Stem cells as therapy for heart disease: iPSCs, ESCs, CSCs, and skeletal myoblasts

Biomedicine & Pharmacotherapy 109 (2019) 304–313

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Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha

Review

Stem cells as therapy for heart disease: iPSCs, ESCs, CSCs, and skeletal myoblasts

T

Reza Rikhtegara, Masoud Pezeshkianb,c, Sanam Dolatia, Naser Safaieb,c, Abbas Afrasiabi Radb,c, ⁎ Mahdi Mahdipourd, Mohammad Nourid, Ahmad Reza Jodatib,c, Mehdi Yousefie,f, a

Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran Department of Cardiac Surgery, Tabriz University of Medical, Tabriz, Iran c Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran d Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran e Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran f Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran b

ARTICLE INFO

ABSTRACT

Keywords: Heart disease Myocardial regeneration Tissue repair Stem cells

Heart Diseases are serious and global public health concern. In spite of remarkable therapeutic developments, the prediction of patients with Heart Failure (HF) is weak, and present therapeutic attitudes do not report the fundamental problem of the cardiac tissue loss. Innovative therapies are required to reduce mortality and limit or abolish the necessity for cardiac transplantation. Stem cell–based therapies applied to the treatment of heart disease is according to the understanding that natural self-renewing procedures are inherent to the myocardium, nonetheless may not be adequate to recover the infarcted heart muscle. Following the first account of cell therapy in heart diseases, examination has kept up to rapidity; besides, several animals and human clinical trials have been conducted to preserve the capacity of numerous stem cell population in advance cardiac function and decrease infarct size. The purpose of this study was to censoriously evaluate the works performed regarding the usage of four major subgroups of stem cells, including induced Pluripotent Stem Cells (iPSC), Embryonic Stem Cells (ESCs), Cardiac Stem Cells (CDC), and Skeletal Myoblasts, in heart diseases, at the preclinical and clinical studies. Moreover, it is aimed to argue the existing disagreements, unsolved problems, and prospect directions.

1. Introduction Cardiovascular diseases that damage the heart and lead to Heart Failure (HF), stimulate myocytes death and generation of fibrosis, as well as ventricular remodeling [1]. Heart failure is considered, deadly, incapacitating and a heavy disorder worldwide. The occurrence of HF in developed countries has extended epidemic proportions increasingly. However, the estimate HF patients referred to the hospital remains low. In the United States, HF is reported to affect about 6 million individuals, with more than 300,000 deaths annually, which costs over 40 billion dollars in the health care service [2]. Recent therapeutic approaches in HF patients increase the lifespan, but so far no document has been reported the essential efforts for the repair of cardiac tissue. Stem cells are cell types distinguished by their ability of self-renewal as well as their capacity to differentiate into developed progenitor cells that themselves could discriminate into

⁎

specific matured cells types [3,4]. Throughout the past 15 years, various preclinical and clinical studies investigated the capability of numerous stem cells to progress cardiac function and weaken adversative Left Ventricular (LV) remodeling in heart diseases [5]. In spite of this quick development, various essential questions arise which need to be determined, beside the fact that up to now no operative cell therapy in patients with cardiomyopathy has been reported. Afterward two decades of focused investigation and efforts of clinical trials, stem cell based therapies for cardiac diseases are not receiving nearer to clinical accomplishment [6]. This review addresses the existing state of advancement of Stem Cell (SC) therapy in heart diseases. We summarize the impact of studies conducted regarding the use of Induced Pluripotent Stem Cells (iPSCs), Embryonic Stem Cells (ESC), Cardiac Stem Cells (CSC), and Skeletal Myoblasts (Fig.1), and argue current debates, unsolved problems, as well as the prospective instructions.

Corresponding author. E-mail address: [email protected] (M. Yousefi).

https://doi.org/10.1016/j.biopha.2018.10.065 Received 9 June 2018; Received in revised form 4 October 2018; Accepted 12 October 2018 0753-3322/ © 2018 Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

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Fig. 1. Schematic of the suggested mechanism of stem cell therapy in the cardiac failure. The figure demonstrates the hypothetical action mechanisms of different stem cell populations proposed in improving of cardiac function and repair. Stem cells and progenitor cells are separated from either autologous or allogeneic sources of the source tissues. Transplanted stem cells have been shown to recover cardiac function and initiate myocardial repair through two direct and indirect mechanisms; 1) Direct differentiation to new myocytes, endothelial cells, and vascular smooth muscle cells. Secretion of angiogenesis stimulant and cytokines for increasing of angiogenesis. Secretion of paracrine stimulant that causes immunomodulation and increase Cardioprotection. 2) Indirect paracrine effects of transplanted stem cells increase the differentiation of resident cardiac stem cells to creating new heart tissue. iPSCs; induced pluripotent stem cells. ESCs; embryonic stem cells. CDCs; cardiac stem cells.

2. Stem cell–based therapies

which is the capacity of self-renewal and differentiation potentiality into several types of cell fates like cardiac myocytes [12,13]. The ability of iPSCs to maintain patient-particular genomic, transcriptomic, proteomic, metabolomics, and additional personalized information, makes it vulnerable in the field of disease modeling and treatment approaches based on personalized medicine [14,15]. Human Induced Pluripotent Stem Cells (hiPSCs) suggest an exceptional prospect to study human physiology and disease at the cellular level. This statement expansively refer to the origin of iPSC lines, their use for cardiovascular disease modeling, their use for precision medicine, and approaches through which to stimulate their wider use for biomedical uses [16]. Precision medicine indicates a revolution in patient carefulness, by affecting the incremental developments in diagnosis and treatment of acute or chronic disease to reach considerate the basic causes of disease and personalized treatment based on individuals’ distinctive genetic structure [17]. Production of particular Consensus Molecular Subtypes (CMSs) from hiPSCs will likewise permit more detailed identification of diseases that differently influence both the ventricles (e.g., Hypertrophic Cardiomyopathy (HCM; a main disorder that displays as asymmetrical ventricular wall thickening with bigger risk of sudden cardiac death (SCD)), Dilated Cardiomyopathy (DCM; most common type of cardiomyopathy, reveals with ventricular enlargement and thinning and heart failure from a severely compromised ejection fraction), Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC; usually a principal disorder in which there is gradual, adult-onset fibro-fatty replacement of cardiomyocytes, mainly in the right ventricle but occasionally affecting the left ventricle, with raised risk of SCD)) [16], or atria (e.g., atrial arrhythmias); moreover, initiates novel predictions for making patient-specific bioengineered pacesetters [18–20]. Important limits for the genome editing technology is not only the interval and price of the process, but further prominently, its effectiveness, and off-

In the previous years, excessive efforts have been conducted to induce the least aggression and more efficient sources of human cardiomyocytes for different application, particularly for myocardial regeneration. The pluripotent stem cell seems to be an appropriate candidate, due to its proliferate properties and its ability to distinguish into various cell types including cardiomyocytes [7]. Stem Cell based therapy has the probable to activate endogenous regenerative processes, containing the recruitment of resident stem and progenitor cells and the motivation of cardiomyocyte proliferation [8]. Secretion of soluble factors is the predominant mechanism of stem cell mediated heart regeneration [9]. Cytokines and growth factors like Transforming Growth Factor (TGF)-β, Stromal Cell-Derived Factor (SDF)-1, and Vascular Endothelial Growth Factor (VEGF), can be secreted by transplanted stem and progenitor cells into the intestinal space or bloodstream that stimulates numerous regenerative processes, for instance, neovascularization, activation of tissue intrinsic progenitor cells, decreased apoptosis of endogenous cardiomyocytes, and enrolment of cells of assistance for tissue repair [9,10]. Some biomarkers, like IL-15, IL-5 and SCF, associate with an improved cardiac function via stem cell treatment representing that higher levels of specific circulating cytokines are appropriate as choice principles for cell-based therapies [11]. The preclinical and clinical trials of stem cell therapy in heart failure and also advantages and disadvantages of these cells for cardiac regeneration are summarized in Tables 1–3, respectively. 2.1. Induced pluripotent stem cells (iPSCs) Induced Pluripotent Stem Cells (iPSCs) are pluripotent stem cells produced from adult somatic cells over a genetic reprogramming process. iPSCs have properties similar to Embryonic Stem Cells (ESCs) 305

306

-CPCs were labeled with EGFP -Intracoronary -CDCs

Rat

-Pigs with post infarct left ventricular dysfunction

Sprague-Dawley rat

Goettingen mini-pigs

CHF147 Syrian hamsters

Rats

-CSCs -Intracoronary

- Murine model of reperfused MI

-Intramyocardial or Intracoronary

-Doxorubicin-induced Cardiomyopathy in -Intracoronary -δ-sarcoglycan deficiency-induced dilated cardiomyopathy -Intramyocardial -Intramyocardial or Intracoronary

-Intracoronary

-Cardiac-committed mouse ESC -Intracoronary

-Sheep with myocardial infarction -Mini-pig

-Mice model of acute MI

-Iron oxide-labeled hiPSC-CMs cell sheets combined with an omentum flap -Epicardial via the median sternotomy -hiPSC-derived cardiomyocytes, endothelial cells, and smooth muscle cells, in combination with a 3D fibrin patch loaded with IGF encapsulated microspheres -Intramyocardial -iPSC-derived EVs -Intramyocardial

Study Design

-Increase LVEF -Increase Vasculogenesis -Increase LVEF -Improve physical activity

-Decrease LV remodeling -Improve regional and global LV function -Promote cardiac and vascular regeneration -Decrease Mortality -Improve hemodynamic parameters -Increase FAC -Decrease Fibrosis

-Improve LV function -Improve vascularization -Ameliorate of apoptosis and hypertrophy. -Improve LVEF -Decrease Infarct size -Improve hemodynamic Parameters -Decrease LV remodeling - Lessen of adverse LV remodeling and dysfunction -Improve global LV systolic and diastolic function -Decrease LV dilation and LV expansion index -Lessen fibrosis in the noninfarcted region -Improve LV function -Increase expression of cardiac proteins by endogenous CPCs. -Increase LVEF

-Increase vascular density in the transplanted area -Increase cardiac troponin T-positive cells -Increase the cardiac function

Outcome

[116]

[115]

[114]

[113]

[98]

[82]

[81]

[61] [78]

[44]

[41]

[40]

Reference

CDCs; Cardiosphere-Derived Cells, CPCs; Cardiac Progenitor Cells, CSC; Cardiac Stem Cells, EGFP; Enhanced Green Fluorescent Protein, ESC; Embryonic Stem Cells, EVs; Extracellular Vesicles, FAC; Fractional Area Change, hiPSC-CMs; Human Induced Pluripotent Stem Cell Derived Cardiomyocyte; LV; Left Ventricular, LVEF; Left-Ventricular Ejection Fraction, MI; Myocardial Infarction.

Skeletal myoblasts

Embryonic Stem Cells Cardiac Stem Cells

-Porcine model

Induced Pluripotent Stem Cells

-Porcine model of acute MI

Animal Model

Cell type

Table 1 Preclinical Trials of Stem Cell Therapy in Heart Failure.

R. Rikhtegar et al.

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Table 2 Clinical Trials of Stem Cell Therapy in Heart Failure. Cell type

Study Design

Delivery Method

Outcomes

Side Effects in Treated Patients

Reference

ESCs

-First clinical case report

-Isl-1+ SSEA-1+ cells were embedded into a fibrin scaffold surgically delivered onto the infarct area

-No most important complications

[70]

-hESCs to generate clinical-grade cardiovascular progenitor cells (SCIPIO) Open-label, randomized, controlled study

-Treatment group=6 patients -Epicardial -Treatment group=16; controls=7 -Intracoronary

-No most important complications -No most important complications

[71]

(CADUCEUS) Randomized, controlled study Phase I/II; (ALLSTAR)

-Treatment group=17 controls=8 -Intracoronary -Phase I: 14 patients -Phase II: 120 patients - Intracoronary -Treatment group =10 -Intramyocardial

-Decrease NYHA -Increase LVEF class -Improve systolic motion -Increase LVEF -Decrease Infarct size -Decrease NYHA class -Decrease scar mass -Reduce scar size

-Serious adverse events

[96]

–

[100]

-Increase LVEF -Increase Regional wall motion -Decrease NYHA class -Increase LVEF -Decrease NYHA class -Increase LVEF -Decrease NYHA class

-Ventricular arrhythmias in 4 patients −2 deaths

[117]

No most important complications

[118]

-Ventricular arrhythmias in 5 patients

[120]

-Decrease LVESV and LVEDV in high dose group

High dose: 5 patients with ventricular arrhythmias and 4 deaths

[121]

-Decrease NYHA class

-Ventricular arrhythmias in 12 patients, 1 death

[122]

Cardiac stem cells

Skeletal myoblasts

Nonrandomized, uncontrolled study

Non-randomized, uncontrolled study (POZNAN) Cohort study

Randomized, Placebo controlled, double-blind study (MAGIC)

Prospective, randomized, open-label study (SEISMIC)

-Treatment group =10; -Percutaneous Trans-coronaryvenous -Treatment group =9 no controls -Intramyocardial injection during CABG CABG -Treatment group =97 controls=30 -Intramyocardial injection during CABG Low dose: 400×106 High dose: 800×106 cells -Treatment group =26 controls=14 -Intramyocardial -Transendocardial

[84,85]

ALLSTAR; ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration, CABG; Coronary Artery Bypass Grafting, CDCs; Cardiosphere-Derived Cells, CPCs; Cardiac Progenitor Cells, CSC; Cardiac Stem Cells, EGFP; Enhanced Green Fluorescent Protein, ESC; Embryonic Stem Cells, EVs; Extracellular Vesicles, FAC; Fractional Area Change, hiPSC-CMs; Human Induced Pluripotent Stem Cell Derived Cardiomyocyte; LV; Left Ventricular, LVEDV; LV End-Diastolic Volume, LVEF; Left-Ventricular Ejection Fraction, LVESV; LV End-Systolic Volume, MAGIC; Myoblast Autologous Grafting in Ischemic Cardiomyopathy, MI; Myocardial Infarction, NYHA; New York Heart Association, POZNAN; Post-infarction Myocardial Contractility Impairment, SCIPIO; Cardiac Stem cell Infusion in Patients with Ischemic Cardiomyopathy, SEISMIC; Safety and Effects of Implanted (Autologous) Skeletal Myoblasts (MyoCell) Using an Injection Catheter).

target special effects [21,22]. Consequently, an extra trial for the nextgeneration sequencing (NGS) technology is to hasten the amount of information investigation. The definite generation of NGS information is gradually rising, particularly the several data being created for Genome-Wide Association Studies (GWAS) have discovered several genetic variants Single-Nucleotide Polymorphism (SNPs) and alternative splicing forms that are related to blood pressure along with human heart progress [23,24]. hiPSC-based sequencing of patient's misery the disease is anticipated to leader diagnosis and treatment conclusions [25]. Through merging the powers of elementary scientific investigation, biomedical documents knowledge, genome editing, and transformative biomedical stages such as hiPSCs, we could essentially initiate to comprehend personal difference in disease advance, progress, and reaction to the particular treatment [26,27]. In 2006, Takahashi and Yamanaka by means of mature fibroblasts from transducing mouse with definite transcription factors known as

Yamanaka factors including; c-Myc, Sex Determining Region Y-box 2 [Sox-2], Octamer-Binding Transcription Factor 3/4[OCT3/4], KruppelLike Factor 4 [Klf4]; generated a population of iPSCs [5]. Subsequently, it was established that these iPSCs have excessive potential for cardiac regeneration, and that iPSC-derived cardiomyocytes have practical characteristics of cardiac cells like contractility, spontaneous beating, and ion channel expression [28]. Functional cardiomyocytes have been produced from both mouse and human iPSCs, whereas ultimate differentiation of iPSCs to completely matured cardiomyocytes in vitro is still an unsuccessful aim [29,30]. Furthermore, hopeful in vivo trials in MI models displayed the engraftment along with developed cardiac efficiency, decreased infarction size and weakened cardiac remodeling after iPSC-derived cardiomyocytes transplantation [31,32]. The main concern about hiPSC is the immature state of discriminated derivatives [33], and numerous signals are under 307

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Table 3 Characteristics of different types of stem cells used for cardiac regeneration. Cell type

Advantageous

Disadvantageous

iPSCs

-Pluripotent differentiation and self-renewal -Low ethical concerns -Easily accessible source tissue -Robust myocardiogenic capacity

ESCs

-Pluripotent differentiation and self-renewal -Easily generation of cell lines - Incorporate electromagnetically into the host myocardium

CSCs

-Autologous transplantation -Multipotent -Safety in clinical trials -Low risk of tumorigenicity -Short culture period (weeks) is required to produce CM −Easy to obtain from muscle biopsies -Autologous transplantation -Resistance to ischemia −Low ethical concerns −Low risk of tumorigenicity

-Teratoma formation - Immunologic rejection - Limited genome editing technology -Possible genomic instability - Untested in clinical setting - Ethical issues -Allogenic only - Teratoma formation -Genomic instability -Lack of availability -Immunologic rejection -Restricted cell quantity -Access from invasive myocardial biopsies -Inadequate cell characterization - Stem cell pool appears to undergo senescence

Skeletal myoblasts

−Lack of functional cardiomyocytes differentiation −Risk of ventricular arrhythmias - Low long-term survival rate - Invasive isolation procedure

CM; Cardiomyocyte, CSC; Cardiac Stem Cells, ESC; Embryonic Stem Cells, hiPSC; Human Induced Pluripotent Stem Cell.

2.2. Embryonic Stem Cells (ESCs)

examination to permit these cells to mature into an adult human heart [34–36]. The transcription factors of c-Myc, Oct4, and Klf4 make these cells are identified as oncogenes that can create teratoma. Innovative approaches comprising transitory expression of the reprogramming factors, might prevent this obstacle, however, the pluripotent feature of these cells can stimulate tumorigenesis [37]. Another complication involved is the ability of iPSC generation, since the variableness exists among every cell lines. By the uprising in the development of equipment in this ground, it is probable that these methodological impediments will get inspired, and iPSC based practices will demonstrate to be beneficial for the treatment of heart diseases, while iPSCs are not yet carried for clinical use [38]. After that, major genomic instabilities in iPSC lines containing epigenetic memory, unusual methylation patterns and mutations have been described due to variants in parenteral somatic cells or happening through the reprogramming procedure and culturing time [39]. Kawamura et al. described the transplantation of cell sheets composed of cardiac myocytes derived from human iPSCs by a pig model of myocardial infarction [40]. Transplantation of human iPSCs derived cardiac myocytes intramyocardially accompanied by smooth muscle cells and endothelial cells, with a 3-dimensional fibrin patch comprising Insulin-Like Growth Factor 1 (IGF-1) was revealed to improved Left Ventricular (LV) function, myocardial metabolism, and arteriole density, whereas decreasing infarct size, ventricular wall stress, and apoptosis without prompting ventricular arrhythmias in porcine model of acute myocardial infarction [41]. A new finding indicates the restoration effect of small membraneenclosed droplets that transport biologically active molecules, and genetic materials including stem cell-specific RNAs and proteins from parent cells; called extracellular vesicles (EVs) [42]. Developing confirmation recommends that stem cell-derived EVs such as iPSC-derived EVs permit to increase and moderate endogenous protection through transportation of the cargo to numerous cardiovascular cells and motivate reparation of the procedures cells [43]. iPSC-derived EVs contain various population of non-coding RNAs including miRNAs and proteins which could impact the cell survival and proliferation. In a study, mice has been used and was injected with only iPSCs, exhibited teratomas, while on the contrary, none of the mice injected with iPSC-EVs developed into teratomas [44].

ESCs are pluripotent cells collected from the internal cell bulk of human blastocysts, the Inner Cell Mass (ICM) in the preimplantation embryos. ESCs have the ability to discriminate into cells of all 3 germ layers, that is, ectoderm, endoderm, and mesoderm when cultivated as 3-dimensional cystic aggregates (embryoid bodies) [45]. Cardiomyocytes are known to be originated from the mesoderm layer [46]. Stage Specific Embryonic Antigen (SSEA-1) and SSEA-4, TRA-1-60 and TRA1-81 antigens, Frizzled proteins (Fzd 1–10), Teratocarcinoma-Derived Growth Factor 1 (TDGF-1) proteins are expressed in human ESC [47]. Numerous procedures have been effectively advanced to stimulate produce cardiomyocytes from ESCs in vitro. Even though the generation of completely matured cardiomyocytes in enormous produces and with great purity is yet impracticable, these studies confirmed influential cardiogenic probable of ESCs [48,49]. Nevertheless, clinical trials of these cells has been vulnerable by major problems, comprising ethical issues, genetic variability, the risk of immune rejection and tumorigenic possibility [50,51]. Actually, several first studies theorize that the cardiac environment is adequate to stimulate the differentiation of ESCs into cardiomyocytes [52]. Though, this recommendation has been disproven, from the time when the creation of teratomas was discovered subsequently intramyocardial injection of undifferentiated ESC [6,53]. Human ESC–derived cardiomyocytes display adult cardiomyocytes morphology expressing sarcomeric proteins. The possibility of derivation of cardiomyocytes from ESCs has enlightened the interest in exploration if their impacts in cardiomyopathy [54]. Cardiomyocytes markers are categorized for two phases of early and late differentiation. After 5–6 days of differentiation, the markers of GATA Binding Protein 4 (GATA-4), Insulin Gene Enhancer Protein (ISL1), and Kinase Insert Domain Receptor (KDR) become highly expressed. Later at the day 8–9, expression level of markers NK2 homeobox5 (NKX2–5), T-Box 5(TBX5), Myocytes-Specific Enhancer Factor 2C (MEF2C), HAND1/2 is in peak, followed by an increase of myofilament genes (Troponin T2 (TNNT2) and Myosin Heavy Chain 6(MYH6)) at day 8–10 [55–57]. Preclinical investigations have emphasized the fact by which retroviral-based gene transfer could assist to avoid cell-based therapy by directing of cardiac fibroblast in the infarct scar to produce useful myocytes [58,59]. Remuscularization in the infarct scar in a mouse model possibly will result in ventricular dysrhythmias. The dependence on retrovirus technology in this method prevents direct clinical transformation; but, this 308

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procedure may work as a plan to renew the fibrotic myocardium in patients with ischemic cardiomyopathy, and inhibit disease progress [60]. Nonetheless, published documents proposes the possible usefulness of cardiomyocytes made in vitro inside the infarct scar possibly will also be accounted in patients with arrhythmia and tachycardia [59,60]. In a study performed by Menard et al. [61], mouse ESCs were transferred into infarcted sheep myocardium resulted in differentiation of these cells into cardiomyocytes and enhanced LV function. Likewise, using of human ESC–derived cardiomyocytes in rat models of myocardial infarction and concluded the steady production of cardiomyocytes grafts, weakening of LV remodeling, and progress of LV systolic activity [62,63]. Regardless of the documented capability of ESCs in cardiac deficiency, the clinical application of these potent cells as a treatment modality in patients has been stopped by ethical and biological alarms. Particularly, pluripotency and allogeneic nature of ESCs, leads to overwhelmed adoptive transmission by creation of teratoma and graft refusal, which are considered as major challenging difficulties that principally prevent the clinical use of these cells [64–66]. The little understanding in the field as well as the complications of tumorigenesis and refusal involved in the clinical applications makes it improbable that interest for the use of ESCs will become favorable [66–68]. Recently, human ESC-derived differentiated cells have been used in patients with spinal cord injury and ocular diseases. Human ESCs were directed into cardiac cells using Fibroblast Growth Factor Receptor Inhibitor (FGFRI) and Bone Morphogenetic Protein 2 (BMP2) [69]. It was revealed that, cells reacting to these signals express the cardiac transcription factors including Insulin Gene Enhancer Protein (Isl-1) and the SSEA-1. In this study, Isl-1+ SSEA-1+ cells were transplanted into the infarct site in a 68-year-old patient with New York Heart Association [NYHA] functional Class III; Left Ventricular Ejection Fraction (LVEF): 26% [70]. Three months post transfer, the patient was in a better health condition (NYHA functional Class I; LVEF: 36%) and no complications like arrhythmias, tumor creation, or immunosuppression adversative were reported [70]. In more recently study, the feasibility of hESCs to generate clinical-grade cardiovascular progenitor cells and their safety in patients with severe ischemic left ventricular dysfunction were assessed. Six patients (median age 66.5 years; median LV ejection fraction 26% received a median dose of 8.2 million hESC-derived cardiovascular progenitors embedded in a fibrin patch that was epicardially delivered during a coronary artery bypass procedure [71]. All patients were symptomatically improved with an increased systolic motion of the cell-treated segments and no tumor was detected during follow-up, and none of the patients presented with arrhythmias. This trial establishes the technical possibility of producing clinical-grade hESC-derived cardiovascular progenitors and supports their short- and medium-term safety [71]. Moreover, human ESC-derived cells expressing Receptor Tyrosine Kinase-Like Orphan Receptor2 (ROR2)+, CD13+, Vascular Endothelial Growth Factor Receptor 2 (KDR)+, Platelet-Derived Growth Factor Receptor A (PDGFRα)+ have been lead to produce endothelial cells, vascular smooth muscle cells and cardiomyocytes, in vitro [72]. The potentiality of these precursor cells is self-renewal and maintenance the capable of differentiating into cardiovascular lineages in vitro. This cell population possibly will provide an innovative origin of cells for cardiac regenerative medication [14,72].

cardiomyocytes, while vascular progenitors differently obtain vascular smooth muscle cell and endothelial cell fates [74]. C-kit+ CSCs sequestered from the grown-up rat heart were revealed to be self-renewing, multipotent, clonogenic and demonstrated all the features of stem cells. Moreover, these sells after inoculated into the damaged myocardium, were reported to be capable of reestablishing the cardiac structure and activity [75,76]. In the heart, a small fraction of c-kit+ CSCs expresses the transcription factors Nkx2.5 and GATA-4, representing their commitment to the myogenic lineage [77]. Significant mechanism for excretion of cytokines and growth factors by CSCs that could apply paracrine activities on endogenous CSCs, lead them to proliferate and discriminate into adult cardiac cells [78]. C-kit+ CSCs considerably improved angiogenesis post MI in a paracrine manner by the secretion of VEGF [79]. In one study intracoronary and intramyocardial delivery of lin−/ckit+/GFP+ cardiac stem cells (CSCs) in a murine model of reperfused MI were compared [80,81]. Intracoronary delivery of CSCs 2 days postMI cause to significant lessening of adverse LV remodeling and dysfunction, which was at least equivalent, to that achieved with intramyocardial delivery. Intracoronary infusion was accompanying with a more homogeneous distribution of CSCs in the infarcted region. Intracoronary CSC delivery resulted in improved function in the infarcted region, as well as in improved global LV systolic and diastolic function, and in decreased LV dilation and LV expansion index. This is the first study to report that intracoronary infusion of stem cells in mice is feasible and effective [81]. In another study, CPCs were labeled with Enhanced Green Fluorescent Protein (EGFP) and then injected intracoronary in rats. A month later, rats displayed more functional myocardium in the danger area, fewer fibrosis in the noninfarcted section, and developed LV activity, after 35 days [82]. Transplantation of CPCs was accompanying with increased proliferation and expression of cardiac proteins by endogenous CPCs. This is the first evidence that exogenous CPC administration activates endogenous CPCs [82]. In another animal model study, three months post MI in pigs, 1 × 10 6 autologous CSCs were transferred into the infarcted artery. One month after the treatment, an augment in left ventricular ejection fraction and systolic thickening fraction, along with reduction in LV end-diastolic pressure were observed [78]. Confocal microscopy showed clusters of small α-sarcomeric actin-positive cells expressing Ki67 in the scar of treated pigs, consistent with cardiac regeneration [78]. Remarkably, CSCs had a considerably bigger valuable outcome in small animal models compared with large animal models (∼12% vs. 5% improved LVEF) [83]. The hopeful consequences of these studies lay the foundation for first phase I clinical trial of CSCs; Cardiac Stem cell Infusion in Patients with Ischemic Cardiomyopathy (SCIPIO) [78,82]. In this study, following to Coronary Artery Bypass Grafting (CABG), 1 million autologous CSCs were delivered by intracoronary infusion [84,85]. In CSC-treated patients, LVEF augmented to 36.0 ± 2.5% at 4 months after infusion and also, there was a deep decrease in infarct size in 1 year (from 33.9 ± 3.0 to 18.7 ± 3.6 g) [84,86]. These encouraging findings warranty for progressive, phase II studies. In SCIPIO, cardiac stem cells were sequestered from the right atrial appendage which could be separated and developed from endomyocardial biopsy samples, that make usage of autologous CSCs for patients with heart disease [87]. Several extra populations of recognized endogenous cardiac stem and progenitor cells have been known in the heart, containing Cardiosphere-Derived Cells (CDCs) [88], Stem Cells Antigen-1(Sca-1)+ cells [89], and Isl-1+ cells [90]. A mass of cells were secluded and amplified as self-adherent bulk and can discriminate into endothelial cells, cardiomyocytes, and smooth muscle cells called cardiospheres were recognized by Messina et al., in 2004, after subcultures of atrial or ventricular human biopsy specimens and murine hearts [91,92]. In addition to, Cardiosphere-Derived Cells (CDCs) were acquired from percutaneous endomyocardial biopsy samples, discriminated into electrically steady cardiomyocytes resulted in stimulation of cardiac

2.3. Cardiac Stem Cells (CSCs) The detection of mature Cardiac Stem Cells (CSCs) and their potential to renovate cardiac tissue has been brought to attention in the recent years [6]. CSCs were introduced for the first time by Beltrami et al. [73]. The expression of KDR in the pool of c-kit+ CSCs differentiates myocytes progenitor cells (KDR−) and vasculogenic progenitor cells (KDR+), both of which can differentiate into cardiomyocytes, endothelial cells, and smooth muscle cells; nevertheless, myocytes progenitor cells have a superior susceptibility to produce 309

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renewal and developed cardiac activity when injected into a murine model of infarction [93]. Cardiospheres and CDCs are a heterogeneous population of different cell types, and express antigenic indicators including CD34, c-kit, Sca-1, KDR, CD105 and CD90 [94–96]. CDCs from advanced HF patients displayed a higher paracrine expression of SDF-1. Transfer of HF CDS into infarcted mice hearts increased the proliferation rate of endogenous endothelial cells by ∼30% [97]. Johnston and colleagues reported that pigs with longstanding MI which have received human CDCs as intracoronary in a preclinical model of post-infarct left ventricular dysfunction, exhibited cardiac regeneration, lessening in comparative infarct size, weakening of unfavorable LV remodeling, progress in cardiac activity, and improves hemodynamics [98]. The confirmation of efficacy without obvious safety stimulates human studies in patients after myocardial infarction and in chronic ischemic cardiomyopathy [98]. Makkar and colleague described a phase I, randomized trial of Cardiosphere-Derived Autologous Stem Cells to Reverse Ventricular Dysfunction (CADUCEUS), in patients with a current MI [96]. After a year of follow-up, CDC-treated patients displayed 42% decrease in scar size, associated with a rise in operable tissue and local systolic wall stiffening in the infarcted area. Nevertheless, CDC therapy was unsuccessful in increased LVEF and reduction of LV volumes [96,99]. Based on the controversy in this area, it is quite complicated to recognize which element(s) direct the health properties. So, greater phase II investigations are required to appraise the healing properties of CDCs [91]. The ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR) trial is a multicenter randomized, double-blind, placebo-controlled phase 1/2 safety and efficacy trial of intracoronary delivery of allogeneic CDCs (CAP-1002) in patients with myocardial infarction (MI) and ischemic left ventricular dysfunction [100]. The phase 1 safety cohort enrolled 14 patients in an open-label, nonrandomized, dose-escalation safety trial. The phase 2 trial is a double-blind, randomized, placebo-controlled trial that will compare intracoronary CDCs to placebo in a 2:1 allocation and will enroll up to 120 patients. The primary endpoint for both phases is safety at 1 month. For phase 2, the primary efficacy endpoint is relative change from baseline in infarct size at 12 months, as assessed by MRI. The results from the ALLSTAR phase 1 trial established that IC infusion of allogeneic CAP1002 was safe and practicable. These results cause to enrollment of the phase 2 trial to more evaluate safety and also assess efficiency of allogeneic CDCs in decreasing scar size in ischemic cardiomyopathy [100]. Sca-1+ progenitors were described by Oh and colleagues in the mature mouse [101]. These cells also expressed CD29 (β1-integrin) and CD44 (hyaluronic acid receptor), GATA-4, MEF2C and mouse embryonic fibroblast (MEF-1) however, they do not express c-kit, Fms-Like Tyrosine Kinase 1 (Flt-1), Fetal Liver Kinase 1 (Flk-1), vascular endothelial cadherin, Von Willebrand factor, and HSC markers [101]. Sca1+ cells have the capability to differentiate into beating cardiomyocytes and endothelial cells. These cells have been reported to cause reduction of LV remodeling in a murine model of MI [102,103]. There is no human homolog of Sca-1 Isl-1+ cells could transform into a matured cardiac phenotype with the complete calcium dynamics. Significantly, these cells neither act as cardiac progenitors nor have any clinical use because of they are not in the postnatal ventricular myocardium [104,105].

derivative from skeletal muscle progenitor cells (satellite cells) with regenerative capacity [1]. Following a damage in the muscle, these progenitor cells experience multiplying and stimulate renewal by discriminating into myotubes and fresh muscle fibers [109]. The first effective transplant of skeletal myoblasts into the damaged human heart was experimented in 1994 [110]. For that, skeletal myoblasts differentiated into myotubes and then inter-connected with decrease of adversarial ventricular renovation, reduced interstitial fibrosis, and increase of cardiac act [111]. After the process of differentiation, the skeletal myotubes miss the capability to form gap junctions because of their deficiency in expressing main gap junction proteins such as connexin-43 and N-cadherin, which results in the lack of electrical integration with the myocardium and enhanced risk of ventricular arrhythmia [112]. The capability of skeletal muscle progenitor cells to gain cardiac action has also been revealed in two studies including nonischemic cardiomyopathy stimulated through doxorubicin in rats [113]and nonischemic cardiomyopathy motivated via δ-sarcoglycan gene mutation in CHF147 Syrian hamsters [114]. In another preclinical study, chronically infarcted Goettingen mini-pigs were divided in four groups that received either media control or one, two, or three doses of skeletal myoblast at intervals of 6 weeks and were followed for a total of 7 months [115]. A significantly greater increase in the LVEF, increase in tissue vasculogenesis and decreased fibrosis was detected in animals that received three doses vs. a single dose. Repeated injection of skeletal myoblast in a model of chronic MI is feasible and safe and induces a significant improvement in cardiac function [115]. Fukushima et al. exhibited that injection of skeletal myoblast via either the intramyocardial or retrograde intracoronary route in the same way improved cardiac function and physical activity, accompanying with decreased cardiomyocyte-hypertrophy and fibrosis [116]. Cardiomyogenic differentiation of grafted skeletal myoblast was very rare. Only intramyocardial injection of skeletal myoblast produced spontaneous ventricular tachycardia up to 14 days. Retrograde intracoronary injection of skeletal myoblast delivered significant therapeutic profits with weakened early-phase arrhythmogenicity in treating ischemic cardiomyopathy, representing the hopeful efficacy of this route for skeletal myoblast -delivery [116]. These hopeful outcomes from animal studies were rapidly transformed into clinical trials in heart diseases. Menasche and colleagues established first human transfer of myoblasts in patients with severe ischemic HF [117]. In this phase I study, inoculation of cells into a damaged LV section at the time of CABG was concomitant with a substantial development in LV function and NYHA functional class. In this study, 4 out of 10 patients practiced ventricular tachycardia [117]. In follow up experiments, minor, non-randomized studies exposed increased LV function, developed LV remodeling, and histological confirmation of myoblast endurance in the myocardium after intramyocardial inoculation in patients with ischemic cardiomyopathy [117]. A phase I study of Percutaneous Transcoronary-venous Transplantation of Autologous Skeletal Myoblasts in the Treatment of Post-infarction Myocardial Contractility Impairment [POZNAN] trial) described an upgrading in NYHA class and LVEF in 10 patients [118]. In Phase-1 randomized, controlled study using 3-dimensional guided Catheter-Based Delivery of Autologous Skeletal Myoblasts for Ischemic Cardiomyopathy (CAuSMIC Study), treated patients showed improvement in NYHA, Minnesota Living with Heart Failure Questionnaire (MLHFQ), ventricular viability, and evidence of reverse ventricular remodeling at 1 year after therapy [119]. In long-term follow-up of the first phase I cohort study of patients with severe heart failure after intramyocardial injection during CABG, both clinical status and LVEF steadily improve over time with a strikingly low incidence of hospitalizations for heart failure and the arrhythmic risk can be controlled by medical therapy [120]. In another randomized phase II trial, Menasche and colleagues performed a placebo-controlled, double-blind experiment, Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) that surveyed the

2.4. Skeletal Myoblasts (SkM) Skeletal muscle degenerative is observed in a variety of chronic diseases comprising chronic heart failure [106]. Muscle wasting is present in about 70% of chronic HF patients [107]. A number of theories have been put forth to describe the HF-related skeletal muscle losing, some of which are physiologic, containing prolonged immobilization and malnutrition, or pathologic, such as insulin resistance, damaged myogenesis and inflammation [108]. Skeletal myoblasts are 310

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effects of intramyocardial inoculation of skeletal myoblasts (400 or 800 × 106) with CABG in competition with CABG lonely as control group in patients with drastic LV dysfunction. It was established that patients treated with 800 × 106 cells had reduction of LV renovation and a lessening in LV sizes [121]. In the current phase IIa, randomized trial of percutaneous intramyocardial transplantation of myoblasts, Safety and Effects of Implanted (Autologous) Skeletal Myoblasts (MyoCell) Using an Injection Catheter (SEISMIC) trial, in patients with HF, myoblast therapy was not accompanying with any progress in LVEF at 6-month follow-up, though there was an advance in 6-minute walk distance [122]. The primary outcomes of randomized, placebo-controlled, multicenter study of trans-catheter intramyocardial administration of myoblasts in HF (To Assess Safety and Efficacy of Myoblast Implantation Into Myocardium Post Myocardial Infarction [MARVEL] trial) [5], displayed development in 6-minute walk distance at 3 and 6 months, and also rise in the incidence of constant ventricular tachycardia in patients [123]. As a consequence of the elongated interval between biopsy and cell implantation, skeletal myoblast implantation was ruled out for patients in requirement of rapid revascularization or other urgent cardiac surgery. Clinical trials of skeletal myoblast implantation distinguished increased ventricular arrhythmias subsequent surgery [117]. As a result of the adverse outcomes of MAGIC, the threat of arrhythmias, and also accessibility of other cell types, the attention to skeletal progenitor cells based therapy of heart diseases was diminished.

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3. Conclusion Epidemic abundance of heart disease carries on rising over the time. Many patients with injured myocardium have to suffer symptoms of heart failure which could be lessened by medicines, repeated coronary revascularization and cardiac transplantation. Disappointingly, a number of the patients fail to satisfactorily respond to these therapies; besides, many patients have no chance of getting cardiac transplantation, because of very restricted accessibility of heart donors and other complications involved. The revolt in stem cell technology, together with the improved considerate of the endogenous processes essential organ repair, has delivered the scientific basis for the progress of regenerative attitudes. New therapies such as stem cell therapy for cardiac regeneration have been progressively examined in the recent years. Considering the present position of cell-based therapies for heart disease, it is significant to retain a historic perception. Many significant concerns (e.g., mechanisms of stem cells action, long-standing engraftment, optimum cell types, dosage, route, and rate of recurrence of cell administration) keep on being determined, and no cell therapy has been determinedly revealed to be operative. It is factual that the detailed instrument of stem cells’ acts residues uncertain and their efficiency in heart diseases has not been recognized. Currently, it is not pure whether and which type of stem cell or technique of cell delivery is better than others. Due to this attitude, it is believed that cell based therapies are probable to develop into a clinical truth that might establish the new generation of treatment for heart diseases. In point of fact, it is expected that increasing amount of comparative studies will be the emphasis issue of impending basic and clinical studies in cardiovascular regenerative medicine. Conflict of interest The authors report no conflicts of interest in this work. Acknowledgments The authors would like to thank the Aging Research Institute, Tabriz University of Medical Sciences, for supporting this work. 311

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