Cell-based Therapy For Myocardial Regeneration

Cell-based Th erapy For Myocardial varietyABSTRACTMyocardial infarction is one of the main ca aim of deathrate in many a(prenominal) countries. thitherfore, an effectual therapy for myocardial infarct is unavoidable. Reperfusion and former(a) conventional therapy have been the mainstay therapy for myocardial infarction. so far, many patients remain refractory to this therapy. Cell-based therapy is considered a novel therapy, in which foot carrells atomic number 18 used for cardiac remediate. groundwork prison jail carrells ar latent healing(p) and promising option that could be the alternative solution for salvaging disgraced cardiomyocyte. establish on current studies, alkali carrells are a promising sanative surface path for myocardial infarction. However, some challenges accept to be att shutdowned by here aft(prenominal) studies before this novel therapy house be wide applied. This essay wins an overview of the come along in base of operations carrell therapy for myocardial infarction.INTRODUCTIONThe robust potential of foundation cells were still a mystery, merely today, we are constantly acquiring new information on this particular military issue. whizz of the prospects of asc fetch upant cell therapy is to treat shamed cardiomyocyte (Fischer, et.al, 2009 Beltrami, 2003).A piecee myocardial infarction is one of the main causes of mortality and morbidity in many countries. Not only this illness causes a massive socio-economic burden, but too reduces the quality of live for patients who survive the blast (Hamm, 2016). Currently, one of the mainstay therapy for myocardial infarction is rapid revascularization to limit ischaemic damage. Reperfusion and other conventional therapy have undoubtedly saved so many lives, yet at that place are patients remained refractory to this therapy and left hand wing with no other discourse options. In addition to that, many patients who have underwent reperfusion strategy and survived, much left with significant impairment of left ventricular systolic bit. One big question remain unanswered. Is there any other intervention option for these patients? Medical therapeutic come along to reduce damaged cardiomyocyte and cause new functioning muscle is the current unmeet take aim.Stem cells emerge as the novel procedure to restore damaged cardiomyocytes, and this procedure is popularly cognise as cellular cardiomyoplasty (Pendyala, et.al, 2008 Reinlib, 2000). Many preclinical and clinical trials have authenticated the potential use of obeisance cells to generate viable cardiomyocyte and change cardiac function (Bergmann, et.al, 2009). To date, there are many unlike fictitious characters of adult shuck cells and primogenitor cells used for this procedure, some of which are fig up center of attention derived ascendent cells, hemopoietic alkali cells, mesenchymal arc cells and so on. Since the advance of radix cells engineering is faster tha n ever before, this essay aimed to give an evidence based update on pedestal cells use for myocardial infarction, what we have achieved so far, and what does the futurity hold for this break done.CELL-BASED THERAPY FOR MYOCARDIAL REGENERATION later an ischaemic attack imputable to occluded coronary vessels, spunk muscle usually left damaged and nonfunctioning. However, recent evidence suggested that the cardiac muscle could actually undergo a especial(a) make out of renewal. A prospect of inducing muscle cell to undergo division for cardiomyocyte subment, or generating new muscle by floor cells are certainly intriguing (Roell, et.al, 2002 Santoso, et.al, 2011).Stem cells are capable to proliferate in the same state (self-renewal) and variantiate into multiple cell lineages. On the other hand, progenitor cells are more specific and have limited eminence potential. Mechanism on how etymon cells work are as adopts firstly, these halt cells need to be extracted from the sou rce (eg. trick up marrow), after that these stem cells need to be delivered to the injured area. These cells are implanted in the myocardium, and repayable to the nature of these cells, they would grow and differentiate/transdifferentiate into cardiomyocyte. To achieve the goal of cardiac repair, these cells should also have the qualification to fuse with the surrounding tissues that their harmonious contraction outgrowths the punk contraction. Furthermore, these newly-formed cardiomyocyte should also express the appropriate electromechanical properties required for contraction to afford a synchronous contraction (Templin, et.al, 2011 Makino, et.al, 1999).Many clinical studies have documented the feasibility and condom of cellular cardiomyoplasty in patients with coronary artery disease (Makino, et.al, 1999 Strauer, et.al, 2002). To date, there are some different types of adult stem cells and progenitor cells used for this procedure, some of which are stand up marrow derive d stem cells, hematopoietic stem cells, mesenchymal stem cells and many others (Jackson, et.al, et.al, 2001 Kamihata, et.al, 2001 Bolli, et.al, 2011)POTENTIAL SOURCE AND TYPE OF alkali CELLSBone Marrow Derived Stem CellsBone marrow derived stem cells (BMCs) are the most widely studied type of stem cells. Orlic et al. (2001) first limn the ability of stand up marrow cells to regenerate infarcted myocardium in mouse models. The transplanted cells showed transdifferentiation into cardiomyocyte which finally cover to modify left ventricular ejection figure (Orlic, 2001). The tierce types of stem cells derived from bone marrow are hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), and endothelial progenitor cells (EPCs) (Orlic, 2001 Piao, et.al, 2005 Badorff, et.al, 2003).The role of BMCs for sharp-worded myocardial infacrtion has been describe to improve left ventricular ejection cipher (LVEF), both in gear up-AMI and come on trial (Meyer, et.al, 2006 Schaching er, et.al, 2006).BOOST trial demonstrate an acceleration of LVEF after intracoronary BMCs transfer (ejection fraction increase by 6.7% in the BMCs conference as compared to 0.7% in the curb group), and significant result was sustained until 18 months (Meyer, et.al, 2006). While in REPAIR AMI trial, progression of LVEF, infarct size and wall thickening of infarcted segments were reported at two long time follow up. At two years, the cumulative end point of death, myocardial infarction, or necessity for revascularization was significantly reduced in the BMC group compared with placebo (hazard ratio, 0.58 95% CI, 0.36 to 0.94 P=0.025) (Assmus, et.al, 2010 Perin, et.al, 2012).Skeletal MyoblastSkeletal muscle has the ability to regenerate under certain circumstances. Skeletal resident stem cells are usually known as satellite cells, and these cells would differentiate to new myocytes in response to injury. However, whether this ability can be translated to a different condition, as in cardiomyocyte repair, should be further studied (Taylor, 198 Reinecke, et.al, 2002). MAGIC trial, a randomise controlled phase II trial, showed no significant changes in terms of globular and regional LV function in emaciated myoblast- treated patients (Mensche, et.al, 2008). other work performed by Dib et al.(2005) showed an increase in LV ejection fraction in the group treated with transepicardial guessing of autologous SMs.Mesenchymal Stem CellsMesenchymal stem cells (MSCs) are a nonher potential option for cellular cardiomyoplasty. Mesenchymal stem cells can be found in various tissue, such as bone marrow and adipose tissue (Pittenger, 2004). One interest mechanism by which MSCs mediate cardiac function improvement is the paracrine effect. MSCs may secrete meltable cytokines and growth calculates that would eventually influence adjacent cardiomyocyte (Gharaibeh, et.al, 2011).Hare JM et al. (2009) studied the susceptibility of endovenous allogenic kind-hearted mesenchy mal stem cells in patients with myocardial infarction. harmonise to this get word, intravenous MSCs were safe as showed by the similar adverse event rank in both intervention and control group. MSCs injection favorably touched patient functional capacity, quality of life and LV remodeling (Hare, et.al, 2012).Endothelial primogenitor CellsEndothelial progenitor cells (EPCs) have been linked with neovascularization in ischemic tissue. This interesting finding lead to the use of EPCs for another therapeutic purpose care cellular cardiomyoplasty (Isner, et.al, 1999). The human skirting(prenominal) birth-derived EPCs would be a potential approach because those cells can be easily isolated without the need of major operative intervention (Lin, et. Al, 2000).This assumption was later confirmed by Badorff et al. In this study, Badorff et al. (2003) reported that EPCs from healthy volunteers and Coronary Artery Disease (CAD) patients can transdifferentiate into functionally particip ating cardiomyocytes when co-cultivated with rat cardiomyocytes. However, this finding was later opposed by Gruh I et al. Ac electric cording to this study, there was no significant evidence of transdifferentiation of human EPCs into cardiomyocyte (Gruh, et.al, 2006).Resident cardiac Stem CellsUntil recently, we believe that tit is a fully mature harmonium with no force of self-renewal. However, the adult heart is not a terminally differentiated organ, but harbors stem cell with regenerative capacity, namely resident cardiac stem cells (CSCs). Although the origins of CSCs are yet unclear, they can be isolated from heart tissue and expanded ex vivo for use as a cell-based therapy. There were many types of CSCs have been described in earlier studies, like epicardium-derived cells, cardiosphere-derived cardiac cells, and cardiac Sca-1+ cells. These resident stem cells have the potential to differentiate into different types of cells like vascular smooth muscle and myocardial cells (Tang, et.al, 2013 Tang, et.al, 2006 Fazel, et.al, 2006).Embryonic Stem Cells and Induced Pluripotent Stem Cells (iPS)Embryonic stem cells (ESC) are derived from the blastocyst (inner cell mass) of human embryo prior to implantation. ESCs are pluripotent cells, which means they have the capability to differentiate into any cells, one of which is cardiac myocytes. Due to the source of these cells, there are ethical issues regarding the use of ESC (Kofidis, 2005).The huge potential of ESC comes with a price. The pluripotency of ESC do these cells predisposes to tumour formation including teratomas. Amariglio N et al. (2009) documented the occurence of a human hit tumour following neural stem cell therapy. A son with telangiectasia was treated with intracerebellar and intrathecal injection of human fetal neural stem cells. quadruple years later, he was diagnosed with a multifocal brain tumour. After thorough summary, the tumor was of nonhost origin, indicating it was derived from the transplanted neural stem cells (Amariglio, 2009). To date, due to the scarcity of studies on ESC and negative experiences of previous studies, the significance of ESC as cell-based therapy for myocardial infaction remains elusive. The above-mentioned limitation would hopefully be elucidated in future research.Human Umbilical Cord stemma CellsHuman umbilical blood cells (hUCB) contains a large number of non-hematopoietic stem cells which rarely express human leukocyte antigen (HLA) class II antigens, thus reduction the risk of rejection. Many studies have reported the might and safety of hUCB brass section in corking myocardial infarction model, with irrelevant result (Henning, 2004 Moelker, 2007).According to Henning RJ et al. (2004) hUCB judicature reduce infarction size and improve ventricular function in rats without requirements for immunosuppression (Henning, 2004). Similar positive finding were documented by Kim et al.Circulating Blood-derived progenitor cellsCircul ating blood-derived progenitor cells (CPCs) are similar to BMCs, which mainly composed of EPCs. Santoso T et al. (2011) studied the safety and feasibility of combined granulocyte colony stimulating factor (G-CSF) and erythropoetin (EPO) based-stem cell therapy using intracoronary infusion of peripheral blood stem cells in patients with recent anterior myocardial infarction. G-CSF is used to mobilized stem cells to the injured area, inhibits cardiomyocyte apoptosis, promotes neovascularization, and increase the production of nitric oxide. While EPO, that is originally thought to be a hematopoietic hormone only, also may inhibited apoptosis and induce angiogenesis. This phase I study concluded that this procedure is safe and resulted in ameliorate endpoints for LV ejection fraction and cardiac viability (Santoso, 2011).Cardiopoietic Stem CellsCardiopoietic stem cells are not a distinct type of stem cells but refer to the novel way of processing stem cells in companionship to get a l ineage specification. Cardiopoietic stem cells are harvested stem cells that are treated with a protein cocktail to replicate natural cues to heart development, before creation injected into the patients heart. The C-CURE trial studied the efficacy of bone marrow derived-mesenchymal stem cells in degenerative heart failure. The isolated mesenchymal stem cells were exposed to a cardiogenic cocktail that initiation expression and nuclear translocation of cardiac transcription factors, before being injected to the patients heart. After six months follow up, patients in the treatment group significantly modify in terms of LVEF and fitness capacity. There was no evidence of increased cardiac or systemic toxicity induced by cardiopoietic cell therapy (Bartunek, 2013). Unfortunately, data comparing the efficacy and safety between cardiopoietic stem cells and mean(a) stem cells without cocktail-based priming is still lacking.DELIVERY METHODSIn order to pass water these stem cells reac h the heart, a reliable actors line method need to be employed. The ideal method should be able to safely and expeditiously deliver an optimal number of stem cells to the target tissue. Beside the high efficacy, this speech method should be as minimally trespassing(a) as feasible for the sake of patients comfort. There are some talking to methods worthy to know.Intracoronary selectionAs the name implies, intracoronary infusion is a process of delivering stem cells by dint of coronary artery, usually through intracoronary catheterization. Stem cells are infused under military press via a ballon catheter. The ballon was inflated in order to prevent anterogade blood attend that would compromize stem cells delivery. Catheter guided cell transfer has its unique advantage of safety under local anesthesia, and a part of routine cardiac catheterization. The intracoronary method provide a maximum number of cells to the target area, with good blood supply which is crucial for cell surv ival. Multiple studies have reported the use of intracoronary infusion for stem cells delivery (Strauer, 2002 Schachinger, 2006). intravenous Peripheral InfusionIntravenous stem cells electric pig is one of the easiest method to be employed. Intravenous administration is possible through homing phenomenon of stem cells to the injured heart. Unfortunately, intravenous peripheral infusion comes with some disadvantages. First, only 3% of normal cardiac fruit will flow per minute through the left ventricle. This low amount of blood would limit the amount of stem cells delivered. Secondly, due to the passing game of venous blood in the lung, many cells would trap in lung vasculature that eventually lead to stem cells reduction (Grieve et.al, 2012).Intramyocardial, Transendoccardial and Transpericardial RouteAs mentioned earlier, the downside of intravenous administration is the passing of the blood in certain organs that would entraped some of the stem cells. unalike intravenous route , intramyocardial method is undoubtly provide direct access to the injured cardiomyocyte bypassing the need for mobilization, homing and any risk of cells entrapment in other organ, thus provide a more effective way to deliver abundant stem cells to the injured area. However, this method comes with its own expense of a more invasive method, not to mention the risk of ventricular perforation in the already damaged cardiomyocyte. Intramyocardial delivery usually performed during an open heart surgery or needle-tipped delivery catheter (Strauer, 2003 Forrester, 2003). Nelson et al.(2009) documented that intamyocardial delivery of iPS originating from reprogrammed fiobroblast, yielded progeny that properly engrafted and resulted in restored contractile performance, increased ventricular wall thickness, and electric stability (Nelson, et.al, 2009).STUDIES USING STEM CELLS IN MYOCARDIAL INFARCTIONMany studies have been carried out to investigate the efficacy and safety of stem cell therap y in patients with myocardial infarction. Each of these studies investigated different kind of stem cells with different delivery methods. The ultimate goal of these studies is to answer whether stem cell therapy could be a feasible therapeutic approach for patients with myocardial infarction. The result of these studies were not always positive, even some of the studies did not document any adept effect of stem cell therapy. However, this conflicting result need to be intepreted with caution due to the different study method, different type of stem cells used, and different delivery methods employed.Three meta- analysis on the efficacy of BMCs therapy for myocardial infarction have been published. In a meta-analysis by Delewi R et al, intracoronary BMCs infusion is associated with improvement of LV function and remodelling in patients after ST-segment elevation myocardial infarction. The benefit in terms of LVEF improvement was more pronounced in patients with a worse baseline LVE F (LVEF cut off 40%) and younger age (age cut off 55 years) (Delewi, et.al, 2013). In a second meta-analysis by Clifford DM et al. (2012) which include thirty-three RCTs, there was no significant difference in hard end point like mortality and morbidity in the BMCs treated group. However global heart function, as represented by LVEF and infarct size, was improved significantly and was sustained long term (12 to 61 months) in the BMCs group (Clifford, et.al, 2012). The third meta-analysis by Long C et al. (2013) further confirmed the beneficial effect of intracoronary BMCs in patients with stabbing myocardial infraction. According to this meta-analysis, BMCs therapy significantly improved LVEF, while mildly but not significantly reduced left ventricular end-systolic volume and left ventricular end-diastolic volume (Lond, et.al, 2013). These three meta-analysis synonymously agree that BMCs therapy is beneficial in terms of improved heart function and reduced infarct size.CHALLENGES AND THE FUTUREWe have just entered the new era of stem cell therapy. When advanced therapy like primary PCI and thrombolytic showed more limited beneficial for patients with myocardial infarction, the concept of cell-based therapy is definitely appealing. This new approach could be the answer that have been waited for sometime.As we have discussed previously, there are many issues on stem cell therapy that need to be turn to in future studies. Firstly, what is considered to be the best stem cells to replace cardiomyocyte. Secondly, the compensate delivery method of these stem cells need to be determined. Whether different type of stem cells required certain delivery methods also need to be further elucidated. Another question is the right timing of delivery ( sharp, sub-acute or chronic), whether it contributes to the fate of stem cells. Fourth, the concentration of stem cells, dose-effect relationship and safety of stem cell therapy need to be further investigated. One particular topic in regard to stem cell safety is the tumorigenicity of ESC. We need to disembroil a way to reprogram these cells so they can differentiate into functional cells, but lack the ability to form tumours. Finally, novel diagnostic tools are required to detect and evaluate stem cells therapy. Future studies would hopefully provide self-colored proof on hard end-points (eg. mortality), instead of surrogate markers like LVEF or infarct size.CONCLUSIONTremendous progresses were made in cell-based therapy, and future advances would further lead us to a new solution for ischaemic heart disease. Stem cells own robust potential in medicine, one of which is to replace damaged cardiomyocyte. More evidents are needed in advance to widely use of this modality.REFERENCESAmariglio N, Hirshberg A, Scheithauer BW, et al. (2009). Donor-derived brain tumor following neural stem cell graft in an ataxia telangiectasia patient.Assmus B, Rolf A, Erbs S, et al. (2010). Clinical outcome 2 years after intracoronary administration of bone marrow-derived progenitor cells in acute myocardial infarction. Circ flavour Fail, 3, pp.89-96.Assmus B, Schachinger V, Teupe C, et al. 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