Review Article Bottlenecks in the Efficient Use of Advanced Therapy Medicinal Products Based on ...

12 Pages·2015·0.57 MB·English

Hindawi Publishing Corporation
Stem Cells International
Volume 2015, Article ID 895714, 12 pages
http://dx.doi.org/10.1155/2015/895714
Review Article
Bottlenecks in the Efficient Use of Advanced Therapy Medicinal
Products Based on Mesenchymal Stromal Cells
NataliaEscacena,1ElenaQuesada-Hernández,2VivianCapilla-Gonzalez,1
BernatSoria,1,3andAbdelkrimHmadcha1,3
1DepartmentofStemCells,AndalusianCentreforMolecularBiologyandRegenerativeMedicine(CABIMER),
41092Seville,Spain
2Newbiotechnic(NBT),BollullosdelaMitacio´n,41110Seville,Spain
3CIBERdeDiabetesyEnfermedadesMetabo´licasAsociadas(CIBERDEM),08036Barcelona,Spain
CorrespondenceshouldbeaddressedtoBernatSoria;[email protected]
andAbdelkrimHmadcha;[email protected]
Received24July2014;Accepted5March2015
AcademicEditor:ClaudiaMontero-Menei
Copyright©2015NataliaEscacenaetal. This is an open access article distributed under the Creative Commons Attribution
License,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperly
cited.
Mesenchymalstromalcells(MSCs)havebeenestablishedaspromisingcandidatesourcesofuniversaldonorcellsforcelltherapy
duetotheircontributionstotissueandorganhomeostasis,repair,andsupportbyself-renewalandmultidifferentiation,aswellasby
theiranti-inflammatory,antiproliferative,immunomodulatory,trophic,andproangiogenicproperties.Variousdiseaseshavebeen
treatedbyMSCsinanimalmodels.Additionally,hundredsofclinicaltrialsrelatedtothepotentialbenefitsofMSCsareinprogress.
However,althoughallMSCsareconsideredsuitabletoexertthesefunctions,dissimilaritieshavebeenfoundamongMSCsderived
fromdifferenttissues.Thesamelevelsofefficacyanddesiredoutcomeshavenotalwaysbeenachievedinthediversestudiesthat
havebeenperformedthusfar.Moreover,autologousMSCscanbeaffectedbythediseasestatusofpatients,compromisingtheir
use.Therefore,collectinginformationregardingthecharacteristicsofMSCsobtainedfromdifferentsourcesandtheinfluenceof
thehost(patient)medicalconditionsonMSCsisimportantforassuringthesafetyandefficacyofcell-basedtherapies.Thisreview
providesrelevantinformationregardingfactorstoconsiderfortheclinicalapplicationofMSCs.
1.Introduction MSCs enter the blood stream and are attracted by proin-
flammatorycytokinesatinjuryareas.Thus,MSCshavebeen
MSCs are considered a heterogeneous population of non- called “guardians of inflammation” [4]. The cytoskeleton,
haematopoietic progenitor cells derived from the mesoder- extracellular matrix molecules, cell contacts, adhesion lig-
malgermlayerthathavebothself-renewalandmultidiffer- ands, and receptors are involved in the repair process [5].
entiation [1] abilities. MSCs found in virtually all postnatal Althoughthe exact mechanismsrelated to themigrationof
organsandtissues[2]possessmultifacetedfeatures,making MSCsintospecificsitesandacrosstheendothelialcelllayer
them promising candidate sources of donor cells for use in remainunknown,chemokinesandtheirreceptorsmayplay
celltherapyandtransplantation.MSCsfunctionintherepair rolesinthisprocess.
and support of tissues, contributing to tissue homeostasis. Although MSC survival, permanent engraftment, and
Although the exact origin of MSCs remains elusive, strong differentiationintoresidentcellswasthoughttobenecessary
evidence has indicated that MSC progenitors are in the toobtainthebeneficialeffectsofthesecellsinitially,clinical
perivascular zone [3] in an environment that promotes a experience and several experiments have shown that one
quiescent-resting state, ensuring homeostasis maintenance. of the primary functions of MSCs, most likely their key
When a tissue is damaged and the whole machinery of the function,istosecreteseveralbioactivemoleculesrelatedto
organism begins to operate the body’s repair mechanisms, the microenvironment in which these cells are immersed.
2 StemCellsInternational
Table1:Summaryofmesenchymalstromacellnomenclature.
Nomenclature Year Authors’references
CFU-Fandosteogenicstemcells 1974 Friedensteinetal.[10]
Stromalstemcells 1988 OwenandFriedenstein[16]
Mesenchymalstemcells 1991 Caplan[17]
Mesenchymalprogenitorcells 1999 Dennisetal.[18]
Skeletalstemcells 2000 BiancoandRobey[19]
MAPCsandmesodermalprogenitorcells 2002 Jiangetal.[20]
Multipotentmesenchymalstromalcells 2006 Dominicietal.(ISCT)[21]
Medicinalsignallingcells 2010 Caplan[22]
CFU-F:colony-formingunitfibroblasts;MAPCs:multipotentadultprogenitorcells;ISCT:InternationalSocietyforCellTherapy.
MSCs secrete a wide variety of proinflammatory and anti- todefineMSCsbynomenclature(Table1)andbybiological
inflammatory cytokines, chemokines, growth factors, and characteristics [10, 16–22] to allow studies from different
prostaglandins under resting and inflammatory conditions groupstobecomparedandcontrasted.Thesecriteriainclude
[6]. These molecules are associated with immunomodula- the following: (i) coexpression of markers such as CD73,
tion(indoleamine-2,3-dioxygenase(IDO),prostaglandin-E2 CD90,andCD105andalackofexpressionofhaematopoietic
(PGE-2),TGF-𝛽,HLA-G5,andHGF),antiapoptosis(VEGF, markers (CD45, CD34, and CD14) and human leucocyte
GM-CSF, TGF-𝛽, Stanniocalcin-1, and IGF-I), angiogenesis antigen(HLA-DR),(ii)multipotentdifferentiationpotential,
(VEGF, MCP-1, and IGF-I), local stem and progenitor cell and (iii) adherence to plastic. However, several researchers
growthanddifferentiationsupport(SCF,Angiopoietin-1,and have noted that adipose-tissue-derived MSCs (AD-MSCs)
SDF-1), antifibrosis (HGF and bFGF), and chemoattraction express CD34 and CD54 in early passages [23] and have
(CCL2, CCL4, and CXCL12) [7]. Additionally, beneficial lower expression of CD106 and that umbilical cord blood-
effectsoftheuseofMSCconditionedmedia(CM)havebeen derivedMSCs(UCB-MSCs)expressCD90andCD105[24].
reported; even CM has been shown to be therapeutically Other markers have been used in different studies, and
betterthanthecellsthemselves[8,9]. other differences have emerged, such as VEGFR-2 (Flk-1)
However,althoughthesepropertiesaregenerallyattrib- expression, which was significantly higher in periosteum-
uted to all MSCs derived from different tissues, evidence derivedcellscomparedtothatinadiposetissue-andmuscle-
fromdifferentstudieshassuggestedthatMSCsfromdiverse derivedcells,ortherateofNGFRpositivity,whichwasmuch
sourcesarenotidenticalanddonotalwaysachievethesame higher in muscle-derived cells compared to that in other
efficacylevelsanddesiredoutcomes.Likewise,diversedonor mesenchymaltissue-derivedcells[25].
conditions can affect the MSC characteristics because the Although some immunophenotypic differences have
environment “niche” in which MSCs are immersed may be been documented, many researchers consider the fact that
affected.Inthisreview,wewilldescribesomeofthebiological thesedifferencescouldbeduetodistinctextractionmethods
characteristics of MSCs that must be considered and the and different culture methodologies, resulting in variations
effectsofthediseasestatusofdonorsandrecipientsonthese ofMSCsurfacemarkers.Thus,thisreviewaimedtofurther
characteristics. investigatemarkersandcharacteristicsthataremorespecific
toselectthebettersourcesofMSCsforclinicalapplications.
Likewise, expanding the cells in vitro is necessary to
2.BiologicalCharacteristics obtain the desired numbers for therapeutic approaches.
Changes in the proteomic phenotype of AD-MSCs have
2.1.PhenotypicProfile. SinceFriedensteinandcolleaguesfirst
been observed during passages [26], although no proper
isolatedacolony-formingunitfibroblast(CFU-F)frombone
approachestoexaminethestateofcellscontinuouslyduring
marrow(BM)[10],bonemarrowhasbeenwidelyusedasa
long-term in vitro culture have been established. Some
source of MSCs for many investigations and clinical trials.
researchers ascribe these variations to the adaptation of
Inadditiontobonemarrow,MSCshavebeenisolatedfrom
cellstotheenvironment;thus,determiningthebiomolecular
different tissues such as adipose tissue [11], umbilical cord
markersthatareinvolvedinthesevariationsisessentialfor
blood[12],dentalpulp[13],synovialliquidandamnioticfluid
obtainingabetterphenotypiccharacterisationofthesecells
[14, 15]. All these tissues vary in their cellular components,
and thus for achieving more effective cell therapy in the
signals, and factors secreted, resulting in different immedi-
future.
ate microenvironment conditions, thus developing several
physiological niches. Although isolated and long-term cul-
turedMSCsofmosttissuesshowsimilarimmunophenotypic 2.2.MSCProliferation. TheproliferativeactivityofMSCsis
characteristics, some differences have been found among anotherfeaturethatmaybeaffectedbythedifferentoriginsof
MSCs of different tissue origins according to data obtained MSCs.TherateandpersistenceofMSCproliferationappear
by in vitro experiments. In 2006, the International Society to vary between source tissues. MSCs are considered adult
of Cellular Therapy (ISCT) published the minimal criteria stem cells, and, unlike embryonic stem cells (ESCs), these
StemCellsInternational 3
cellshavealimitedproliferativecapacity.Physiologicalniches NewinsightsintothebiologicalcharacteristicsofMSCsare
maintain adult stem cells in an undifferentiated state; how- neededtoachievefuturetherapies.
ever,whenMSCsareculturedinvitro,theyage,whichaffects
theirtherapeuticproperties,suchasalterationsinphenotype, 2.4.ImmunomodulatoryActions. Immunomodulatoryprop-
differentiation potential, global gene expression patterns, ertiesofMSCsandtheirimmunoprivilegedconditionmake
miRNA profiles [27], and even chromosomalabnormalities these cells good candidates for use in several clinical trials
[28], particularly after long-term culture or when cells of relatedtochronic,inflammatory,andautoimmunediseases.
multiple doublings are used. Large numbers of MSCs are MSCs interact with cells of the innate or adaptive immune
neededfortherapeuticapplications,andinvitroexpansionis system(Tcells,Bcells,NKcells,monocyte-deriveddendritic
requiredtoproducethedesiredMSCnumbers.Invivo,MSCs cells, and neutrophils) [39, 40]. For a cell to be recognised
represent 0.0001% of nucleated BM cells, and their number by the immune system, the expression of major histocom-
decreases with the age of the donor. The quantity of MSCs patibility complex (MHC) and costimulatory molecules is
(CFU-Fs)amongnucleatedBMcellsdecreaseswithagefrom necessary.MHCclassIandclassIIhumanleukocyteantigens
4 5
oneMSCin10 BMcellsinnewbornstooneMSCin10 cells (HLAs)aremastertriggersofrobustimmunologicalrejection
6
inteenagersandtooneMSCin10 cellsinolderindividuals ofgraftsbecausetheypresentantigenstocytolyticTlympho-
[29]. Furthermore, MSCs from older human donors differ cytes(CTL)[41].Humanmesenchymalstemcells(hMSCs)
significantlyfromthosefromyoungerdonorsinmorphology, are characterised by low expression of MHC class I HLAs
replicativelifespan[30],doublingtime,healingcapacity[31], but are constitutively negative for class II HLCs; these cells
and differentiation potential. Sufficient evidence has indi- do not express costimulatory molecules such as B7-1, B7-2,
catedthatMSCsfromolderdonorshavelimitedtherapeutic CD80, CD86, CD40, and CD40L [42]. However, similar to
efficacy,andsomestudieshavesuggestedthatthedifference the thymic epithelium, MSCs express the surface markers
betweenpreclinicalandclinicalfindingsisduetothedonor VCAM-1, ICAM-2, and LFA-3 [42, 43], which are crucial
age. Therefore, considering that several age-related diseases for T cell interactions. Although a T cell response should
exist and that elderly patients are potential users of cell be expected, hMSCs are able to modulate the activation
therapy,understandingthemolecularandbiologicaleffectsof and proliferation of both CD4+ and CD8+ cells in vitro by
ageingonMSCsisessentialfordevelopingsafeandeffective arresting T cells in G0/G1 phase [44, 45]. Different studies
MSC-based autologous cell therapy. Meanwhile, the use of havesuggestedthatcell-cellinteractionsandcertainsoluble
allogeneicMSCsmaybeatreatmentoptionforthesespecific factors are the mechanisms used by MSCs to mediate the
patients. As we comment below, MSCs elude allogeneic immuneresponse.FactorssuchasIDO,TGF-𝛽1,IFN-𝛾,IL-
rejection,andtheirinfusionisfeasibleandwelltolerated,with 1𝛽,TNF𝛼,IL-6,IL-10,PGE-2,HGF,andHLA-G5aresecreted
noadverseeffects[32,33]. by MSCs or released after interactions with target cells. As
wementionedabove,MSCsremaininarestingstate,display
2.3.DifferentiationCapacity. MSCshavetheabilitytodiffer- antiapoptoticpropertiesandmaintaindifferentcellssuchas
entiateinvitrointoseveralmesenchymallineagesincluding haematopoieticstemcells(HSCs),thuscontributingtotissue
adipose tissue, bone, cartilage, and muscle [15, 34, 35]. homeostasis. However, in an inflammatory environment
Furthermore, MSCs can differentiate into endothelial cells, such as that created by cytokines such as IFN-𝛾, TNF-𝛼,
neurons,andglialcellsbecauseMSCsexpressgenesrelated IL-1𝛼, and IL-1𝛽, MSCs begin to exert their immunosup-
tospecificlineagesratherthantothoseofthemesenchymal pressive effects and polarise, inhibiting the proliferation of
lineage[36].Althoughmultilineagedifferentiationisanother effector cells and their production of cytokines. In this
minimal criterion advised by the ISCT and undoubtedly regard, IFN-𝛾 is postulated as a “licensing” agent for MSC
represents a fundamental property of MSCs, this ability antiproliferativeaction.MSCsmayalsoacquirebehaviouras
depends primarily on the source tissue from which these antigen-presentingcells(APCs)undercertainconcentrations
cellsarederived.AsdiscussedbySakaguchietal.[25],who of IFN-𝛾 [46, 47]. However, no consensus regarding what
compared human MSCs isolated from bone marrow, syn- concentrationofIFN-𝛾ismorenecessaryforMSCstoshow
ovium, periosteum, skeletal muscle, and adipose tissue and that inhibitory or APC functions exists. Likewise, TNF-𝛼
expandedthembysimilarprocesses,synovium-derivedcells is another proinflammatory cytokine involved in the MSC
have the greatest ability for chondrogenesis; adipose- and immuneresponse,andTNF-𝛼enhancestheeffectofIFN-𝛾
synovium-derivedcellshavethegreatestabilityforadipogen- [48].IFN-𝛾,withorwithoutthehelpofTNF-𝛼,stimulatesthe
esis;andbonemarrow-,synovium-,andperiosteum-derived productionofIDObyMSCs,inhibitingtheproliferationof
cells have the greatest ability for osteogenesis. In another activatedTorNKcells[49]andthusenhancingthehoming
comparativeanalysis,UCB-MSCsshowednoadipogenicdif- potential and reparative properties of these cells; however,
ferentiationcapacityincontrasttoBM-andAT-MSCs[37]. somepotentialrisksareassociatedwiththeroleofIFN-𝛾[50].
AsdiscussedbyHorwitzetal.[38],whouseddifferentiated Someauthorshavemaintainedthattheimmunomodula-
MSCsinastudytotesttheregenerationofdamagedtissues, torypropertiesofMSCsarecomparable[51,52],whileothers
BM-MSCs can engraft after transplantation, differentiate to havearguedthatMSCsofdifferenttissueoriginsorspecies
functionalosteoblastsandcontributetotheformationofnew cannot have equivalent immunomodulatory properties [53,
dense bone in children with osteogenesis imperfecta. Most 54]. For example, MSCs from perinatal sources (umbilical
likely,themicroenvironmentinwhichMSCsaretransplanted cordandamnioticmembrane)showahigherimmunomod-
directly influences their distinct differentiation pathways. ulatory capacity, differential gene expression profiles, and
4 StemCellsInternational
paracrine factor secretion compared to BM-MSCs [55]. 4.AutoimmuneDiseases
Interestingly,in2012,LeeandcolleaguesfoundthatHLA-G,
aspecificMHC-Iantigenthatiscriticalformaintainingthe MSCs are being used to facilitate the engraftment of trans-
immune-tolerantstateofpregnancyandthatisacontributing plantedHSCsandtotreatgraft-versus-hostdisease(GVHD)
factortotheinductionofstrongerimmunosuppression[56], after allogeneic haematopoietic stem cell transplantation
is strongly positive only in placenta-derived MSCs (PD- (HSCT) based on their immunomodulatory properties and
MSCs) in contrast to BM-MSCs and AD-MSCs, suggesting their ability to provide appropriate conditions; however,
thattheimmunophenotypeofPD-MSCsmaybesuperiorto preclinical and clinical experiments with MSCs do not
other MSCs in terms of their immunosuppressive function alwaysshowsimilarresultsforthepreventionandtreatment
[57].Nevertheless,inanotherrelatedstudy,BM-MSCswere of GVHD. In a study using a mouse model of GVHD
moreimmunomodulatorythanPD-MSCs[58].Meliefetal. [74], MSCs suppressed alloantigen-induced T cell prolif-
[59] concluded that the immunomodulatory capacities of eration in vitro in a dose-dependent manner but yielded
BM-MSCs and AD-MSCs are similar but that differences no clinical benefit regarding the incidence or severity of
in cytokine secretion cause AD-MSCs to have more potent GVHD. Instead, when UCB-MSCs were administered in
immunomodulatoryeffectsthanBM-MSCs. weekly doses in a xenogeneic model of GVHD, a marked
decrease in human T cell proliferation was observed, and
A 2002 study showed that allogeneic MSCs prolonged
none of the mice developed GVHD. No therapeutic effect
skin graft survival in baboons [60]. Mouse MSCs have
was obtained when UCB-MSCs were administered at the
been used in related experiments; these cells use inducible
onset of GVHD [75]. In the same line of research, serial
nitricoxidesynthase(iNOS)forimmunosuppressioninstead
infusions of mouse AD-MSCs could efficiently control the
of IDO. These findings indicate that MSCs differ between
lethal GVHD that occurred in recipients transplanted with
species[61].Sincethen,severalpreclinicalmodelshavebeen
haploidenticalhaematopoieticgrafts[76].Mixedresultshave
used to analyse the biological effects of MSCs and their
also been achieved in human patients. One study found
abilitytomodulateimmuneresponses,consideringthatnot
that the cotransplantation of culture-expanded MSCs and
allanimalmodelsmimichumandiseases.
HSCs from HLA-identical sibling donors after myeloabla-
Once more, these differences could be due to isolation
tive therapy accelerated haematopoietic engraftment [77];
procedures,toculturemethodology,or,morelikely,todiff-
however, a significant reduction of GVHD symptoms was
erencesinthemicroenvironmentswherecellsreside. These
not shown, although the incidence or severity of GVHD
and other findings lead us to believe that determining
did not increase. Koc¸ et al. [78] reported a positive impact
whether these differences may be relevant for their clinical
ofMSCsonhaematopoiesis;rapidhaematopoieticrecovery
applications and whether MSCs of a particular tissue type
was observed in a clinical study with breast cancer patients
are more appropriate for specific therapies or diseases is
who received autologous HSCT together with autologous
important.
MSCs. Therapeutic effects have also been reported at the
onset of GVHD, such as the case of a 9-year-old boy with
severetreatment-resistantGVHDafterallogeneicHSCTfor
3.PreclinicalApplications
acute lymphocytic leukaemia who received haploidentical
MSCs derived from his mother. He showed improvement
Preclinical models are essential for clinicians, researchers,
after 2MSC administrations [79]. Similar results have been
and both national and international regulatory agencies to
obtainedinsteroid-refractoryGVHDpilotstudieswithBM-
demonstratethesafetyandefficacyofMSC-basedtherapies
MSCs and AD-MSCs [80, 81]. Several infusions appear to
[62]. Because MSCs are able to exert immunomodulatory
berequiredtomaintainthelevelofactiveimmunomodula-
propertiesandtoactondifferentimmunecellsbothinvitro
tionbyMSCs.Similarly,theexpressionofproinflammatory
andinvivoasmentionedabove,thesecellshavebeguntobe
cytokines such as IFN-𝛾 in the environment at the time of
usedagainstautoimmunediseasesbasedonvariousautoim-
MSCadministrationisrequiredbythesecellstoexerttheir
muneexperimentalmodels.Pioneerstudiesinexperimental
immunosuppressiveeffectbecausealackofMSC“licensing”
autoimmuneencephalomyelitis(EAE),amodelformultiple
canresultintheabsenceofthedesiredtherapeuticeffect.
sclerosis, reported that MSCs derived from various tissue
origins show efficacy against neurodegenerative disorders While evidence that MSCs are effective in combination
[63–68].BM-MSCandUCB-MSCtreatmentshavebrought or after HSCT in specific haematological and nonhaema-
aboutimprovementsinclinicalandlaboratoryparametersin tological diseases has been shown, adverse reactions and
systemic lupus erythematosus (SLE) [33, 69]. Furthermore, risk factors intrinsic to this practice have been reported.
ameliorating effects have been observed in experimental In a pilot study, HLA-identical sibling-matched HSCs were
mouse models of rheumatoid arthritis (RA) [70]. Diabetes transplantedwithorwithoutMSCsinhaematologicalmalig-
is another autoimmune disorder in which MSCs have been nancypatients.AlthoughMSCswerewelltoleratedandthis
employed[71–73].Althoughpromisingresultsandprogress treatmenteffectivelypreventedGVHD,sixpatients(60%)in
havebeenobservedinthisfield,theinterspeciesdifferences theMSCgroupandthree(20%)inthenon-MSCgrouphad3-
and contradictory experimental outcomes, as well as the yeardisease-freesurvivalratesof30and66.7%,respectively
inability to recreate the complete pathophysiology of some [82].Therelapserateintheexperimentalgroupwashigher
diseases,makeitnecessarytosearchfornewanimalmodels than that in the control group, suggesting that MSCs may
toyieldcomparableresults. impairthetherapeuticgraft-versus-leukaemia(GVL)effect.
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Invitroandinvivostudiesregardingtherelationshipbetween [96]. In metabolic diseases such as diabetes, alterations in
the immunosuppressive properties of MSCs and the stimu- autologousMSCshavealsobeendocumented.Astudyusing
lationofcancergrowthhavebeenperformed.MouseMSCs MSCsfromtype2diabeticmiceshowedthatthenumberof
fromBM,spleen,andthymusthatwereinjectedtogetherwith these cells was diminished and that their proliferation and
ageneticallymodifiedtumourcellvaccinecouldequallypre- survival abilities were impaired in vitro. Moreover, diabetic
venttheonsetofanantitumourmemoryimmuneresponse, MSC engraftment produced limited improvement in the
thus leading to tumour growth in normally resistant mice diabeticsubjectsandcouldnotproducethesametherapeutic
[83].Inanotherinvivoexperimentwithamurinemelanoma outcomes as in their nondiabetic counterparts in vivo [97].
tumourmodel,theauthorsobserved thatthesubcutaneous Advancedglycationendproducts(AGEs)accumulateinthe
injection of B16 melanoma cells led to tumour growth in tissues of aged people, and these products are involved in
allogeneicrecipientsonlywhenMSCswerecoinjected[84]. diabetesandinmusculoskeletaldiseases.In2005,Kumeetal.
The functions of MSCs can be influenced by the existing [98]investigatedtheeffectofAGEsonMSCsandshowedthat
microenvironment, making them acquire supportive prop- AGEsinhibitedMSCproliferation,inducedMSCapoptosis,
erties towards cancer cells and decrease immune reactions andinterferedwithMSCdifferentiationintoadiposetissue,
[85].Therefore,potentialrisks,relatedtothegrowthsupport cartilage,andbone.Anotherstudyexaminedtype2diabetes-
andenhancementofundetectedor“resident”cancer,doexist, derivedAD-MSCsandfoundthatthesecellshadfunctional
and the administration of MSCs in these patients must be impairmentsintheirmultilineagepotentialandproliferative
thoroughlyevaluated. capacity because of prolonged exposure to high glucose
concentrations[99].Wedemonstratedthatdiabetic-derived
AD-MSCshaveanalteredphenotyperelatedtoplasminogen
5.DoMSCsCarryoutthePatient’sDisease? activator inhibitor-1 (PAI-1) expression levels and display
reduced fibrinolytic activity [100]. In this respect, our pre-
OneofthestrategiestoobtainMSCsfortherapeuticpurposes liminaryresultsandotherssuggestthattheimmunogenicity
is an autologous approach. These cells are collected from ofMSCscouldhaverelatedeffectsonthecoagulationsystem
patients by more or less invasive methods, isolated, seeded [101,102].Thus,MSC-basedtherapycouldleadtothrombotic
incultureundergoodmanufacturingpractice(GMP)quality eventsinparticularrecipients.
standards, and reinjected into the patient. Nevertheless, Althoughthepossibilityofhealingwithourowncellsis
whentherepairmechanismsofthebodyareinsufficientor extremely attractive, little is known regarding the influence
ineffective,thistreatmentresultsinahomeostaticimbalance of different disease states and concomitant medications on
in the organism, producing degradation and disease and MSCs[103,104].Thus,althoughtheuseofautologousMSCs
compromisingthepoolofendogenouscells,thusresultingin forcelltherapyiswidespread, theiruseinhumansmustbe
lowefficacy.Somediseasesprovokechangesinthebonemar- handled with extreme caution. Researching and analysing
rowmicroenvironment,whichisoneoftheprimarysources both the risks and benefits of this therapy in individual
ofMSCs,thusproducingchangesintheendogenouspoolof patientsandforeachdiseasestatearenecessary.
MSCsandalteringtheirbiologicalfeatures[86].MSCsfrom
patients with acute myeloid leukaemia showed abnormal
biologicalproperties,includingmorphologicalheterogeneity, 6.SafetyandEfficacyinClinicalTrials
limited proliferation capacity, and impaired differentiation
andhaematopoiesissupportability[87].MSCsderivedfrom Several clinical trials are in progress to ensure the safety
patientswithmultiplemyelomashowedimpairedimmune- and efficacy of MSCs used as medicaments. For cell-based
inhibitory effects on T cells, decreasing their osteogenic products, we must consider that cells are living products
potential [88]. Poor proliferation, differentiation potentials, and that their interactions with body fluids remain unclear
andcytokinereleasedefectswerefoundinBM-MSCsderived [100,102,105].
frompatientswithaplasticanaemia,anotherhaematopoietic PhaseIclinicaltrialsarethefirststepintheinvestigation
disorder[89,90]. ofanewdrugandincludepharmacokineticandpharmaco-
Although the mechanisms remain unknown, MSCs ap- dynamicstudiesinwhichthepatient’ssafetyplaysanessential
peartobeinvolvedinautoimmunepathologies.Forinstance, roleinthedevelopmentofmedicaments.Theprimarygoalof
MSCs derived from patients with autoimmune diseases phaseIIclinicaltrialsistoprovidepreliminaryinformation
display the following altered functions. (i) MSCs from regarding the drug efficacy and safety supplement data
rheumatoid arthritis (RA) patients have an impaired abil- obtained in phase I trials. Usually, safety evaluations are
ity to support haematopoiesis [91] and lower proliferative basedonpossiblecomplicationsderivedfromtheprocedure
and clonogenic potentials [92]. (ii) MSCs from immune in a time-dependent manner after the administration of
thrombocytopenic purpura (ITP) patients have a reduced the cells. Efficacy parameters focus on the improvement
proliferative capacity and a lower inhibitory effect on T of clinical effects at a given time. MSC-based cell therapy
cellproliferationcomparedwithMSCsfromhealthydonors is a relatively new therapeutic option for certain diseases,
[93]. (iii) MSCs from systemic lupus erythematosus (SLE) and data regarding the long-term monitoring of patients
patientsdisplaydeficientgrowth,abnormalmorphology,and remain lacking. Nevertheless, the administration of MSCs
upregulated telomerase activity [94, 95]. (iv) MSCs from is considered a feasible and safe procedure with no adverse
systemic sclerosis (SSc) patients display early senescence eventsreported.However,therisksassociatedwithstemcell
6 StemCellsInternational
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vi
ued. Indication Articularcartilagedefects Forimplanttorepaircartilagedefectsattheendsofthebonesofthekneejoint Foruseinunrelateddonorhaematopoieticprogenitorcelltransplantationproceduresinconjunctionwithanappropriatepreparativeregimenforhaematopoieticandimmunologicalreconstitutioninpatientswithdisordersaffectingthehaematopoieticsystemthatareinheritedoracquiredorthatresultfrommyeloablativetreatment eticprogenitorcells;PB-MNS:peripheralbloodmononuclearcells.deneeredmedicinalproduct;biotechnology-basedproduct(KFDAClassification);medicalde
ntin ous opoiengi
Table2:Co Celltype Autologousculturedcartilage Matrix-inducedautologculturedchondrocytes AllogeneicHPC,cordblood ulatingfactor;HPC:haematcnalproduct;TEMP:tissue-
mci
y-stimedi
AuthorisedbyJapan’sMinistryofHealth,Labour&Welfare(2012) EMA(2013) FDA(2013) cyte-macrophagecolonP:somaticcelltherapy
oM
Company J-TEC(JapanTissueEngineeringCo.,Ltd.) Genzyme(SanofiBiosurgery) SSMCardinalGlennonChildren’sMedicalCenter prostaticacidphosphatasegranulbherapymedicinalproduct;SCTation).
Tradename eJACC cMACI bAllocord FAP-GM-CSF:aGTMP:genet(JapanClassific
8 StemCellsInternational
Table3:MSCcell-basedtherapieswithavalidmarketingauthorisation.
Tradename Company Authorisedby Celltype Indication
∗ Treatmentforpostacute
Hearticellgram FCBPharmiCell KFDA(2011) AutologousBM-derivedMSCs
myocardialinfarction
∗ Treatmentoftraumaticand
Cartistem Medipost KFDA(2012) AllogeneichUCB-MSCs
degenerativeosteoarthritis
TreatmentofacuteGvHD
∗ HealthCanada(2012)
Prochymal OsirisTherapeuticsInc. AllogeneicBM-MSCs childrenwhoareunresponsiveto
NewZealand(2012)
steroids
MSCs:mesenchymalstemcells;BM:bonemarrow;hUCB:humanumbilicalcordblood;GvHD:graft-versus-hostdisease;KFDA:KoreanFoodandDrug
Administration.
∗
SCTMP:somaticcelltherapymedicinalproduct.
therapy[106]mustbeconsideredbecausetheserisksincrease 2011,threeMSCproductshavereceivedmarketingapproval
theprobabilityoftheoccurrenceofanadverseevent.Thecell inotherregions[115](Tables2and3).
source,donororigin,productmanufacturing,andrecipient The MSC field continues its upward progression, with
diseasestatusareimportantfactorsrelatedtothesafetyand a growing number of established companies and ongoing
efficacyoftheuseofMSCs.Inthisregard,theuseofbovine clinical trials, but remaining challenges must be overcome.
proteinsinthemediumusedtoculturethesecells[38]and Bottlenecks exist regarding donor selection, cells sources,
the observed formation of ectopic tissue in animal models isolation protocols, culture media used, open-culture sys-
[107,108],aswellasmalignanttransformation[109,110]and tems,bioreactors,andrecipientdiseasestatus.Establishinga
immune responses, must be evaluated before wider clinical standardisedandcomparableprocessisalsocrucialtoensure
applicationsandregistrationareaccepted. biologicalandfunctionalequivalencebetweenproductlots.
7.ClinicalManufacturingof 8.ConcludingRemarksand
MSC-BasedMedicines FuturePerspectives
Withtheexceptionofhaematopoieticstemcelltransplants, Treatments based on the use of human stem cells are novel
stem cell therapies used for the treatment of any disease and promising therapeutic alternatives for some diseases.
areconsidereddrugs;therefore,theirdevelopment,approval, Spain is at the forefront of research using such treatments,
and use must be in accordance with specific standards and these treatments are developed and evaluated with
established for such medicines nationally and internation- great scientific rigor. Currently, the use of living cells as a
ally. MSCs are called advanced therapy medicinal products medicinalproductisbecomingrealistic.Celltherapyshould
(ATMPs)andareunderregulationnumber1394/2007.Relat- be safe, pure, stable and efficient. Cell-based products are
ing production processes and development staff, clinicians, morecomplexanddependonthephysiologicalandgenetic
and researchers is obligatory to achieve GMP procedures heterogeneityofthepatient.Obtainingasmuchinformation
underEuropeanregulations[111,112].Currently,nostandard- aspossiblewiththetoolswehaveatourdisposalisessential
isedmanufacturingplatformexists,althoughmostfacilities forensuringthesafety,reliability,quality,andeffectivenessof
employ standard release criteria to measure sterility, viabil- the manufactured product. MSCs are leading the way into
ity, and chromosomal stability to meet European or FDA a new era of regenerative medicine, and their multifaceted
regulations [113]. Although regulation establishes common features make them powerful candidates to become tools
parameters to follow, different protocols are used to isolate to treat several diseases. However, their indiscriminate use
thesecells,andtheprocesses,platingdensities,andreagents has resulted in mixed outcomes in preclinical and clinical
usedcausetheresultstodifferfromeachother.Donorselec- studies.WhileMSCsderivedfromdiversetissuessharesome
tionintermsofageanddiseasestatusisanothervariableto common properties, they markedly differ in terms of their
considerduetoknownMSCdonor-to-donorheterogeneity differentiation abilities, growth rates, healing capacity, and
[114].Thecellsourceisanotherimportantfactorrelatedtothe gene expression profile. Similarly, the disease statuses of
efficacyoftheproduct.Asreportedpreviously,MSCsderived donorsandrecipientsareimportantfactorstoconsiderwhen
fromdifferenttissuesdonotalwaysachievethesamelevelof using MSCs as therapeutic agents because factors such as
efficacy.Additionally,culturemediausedfortheproduction the MSC behaviour with body fluids and specific disease
of MSCs could affect the basic characteristics of cells; thus, environments remain unclear. Available data suggest that
designingafullydefinedmediumfreeofanimalandhuman sometissue-specificMSCsaremoreappropriatethanothers
originsiscrucial. accordingtoparticularpathologies.Equally,someevidence
Thusfar,noMSC-basedmedicineproducthasmarketing hasindicatedthatcertainpatientprofilesarenotsuitableto
authorisation in the European Union, although four gene be treated with these therapies. Thus, multiple bottlenecks
andcell-basedproductshaveavalidmarketingauthorisation forthestandardisationoftherapeuticprotocolsexist.Future
awardedbytheEuropeanMedicinesAgency.However,since well-designed clinical trials and long-term monitoring of
StemCellsInternational 9
patients are crucial for obtaining additional information [10] A.J.Friedenstein,U.F.Deriglasova,N.N.Kulaginaetal.,“Pre-
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[13] S.Gronthos,M.Mankani,J.Brahim,P.G.Robey,andS.Shi,
The authors are supported by the Fundacio´n Progreso y “Postnatalhumandentalpulpstemcells(DPSCs)invitroand
Salud, Consejer´ıa de Salud, Junta de Andaluc´ıa; FEDER invivo,”ProceedingsoftheNationalAcademyofSciencesofthe
cofunded grants from Consejer´ıa de Innovacio´n Ciencia y UnitedStatesofAmerica,vol.97,no.25,pp.13625–13630,2000.
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1615-900000); FEDER cofunded grants from Instituto de “Multilineagedifferentiationpotentialofcellsisolatedfromthe
Salud Carlos III (Red TerCel-Grant RD12/0019/0028; PI10/ humanamnioticmembrane,”JournalofCellularBiochemistry,
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