)

(D.M.Hodgson et al , 2003De-novo cardiogenesisi , limited information on their therapeutic value, talking bout es celsl , goup treated Infarcted rat hearts with CGR8 embryonic stem cells pre examined for cardiogenicity probed left ventricular function and determined final pathology out come , stem cells delivery generated new cardio myocytes of embryonic stem cell origin that integrated wit host myocardiium with infart regions resulted n a functional benfit within three weeks , no evidence of graft rejection , ectopy , sudeen cardia c death , no tumor formation was onbserved after therapy , finidn indicates that es cell through differnciation within host myocardium can contribute to stable beneficical out co me within host(D.M.Hodgson et al , 2003 currnt clinical applications in cardiac stem cell therapy ABM injection , trans cartherter , surgical , abm intracoronary infusion .stem cells mobilization / G-CSF(acute)myoblast injection , trancartherter, autologus bone marrow E.C.Pesen , 2006

Dosing and timinig . in pigs bebnfical effects of certain cell . dosing study . cell trafking study in which label the cells so that we can track tham invivo with postiron emission tomography and imaging resonance imaging in clinical applications , E.C.Pesen , 2006 timing of injection , are all still been defined for in other for stem cel therapy to be widely clinically applicable the optimal cell has to be compatible both mechanically and electrically with host myocardium limitiation o(rrmarker,2003)

Limitations several potential uissues rasised last year I nclude , electrical stability , increased restenosis , progression of atherosclerosis disease . nomneof the cli ncval studies have reported arrtyhmia but it has been seenin some of the myo blast trilas . restenosis increase in the study usi9gn CD133+. Intra myocardial classification occurred in murine models . Mechanism of action difficult to rest clinical scenarios

In many cases freq of stem cell engraftment and no of newly generated cardio myocytes and vascular cells either y transdiffernciation or cell fusion appear too low to explain the significant cardiac improvement described M.Gnecchi et al , 2008

(rrmarker,2003)ventricular tachycardia rre quires implantable cardiavertere defibrillator replacement /,un published experience of 2 suddden death ans 3 serious ventricular arrhytmials in 8 additional patients . four out of 10 pateints required ventricular arrhythmias after open chest autologous myoblst transplantation , pro arrhythmia after stem cell therapy might be attributed to one or more of the following reason s ,heterogeneity of action potential between mature and transplanted stem cells , inrinic arrhythmic potential of injected cells , increasing nerve spouting induced by stem cells injection , ilocal injury or oema induced by intra myocardial injection , electrophysiologaical hertrogenicity , no rmadic cardiac cell exhibit significant transmusal hetrogenicity of action potentiual , duration of action potential a delicate balance has to be mainted to prevent arrhythmia . zhang et al studied intrinsic arrythromogenic properties of cardio myocyes derived fform mouse pluripoten embryonic stem cells in vitro using whole cell patch clamp , diluted stem cells , exhibited all the arrhythmogenic mechanism , -- reentry , automacity , trigerd activity , local injury most caes of arrhythmias in the early clinical trials have been associuated with inttramyocardical rather than intracoronary injections .tissue injury may be responsible for arrhytomogenesis after intra myocardial injection no increae in ventricular arryhtmias have been reported after therapy is such as direct laser trans myocardial revasculation thjat causes local tissue damage and tearing , searing , ?myoblast and(rr marker,2003)

invivios cells transplanted cardiomyocytes that repopulate significant regions of dysfunctional myocardium and decereased functioniong mortality(D.M.Hodgson et al , 2003

immune rejection of such allogenic cell grafts possibly of derving patient specifi hese lines as models to study disease specific process largely limiting Methods . hips cells eher generated by retroviral transduction of human fibroblasts L.Ziwi et al , 2009 limitation of hips derived cardio myocutes Electro physiological properties of hips cm may be relatively immature and that the generated tissue is isotropic and differes from that of adult heart ,( L.Ziwi and collegues in 2009)

because of electrotonic interactions in adition micro architecture of contracting tossue is un predicatable ranging in size and shape in a manner similar to hesd and esc systemc (L.Ziwi and collegues in 2009) Electro physiological properties of hips cm may be relatively immature and that the generated tissue is isotropic and differes from that of adult heart , the phenol type of cardio myocytes within the contracting ebs may be diverse comprised of atrium like , ventricle like , node like cell, variation from one ip cell line to nanother(L.Ziwi and collegues in 2009) . although eb where characterized by a bro ad cardio myocyte area and a relatively homogenous and fast conduction others contained more complex structures with narrow tissue strands leading to relatively slow conduction this structural draw back is counter balanced by the ability of each eb as it own controlled to follow its electrophysiological properties(L.Ziwi and collegues in 2009) (D.M.Hodgson et al , 2003)

. research .CGR8 murine es cells differentiated using established imaging drop method to generate embryoid bodies .myocaridal infarction was induced at 6 week of age by ligation of left anterior descending coronary artery in male spragnue results , CGR8 es cells colony demonstrated typical features of undifferniated cells cardiogenic capacity of es cells was probed with inviro differentiation with cells readily derived that ex press MEF2C , cardicac contractile proteins alpha actin and sacromere striation . stem cell differentiated with action potential activity improved function in response to stress , use of fluorescene to demonstrate presence of cardio myocytes derived from injected es cells Invivo. (D.M.Hodgson et al , 2003) A.Rosenzweigh, 2006 Largest steudy of stem cell therapy to dtae schachinger et al tomital et al showed msc pre treated with 5-azacytine in to acryo injured rat hearts could home and jdifferenciate inot cardiac like muscle cells and function to detct permanent engraft ment and transdiffernciastion of transplanted bone marowe derives hemaotpoetic stem cells . cell fusion o f bone marrow derived stem cell with receipnetn cardio mycytes reported frequency of cell fusion debated . K.E.A.V.Dbogt6 et al , 2008

Carried out a comparative Analysis of of the efficiency of different cell candidates for the treatment of heart diseases remains to be described .murine model . bone marrow mono nuclear cells . msc cells . skeletal myoblasts , fibroblast expressing firefly luciferase and green fluopresent protei9n where characterized by flow cyto metry bioillumiscence imaginig and immune metry . female fob mice underwent LAD lighation and intamyocardially received obne cel type suruvial measured by Bu and taq man pcr cardiac functional accessed by echocardiography and I nasive heno dynakics measurements `.cornoray artery disease no 1 cause of morbidity in the united staes . despite wide rnage of therapeutic approaches heart failure remains he leadi9gn cause of death in the westrern world . Clinical out come are divergent . molecular imaging for tracki ng cells inmice opposed topost mortem histology . molecular imaging is non in vbasive and favilitated repetive imaging providing insight into cell postion and count . animal standard protocols . cell characterization . mn population consisted of CD34 and CD 45 CD 11b+ representing portions of heamtopetic cells . after 6 passage of msc , flow cytometry results showed absence of CD 34 , CD45, amd c kit heamtopoetic cells with msc . myoblast cultures steadilty developed . characterization of cell types based on cell surface expression and cell morphology . luciferase expression reflexcts viable cell cary number cell plates with incrasesing number . .MN showed poor exvivio signal ciompared to other cell groups which maY ACCOUNT FOR HUBERATION OF CELLS DIE TO HOSTILE ENVIROMET

M.Gnecchi et al , 2008 . Akt msc injected into pig infracted hearts lead to limitation of infart size and preservation of herart function . cyto protective factors .VEGF,PDGF,IL-1B,IG-F-1,some up regulated in hypoxia . stem cel relase factor exert autocrine effects on the clls themselves influencing cell survuival self remewal . cel growth . K.E.A.V.Dbogt6 et al , 2008 . increase of mn signals represnent increase of mn ion the heart . nmore mn in receipent heart than compared to sk mb and ms cans fibro . Functional effects of cel transplantation ecto cardio graphic measure mentsd of cardial perfeomance was conducted 4- 6 weeks after cel transplantation at 6 weeks LVFS for mn was significantltty higher than pbs and fibro groups . it has been previously reported htta cell transplantation accounted for shoert term preservatuion of cardiac function after . al cel . ref 17 all cel groups showed decreased LVFS on week 6 compared to week 4 . this findings suggest that the beneficial effectys of cell transplantation may laast onlty for acute most myocardiacl period . measurement of functional consequences of cell transplantation into the infarted mouse heart . validation of no

ninvasive measure ment of left cventricular dimensions . electrcardio graphy in preserved situ left ventricular end systolic (LVSD) and end diastolic ()LVDD) DIAMETER transdiferncation does not account for better cardiac performance GFP expressing mn could easily be found confirming engraftment and BLI results . However histological samples showed no overlay of donor specific GFP nucleus specific DAPI and cardiac nucleus specific troponin 1 and conexin 43 marjkers two weeks after transplantation . had difficulty identifying gfp expressing stem cells use or fibro indicating that only low counts of ther cells were present in the heart . immune histochemical stain reveals no evidence of mn trans differenciation inot cardio myocytes . this study is the first to evaluate the efficiacy of three different clinical candidates fopr the treatment of myocardial I nfarction as compared to cellular co ntrol . molecular imaging using fluc rep[orter gebe is a reliable tool for monitoring donr cells survival proliferation and migration invivo , compared to sk mb , msc and fibro mn showed the most favourable survival patern after in farction inot infarted heart . mn injuerctuion lead to a better but transient preservation of cardiac function. Is not attributed to repopulation by transdifferncation . Discovery of mechanism involved . functional bebfitys of mn transplantation might be attributable to an augumentation of the natural healing by paoprcrine signalling and promote ng neovascularisation among other factors . shownm mice over expressin MCPI which leads to increased inflyux of m n into damaged myocardium after infarction had ddecreased infracted areas and scar formation and yielded better left ventricular function compared to wild ttpe . infarted myocardium cd 116+ macrophages are all important sources of ctytoki nes and growth factors and potential regulators of the extracellular matrix syntheisis .

extra E.C.Pesen , 2006 , substances like G-CSF(granulocyte colony stimulating factor )can be used to stimulate thet body to relaes preceursor cells from the bone marrow which can be allowed to intergarte naturally to an area of infarction ,. Editorial comment , R.R.Marker, 2003and injection of stemc elsl and bone marrow stimulating cyokines also improves cardiac function ,.

. . it has been sh own that s ingle dose of specific growth fcatyors is effective in enhancing neovascularisation in animal but not in humans .(m,genchii,2008)

conclusion

m.genniiccc getting consistent results across labs is n o t occuri9ng ,. Demonstration that stem cell may secret therapeutic factors may be one may be able to adnmister specific proteins produced by t his cell for cardiac therpay . possible that factors might influence the micro envitroment maintain stem cell niches in the heart or may activate cardiac progenitor cells and induce migration differnciatioon . tailored studied analysisn fate of both exogenous transplanted cells and resident cardiac progenitor will help clarify the specific role of these cells poluations in heart repair . acute envirometn io f myo cardidl I nfarctiion environment may influence cell detah devoid of nutrients and oxygebn coupled with loss of survival signals from matrix attachment and cell0-cell interactions . to improve cell survivial by over expressing protective genes purposed that pere conditioning of adult stem cells with different cyto kines may result in I mproved cell engraft ment ref 66 . bm derived stem cell shown no pro arrhythmric effects . msc immune priviled phenotype and may not be sugject to allogenic rejection in human and ani9mals . stem cel for therpy bebnfical si nce the full mechanism is still no tknown different actions may require difffernty concentrations , timing , differncesd between anuimal models and h8man further complicate scenaruios Null fundamentally different patho physiologic processes are targeted , patient with acute mi , progenitor celsl transplantation aims to prevent or ameliorate post infarction lef venticl e remodeling ther by reuciing post infarction heart failure , effects achieved by enhanced neovascularization and reduced cardio myocyte apoptosiss irrespective of long term engraft ment and trans differnciation , optimal time of clrll delivering dose response comparism of different cell types notin stage to be used in routine clinical procedures despite weathering data .

Improved ejectuion factions ,

reduction in scar tissue size

Tittle of ppare . myocardidal transplantation of progenitor cells leads to a decrease in myocardial fibrosis after myocardial infarction(null)

, A.J.Boyle eta l ,2006

United statet ther are 7.1 million survivors of myuocardial infarction and 4. 9 million people living with congestive heart failure early clincval experience in studies . myo blast transfer in early studies was associated with sustained ventricular tachycardia , life threatening arrhythmia , adult bone marrow . intrinsic reppai9r mechanism for minor cardiac dmage within bone marrow bit not adequate tolarghewrr amounts of damage after myo cardial infarction by fin dign GF[P posistve cardio myocytes and endothelial cells . lineage ve c ki cells positive bone marrow derived cells differnciated into new cardio myocytes after implantation imp roved cardiac function I n mouse models . es cells differentiate to all cell lines necessary for formation of new blood cells . a stimulataneous increaser in blood supply my be necasary for opti mal and prolonged engraftment resident cardiac stem cells . cardiac stemc ell can be harvested from patients and expanded ex vivov to gebrat6e l arge numbers of cells cardiac stemc ekl kls increased invivo immediately after yocardial infarction . no clinical trials of human cardiac stem cells . skeletal myo blast have no ethical and immunological problems . mesenchymak stem cells ,use fom adult bone marrow can be separated by ddensity gradient centrifugation and adhering cel culture in derined serum containg medium . cells isolated after adherence in culture are negative for CD34 nad CD45 unlike hematopoietic progoosis fom bone masrow . msc differenciate inot cardio myocytes . act by regherating functionally effective I ntergrated cardio myocytes and possibly new blood vessels . autologous cell based therapy poses no risk of rejection an off the shelf allogenic cell product would be much more cost effecti9ve and much easier to adnminster could allow more greater number of cells than autologous cell therapy . msc avoid the pro blem of rejection by b ei ng hypo immunopenic cell s lack MHV-11 and B-7 . costimulatory molecule expression therby preveting t cel response . endo thelial progenitor cells and umbilical cord blood stem cells if still time check a paper