Review Ethical And Safety Issues Of Stem Cell-Based Therapy

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Int. J. Med. Sci. 2018, Vol. 15IvyspringInternational Publisher36International Journal of Medical Sciences2018; 15(1): 36-45. doi: 10.7150/ijms.21666ReviewEthical and Safety Issues of Stem Cell-Based TherapyVladislav Volarevic1 , Bojana Simovic Markovic1, Marina Gazdic2, Ana Volarevic1, Nemanja Jovicic3,Nebojsa Arsenijevic1, Lyle Armstrong4, Valentin Djonov5, Majlinda Lako4 and Miodrag Stojkovic21.2.3.4.5.University of Kragujevac, Serbia, Faculty of Medical Sciences, Department of Microbiology and Immunology, Center for Molecular Medicine and Stem CellResearch;University of Kragujevac, Serbia, Faculty of Medical Sciences, Department of Genetics;University of Kragujevac, Serbia, Faculty of Medical Sciences, Department of Histology and Embryology;Institute of Genetic Medicine, Newcastle University, UK;Institute of Anatomy, University of Bern, Bern, Switzerland. Corresponding author: Prof. Vladislav Volarevic, Department of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research,Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia. Phone: 38134306800; fax: 38134306800 ext. 112.E-mail: drvolarevic@yahoo.com Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) /4.0/). See http://ivyspring.com/terms for full terms and conditions.Received: 2017.06.28; Accepted: 2017.10.11; Published: 2018.01.01AbstractResults obtained from completed and on-going clinical studies indicate huge therapeutic potential of stemcell-based therapy in the treatment of degenerative, autoimmune and genetic disorders. However, clinicalapplication of stem cells raises numerous ethical and safety concerns.In this review, we provide an overview of the most important ethical issues in stem cell therapy, as acontribution to the controversial debate about their clinical usage in regenerative and transplantationmedicine.We describe ethical challenges regarding human embryonic stem cell (hESC) research, emphasizing thatethical dilemma involving the destruction of a human embryo is a major factor that may have limited thedevelopment of hESC-based clinical therapies. With previous derivation of induced pluripotent stem cells(iPSCs) this problem has been overcome, however current perspectives regarding clinical translation ofiPSCs still remain. Unlimited differentiation potential of iPSCs which can be used in human reproductivecloning, as a risk for generation of genetically engineered human embryos and human-animal chimeras, ismajor ethical issue, while undesired differentiation and malignant transformation are major safety issues.Although clinical application of mesenchymal stem cells (MSCs) has shown beneficial effects in the therapyof autoimmune and chronic inflammatory diseases, the ability to promote tumor growth and metastasisand overestimated therapeutic potential of MSCs still provide concerns for the field of regenerativemedicine.This review offers stem cell scientists, clinicians and patient’s useful information and could be used as astarting point for more in-depth analysis of ethical and safety issues related to clinical application of stemcells.Key words: embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, stem cell-basedtherapy.IntroductionStem cells have raised tremendous expectationsamong the medical doctors, researchers, patients, andthe general public due to their capacity to differentiateinto a broad range of cell types. Stem cell researchersare engaged in different endeavors, including treatinggenetic disorders and generating new stemcell-derived human tissues and biomaterials for use inpharmacy genomics and regenerative medicine.Results obtained from completed and on-goingclinical studies indicate huge therapeutic potential ofstem cell-based therapy in the treatment ofdegenerative, autoimmune and genetic disorders [1,2].However, clinical application of stem cells raisessome ethical and safety concerns. In this review weprovide an overview of the most important ethicalhttp://www.medsci.org

Int. J. Med. Sci. 2018, Vol. 15issues in stem cell research and therapy, as acontribution to the debate about their clinical use inregenerative and transplantation medicine. Wedescribe and discuss ethical challenges regardinghuman embryonic stem cell (hESC) research,therapeutic potential and clinical translation ofinduced pluripotent stem cell (iPSC) and safety issuesof mesenchymal stem cell (MSC)-based therapy.Our hope is that stem cell scientists andclinicians will use the information presented herein asa starting point for more in-depth analysis of ethicaland safety issues related to clinical translation of stemcells since controversial regulation and application ofstem cell therapy has been falsely celebrated not onlyin countries with lax medical regulations but also inmany developed countries. For instance, in 2016, 351US businesses engaged in frequently unproven anddirect-to-consumer marketing of different stem cellinterventions was offered at 570 clinics [3].Ethical and safety concerns regardinghESC-based therapyhESCs are stem cells derived from thepluripotent inner cell mass of the pre-implantationembryos [4, 5]. hESCs express typical pluripotentstem cell markers such as octamer-bindingtranscription factor 3/4 (OCT3/4), stage specificembryonic antigens 3 and 4 (SSEA-3 and SSEA-4),TRA-1-60, TRA-1-81 and alkaline phosphatase,37possess high levels of telomerase activity and shownormal karyotype [6, 7]. hESCs have capacity todifferentiate into cell types of all three germ layers[endoderm, mesoderm, and ectoderm] under in vitroand in vivo conditions [6, 7]. Consequently, hESCshold great promise in understanding of early humanembryology and for developing the cell replacementstrategies for the treatment of human diseases (Figure1).Nevertheless, the ethical dilemma involving thedestruction of a human embryo was and remains amajor factor that has slowed down the developmentof hESC-based clinical therapies.The fundamental question is: Whether it ismorally acceptable to pursue novel therapies forcuring illnesses at the expense of destroying an earlyhuman embryo? This debate brings out individualopinions so deeply rooted in basic moral beliefs thatdeveloping a definitive policy acceptable to everyoneseems unlikely. This ethical dilemma is portrayed indifferent legislation that exists throughout the worldregulating hESCs research [8, 9]. For example, inmany countries including United Kingdom, it isillegal to perform nuclear transfer (NT) forreproductive or therapeutic purposes, while use ofhESCs for research is allowed. Other countries retainmore extreme stances, as is the case of Italy wherethere is a prohibition on all hESC-based research. Oncontrary, it is legal to use supernumerary in vitroFigure 1. Schematic diagram describing characteristics of ESCs. Embryonic stem cells (ESCs) are harvested from a blastocyst. Embryonic stem (ES) cells arederived from the inner cell mass of the pre-implantation embryo. Fully characterized hESCs express typical pluripotent stem cell markers such as octamer-bindingtranscription factor 3/4 (OCT3/4), stage specific embryonic antigens 3 and 4 (SSEA-3 and SSEA-4), TRA-1-60, and TRA-1-81.These cells are pluripotent, meaning theycan differentiate into cells from all three germ layers (ectoderm, mesoderm and endoderm). Main ethical issues (labeled with question marks): isolation of ESCsinvolves the destruction of a human embryo; transplantation of undifferentiated ESCs may result with a formation of teratomas, tumors that contain all three germlayers.http://www.medsci.org

Int. J. Med. Sci. 2018, Vol. 15fertilization (IVF)-derived embryos for derivation ofnew hESCs lines and to perform NT for the generationof patient-specific stem cells in the United Kingdom[10-12]. United States banned production of anyhESCs line that requires the destruction of an embryoand research using hESCs lines is limited on usage oflines created prior to August 9, 2001. Presentrestrictions have additionally slowed the progress ofhESCs technology and provide a significant barrier tothe development of cell based clinical therapies.Additionally, the ethical debate surrounding theharvest of hESCs has made research on this topiccontroversial, and as a result, the majority of studieswere focused on animal models [13].It is important to highlight that beside ethicalconcerns, safety issues regarding hESC-based therapyare the main problem for their clinical use. Thepluripotency of hESCs is a double-edged sword; thesame plasticity that permits hESCs to generatehundreds of different cell types also makes themdifficult to control after in vivo transplantation [14].When undifferentiated hESCs are transplanted,teratomas, tumors that contain all three germ layers,could develop [Figure 1] [15]. Studies have revealedthat appearance of teratoma is between 33-100% inhESC-transplanted immunodeficient mice, dependingon the implantation site, cell maturation, purity, andimplantation techniques [16, 17].Currently, the only way to ensure that teratomawill not develop after hESC transplantation is todifferentiate them in desired and mature cell typebefore injection and screen them for the presence ofundifferentiated cells. When such procedures wererigorously followed, teratomas were not observed inover 200 animals transplanted with hESC-derivedcardiomyocytes [18]. However, unwanted anduncontrolled differentiation of hESCs was still noticeddespite following up of this procedure. Primitivepopulation of nestin neuroepithelial cells, thatcontinued to proliferate in the striatum, was noticedin rats with Parkinson disease, 70 days aftertransplantation of hESC-derived dopamine neurons[19]. This raises a cautionary flag and suggests thateven committed progenitors can proliferateexcessively after transplantation, a problem that maybe solved by improving purification methods.However, despite these safety concerns, recentlypublished data [20] suggest that under controlledconditions, hESC-derived cells could serve as apotentially safe new source in regenerative medicine.Clinical trial that investigates potential ofhESC-based therapy for the treatment of diabetesmellitus is opened and recruitment of patients hasbegun in 2014 [21]. The goal of this study is toevaluate the safety and efficacy of VC-01, an implant38containing hESCs derived pancreatic progenitor cellsencapsulated by an immune protecting device, whichwould allow the cells to proliferate and differentiateinto mature β-cells in vivo without the possibility ofimmune rejection [22].Recently, Song and co-workers [20], reportedthat subretinal transplantation of hESC-derivedretinal pigment epithelial cells (hESC-RPE) in fourAsian patients: two with dry age-related maculardegeneration and two with Stargardt maculardystrophy was safe and well tolerated procedure.Visual acuity improved 9–19 letters in three patientsand remained stable [ 1 letter] in one patient. Duringone year follow-up period, serious safety issuesrelated to the transplanted cells such as: adverseproliferation, tumorigenicity, ectopic tissue formation,was not observed. Based on these encouraging results,during the past few years, several clinical trials areinvestigating therapeutic potential of hESC-RPE inpatients with Stargardt macular dystrophy andadvanced dry age related macular degeneration(Table 1, left panel) and promising results areexpecting in next year.Advances and challenges of iPSCtechnologyiPSC are very similar to hESCs in terms ofkaryotype, phenotype, telomerase activity andcapacity for differentiation. However, iPSCs areconsidered morally superior to hESCs since theirgeneration does not require destruction of embryos[23]. Takahashi and Yamanaka demonstrated the firstdirect reprogramming of mammalian somatic cells[24]. Up-regulation of “Yamanaka factors”: sexdetermining region Y box-containing gene 2 [SOX2],OCT3/4, tumor suppressor Krüppel-like factor 4[KLF4], and proto-oncogene c-MYC managed toreprogram differentiated somatic cells in thepluripotent state [24].Since then, iPSCs technology provides a historicopportunity to move away from embryo destructionand opened a new era of personalized medicine.Patient-specific iPSCs may be helpful in drugscreening, generating in vitro models of humandiseases, and novel reproductive techniques (Figure2). In vitro, patient-specific iPSCs can differentiate tospecific cell types which enable testing of new drugsin patient-specific conditions. Since iPSC-derived cellsare generated from somatic cells previously obtainedfrom a patient, there is no risk of immune rejectionafter their transplantation [25]. The development ofreproductive technology enables generation ofgametes (sperm and eggs) from human iPSCs [26].This technique could be helpful for treating infertility,however, the use of iPSC-derived gametes raises set ofhttp://www.medsci.org

Int. J. Med. Sci. 2018, Vol. 1539ethical concerns related to the potential exploitation ofcreated embryos, human NT, and risk of changenatural reproduction including the possibility toderive gametes for same-sex reproduction, as well asin the asexual reproduction [26].Table 1. Clinical trials using hESC-RPE and iPSC-derived cellshESC-RPE cellular therapyConditioniPSC-derived cells in clinical trialsClinicalTrials.gov Identifiernumber/ Phase/ StatusConditionClinicalTrials.gov Identifier number/Source/ StatusAge Related MacularNCT02903576/ I/II/ study isDegeneration, Stargardt's Disease, currently recruiting participantsExudative Age-related, MacularDegenerationLeukemia, LymphomaNCT02564484/ blood/ study iscurrently recruiting participantsDry Age Related MacularDegenerationNCT01344993/ I/II/ study has beencompletedAtaxia-Telangiectasia (A-T)NCT02246491/ blood, skin/ study iscurrently recruiting participantsStargardt's Macular DystrophyNCT01345006/ I/II/ study has beencompletedChronic Granulomatous DiseaseNCT02926963/ hair, skin/ study iscurrently recruiting participantsDry Age-related MacularDegenerationNCT03046407/ early 1/ study iscurrently recruiting participantsRetinoblastomaNCT02193724/ skin, blood/ study iscurrently recruiting participantsStargardt's Macular DystrophyNCT01469832/ I/II/ study has beencompletedAutism Spectrum DisorderNCT02720939/ blood/ study iscurrently recruiting participantsDry Macular Degeneration,Geographic AtrophyNCT02590692/ I/II/ study iscurrently recruiting participantsEctodermal DysplasiaNCT02896387/ skin, cornea/ study iscurrently recruiting participantsDry Age-related MacularDegenerationNCT02755428/ early 1/ study iscurrently recruiting participantsMacular Degeneration,Stargardt's Macular DystrophyNCT02749734/ I/ study is currentlyrecruiting participantsIntellectual Deficiency, AsymptomaticCarrier of the Mutation of the GeneMYT1L, Healthy VolunteersAge-related MacularDegenerationNCT02286089/ I/II/ study iscurrently recruiting participantsAge-related MacularDegenerationNCT03102138/ I/ study is currentlyrecruiting participantsNCT02980302/ skin/ study iscurrently recruiting participantsFigure 2. Potential applications of human induced pluripotent stem cells (iPSCs). iPSC technology can be potentially utilized in disease modeling, drugdiscovery, gene therapy, and cell replacement therapy. Genetic mutations can be corrected by gene targeting approaches before or after reprogramming. iPSCs areconsidered morally superior then ESCs since their generation do not require destruction of embryos. Introduction of the four transcription factors-“Yamanakafactors“ (Oct-4, Sox-2, Klf-4, and c-Myc) leads to reprogramming of a somatic cell to an iPSC which can further differentiate into different types of cells. Two typesof methods for the delivery of reprogramming factors into the somatic cells can be used: integrating viral vector systems and non-integrating methods. The main safetyissue regarding iPSC-based therapy (labeled with question marks) is the risk of teratoma formation which might happen if patient receive iPSC-derived cells thatcontain undifferentiated iPSC and dilemma whether retroviral and lentiviral-free iPSC are safe for clinical application.http://www.medsci.org

Int. J. Med. Sci. 2018, Vol. 15As for hESCs the main safety issue regardingiPSC-based therapy is the risk of teratoma formationwhich can happened if patient receive iPSC-derivedcells that contain undifferentiated iPSC (Figure 2).Uncontrolled proliferation and differentiation oftransplanted undifferentiated iPSCs may result ingenerationoftumorsand/orundesireddifferentiation of iPSCs in broad range of somatic cells[27]. Thus, development of more effective methods forgeneration of purified populations of autologousiPSC-derived differentiated cells remains a challengefor personalized and regenerative medicine [28].It is important to highlight here that due to thegenomic instability of iPSCs [29], even improvedprotocols for their differentiation, does not guaranteesafe clinical application and underlines severaldifferences compared to hESCs [30-32].Transformation of iPSCs into tumor cells couldbe a consequence of oncogenic properties of thereprogramming cocktail (use of c-MYC) [33], orinsertionalmutagenesisinducedbythereprogramming with integrating retroviral orlentiviral vectors which disrupts endogenous genes[34]. Recently, clinical trial that investigated potentialof autologous iPSC-RPE for the treatment of advancedneovascular age-related macular degeneration hasbeen stopped [35]. Although transplantation ofiPSC-RPE in the first enrolled patient was welltolerated after one year follow-up, study was stoppedwhen it moved on to a possible second patient. SinceiPSC, derived from second patient containedmutation, they did not pass a genomic validation stepand the team led by Takahashi decided to at leasttemporarily suspend the trial. However, whatremains unclear at this time and what should beexplored is whether the mutation in the secondpatient’s iPSC was pre-existing in the patient’sfibroblasts or it occurred during the reprogrammingprocess itself.In order to make the transition of iPSC-basedtherapy from lab to clinic, recently conducted researchstudies are focusing on identifying new molecularstrategies that can increase cell reprogrammingefficiency without causing genetic and epigeneticabnormalities in the iPSCs [36]. Several types ofnon-integrating methods have been developed [use ctionofplasmids,Cre–loxP– mediatedrecombination, PiggyBac-transposition] [37-41].Unfortunately, there is still insufficient data toargue that these retroviral and lentiviral-free iPSC aresafe for clinical application (Figure 2). Accordingly,further in vitro and in vivo, animal, studies arenecessary to develop optimized growth and40differentiation protocols and reliable safety assays toevaluate the potential of iPSCs and iPSC-deriveddifferentiated cells for clinical application in patients.Several clinical trials that are going to exploreclinical potential of iPSC-derived cells are currentlyrecruiting patients (Table 1, right panel) and scientificand public community curiously expects these results.Mesenchymal stem cells: key players inthe cell-based therapy ofimmune-mediated ke, multipotent cells, most frequentlyisolated from bone marrow (BM), adipose tissue (AT)and umbilical cord blood (UCB) [42]. TheInternational Society for Cellular Therapy formulatedminimal criteria for uniform characterization of MSCssuch as plastic adherence, potential for differentiationin osteogenic, chondrogenic, and adipogenic lineage,cell surface expression of CD105, CD73, CD90 and theabsence of hematopoietic markers CD45, CD34, CD14or CD11b, CD79α or CD19 and HLA-DR (Figure 3)[43].These cells can differentiate into a variety of celltypes of mesodermal origin and due to their plasticity,some studies [44-46] claim that MSCs can differentiatetowards cells of neuro-ectodermal (neurons,astrocytes, and oligodendrocytes) or endodermal(hepatocytes) origin [47]. In addition to theirdifferentiation potential, MSCs possess broadspectrum of immuno-modulatory capacities [48].MSCs ‘primed’ by pro-inflammatory cytokines(interferon gamma and tumor necrosis factor alpha)adopt immunosuppressive phenotype, and throughcell-to-cell contact (engagement of the inhibitorymolecule programmed death 1 with its ligands) orthrough the production of soluble factors(transforming growth factor-β (TGF-β), staglandin E2, nitric oxide, indoleamine 2,3dioxygenase and heme-oxygenase-1) modulate theadaptive and innate immune response [42, 49]. Inaddition, MSCs lack the expression of membranebound molecules involved in immune rejection whichenable their allogenic transplantation [50].Accordingly, the past decade has witnessed anoutstanding scientific production focused towards thepossible clinical applications of MSCs in the therapyof autoimmune and chronic inflammatory diseasesincluding inflammatory bowel diseases (IBD), liverdisorders and cardiac diseases with very encouragingresults (Figure 3) [51-70].http://www.medsci.org

Int. J. Med. Sci. 2018, Vol. 1541Figure 3. Differentiation ability and immune-modulatory characteristics of MSCs. MSCs are adult, fibroblast-like, multipotent cells, most frequentlyisolated from bone marrow (BM), adipose tissue (AT) and umbilical cord blood (UCB). Minimal criteria for characterization of MSCs are: cell surface expression ofCD105, CD73, CD90 and the absence of hematopoietic markers CD45, CD34, CD14 or CD11b, CD79α or CD19 and HLA-DR. MSCs have been applied clinicallyin patients with inflammatory bowel diseases (IBD), liver disorders and cardiac diseases with very encouraging results. MSCs possess broad spectrum ofimmuno-modulatory capacities. Serious adverse events noticed in some of MSC-treated patients could be explained by the fact that MSCs either suppress or promoteinflammation in dependence of inflammatory environment to which they are exposed to. The primary concerns for clinical application of MSCs (labeled with questionmarks) are unwanted differentiation of the transplanted MSCs and their potential to suppress anti-tumor immune response and generate new blood vessels that maypromote tumor growth and metastasis.MSCs in IBD therapyInstantly, there are two routes for theadministration of MSCs in IBDs patients: intravenousadministration for the systemic control of intestinalinflammation in the therapy of luminal Chron’sdisease (CD) and ulcerative colitis (UC), and the localadministration as a therapeutic approach for patientswith perianal fistulazing CD [51-58]. Administrationof autologous or allogeneic MSCs derived from BMand AT achieved significant clinical efficacy inpatients with fistulazing CD by attenuating localimmune response and by promoting tissue repair[51-58].Results obtained in huge number of clinical trials[51-55] indicate that local application of autologousand allogeneic BM-MSCs and AT-MSCs are simple,safe, and beneficial therapy for the treatment ofperianal fistulas in CD patients with no adverseeffects. On contrary, adverse effects have beenreported in three of nine improved clinical trials ously injected MSCs.Study conducted by Duijvestein and coworkers[56] documented that 6 weeks after MSCs treatment,three patients required surgery due to diseaseworsening. Similar results were noticed in anotherclinical trial [57]. In this study, autologous MSCs,http://www.medsci.org

Int. J. Med. Sci. 2018, Vol. 15derived from marrow aspirate and propagated for 2-3weeks with fibrinogen depleted human plateletlysate, were administered to IBD patients. Twelvepatients received single MSCs intravenous infusion of2, 5 or 10 million cells/kg and serious adverse eventswere seen in seven patients. Aggravation of diseasewas noticed in five patients while adverse events inother two patients were possibly related to theinfusion of MSCs [57].Moreover, serious side effects were seen inpatients with moderate to severe UC that receivedMultistem (stem cells derived from adult BM andnon-embryonic tissue sources) as potentially newtherapeutic agent for the treatment of UC [58].Serious adverse events noticed in some ofMSC-treated patients could be explained by the factthat MSCs either suppress or promote inflammationin dependence of inflammatory environment to whichthey are exposed to [59]. When MSCs are transplantedin the tissue with high levels of pro-inflammatorycytokines (IFN-γ, TNF-α, IL-12, IL-6, IL-17 and IL-23),MSCs adopt an immuno-suppressive phenotype andmodify maturation of DCs, promote conversion ofmacrophages in anti-inflammatory M2 phenotypeand suppress proliferation and activation of Tlymphocytes, NK and NKT cells. In the presence oflow levels of inflammatory cytokines, MSCs adopt apro-inflammatoryphenotypeandproduceinflammatory cytokines that promote neutrophil andT cell activation and enhance immune response andinflammation [59].MSC-based therapy of liver diseasesOver the past few years, several clinical trialsused MSCs to treat patients with liver diseases [60-65].Obtained results demonstrated that MSCs treatmentimproved liver function in safe and well toleratedmanner [60-65]. Amer and colleagues demonstratedthe safety and short-term therapeutic effect ofautologous transplantation of bone marrowMSCs-derived hepatocyte-like cells in patients withend-stage liver failure [61]. In patients with liverfailure caused by hepatitis B virus infection,autologous transplantation of BM-MSCs providedshort-term efficacy in respect to several clinical andbiochemical parameters, but long-term outcomeswere not markedly improved [62]. Recent studiesreported that infusion of umbilical cord-derivedMSCs was well tolerated in patients withdecompensated cirrhosis, and in patients sufferingfrom acute on chronic liver failure, resulting insignificant improvement of liver function andincreased survival rates [64, 65].42MSCs as a promising tool in the therapy ofcardiac diseasesSeveral studies have examined therapeuticpotential of autologous and allogeneic MSCs in thetreatment of acute myocardial infarction (MI) [66-70].In a phase I clinical study [66], 53 patients wererandomized to receive either allogeneic MSCs orplacebo, 7 to 10 days after MI. An improvement ofoverall clinical status was noticed 6 months afterintravenous infusion of MSCs. Chen and colleagues[67] administered autologous MSCs intra-coronary inpatients with subacute MI and observed decreasedperfusion defect, improved left ventricular ejectionfraction, and left ventricular remodeling 3 monthsafter therapy.Currently, there are several published orongoing clinical trials that demonstrated beneficenteffects of MSC-based therapy in the treatment ofchronic ischemic cardiomyopathy. Injection of MSCsattenuated fibrosis, induced neo-angiogenesis,enhanced contractility, and improved the quality oflife of patients with chronic ischemic cardiomyopathy[66-70]. Additionally, it was reported thatintracoronary transplantation of autologous MSCsreduced episodes of tachycardia in patients withchronic ischemic cardiomyopathy and implantedcardioverter defibrillator [69]. Haack-Sørensen dial injections of autologous MSCsignificantly improve quality of life, physicallimitation and angina stability of patients with chroniccoronary artery disease and refractory angina [70].The other side of the coin: safety issuesregarding MSCs-based therapyDespite these promising results, safety issuesregarding MSCs-based therapy are still a matter ofdebate, especially in the long-term follow up. Theprimary concern is unwanted differentiation of thetransplanted MSCs and their potential to suppressanti-tumor immune response and generate new bloodvessels that may promote tumor growth andmetastasis.MSCs have a potential to differentiate intoundesired tissues, including bone and cartilage.Encapsulated structures were found in the infarctedareas of myocardium after transplantation of MSCs.The structures contained calcifications or ossifications[71]. Study conducted by Yoon et colleagues showedthat transplantation of unfractionated BM-derivedcells into acutely infarcted myocardium may inducedevelopment of intra-myocardial calcification [72].It was recently reported that three womensuffering from macular degeneration, within a weekhttp://www.medsci.org

Int. J. Med. Sci. 2018, Vol. 15of undergoing “adipose tissue stem cell”-basedtherapy developed complications including visionloss, detached retinas and bleeding and are nowtotally blind and unlikely to recover [73]. Thetreatment involved combining fat tissue removedfrom the patients’ abdomens with enzymes to obtain“adipose-derived” stem cells. These were mixed withblood plasma containing large numbers of plateletsand injected into the women's eyes. Although, usuallyexperimental eye procedures are tested on one eyefirst so that if something goes wrong the patient is stillable to see with the other eye, in this trial both eyeswere treated at once which, at the end, resulted withcomplete blindness in these ent in which MSCs engraft containsfactors that induce unwanted differentiation oftransplanted MSCs in vivo. Therefore, new researchstudies should be focused in definition of factors andsignaling pathways that are responsible for the fate ofMSCs after their in vivo administration.In addition to unwanted differentiation, MSCsmay bridge the gap between anti-tumor immuneresponse and neo-angiogenesis in malignant diseases,thus promoting tumor growth and metastasis. Afterinjection, MSCs migrate towards primary tumors s; suppress anti-tumor immune responseresulting with an increased tum

This review offers stem cell scientists, clinicians and patient's useful information and could be used as a starting point for more in -depth analysis of ethical and safety issues related to clinical application of stem cells. Key words: embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, stem cell-based therapy.

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