BioMed Cen al
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Jou nal o In lamma ion
Open Access
Re iew
Mesenchymal s em cells a oid allogeneic ejec ion
Jenni e M Ryan1, F ank P Ba y2, J Ma y Mu phy2 and Be na d P Mahon*1
Add ess: 1Ins i u e o Immunology, Na ional Uni e si y o I eland, Maynoo h, Co. Kilda e I eland and 2Regene a i e Medicine Ins i u e (REMEDI),
Na ional Cen e o Biomedical Enginee ing Science, Na ional Uni e si y o I eland, Galway, I eland
Email: Jenni e M Ryan - [email protected]; F ank P Ba y - [email p o ec ed]; J Ma y Mu phy - ma y.mu [email protected];
Be na d P Mahon* - [email p o ec ed]
* Co esponding au ho
Abs ac
Adul bone ma ow de i ed mesenchymal s em cells o e he po en ial o open a new on ie in
medicine. Regene a i e medicine aims o eplace e e e cells in a b oad ange o condi ions
associa ed wi h damaged ca ilage, bone, muscle, endon and ligamen . Howe e he no mal
p ocess o immune ejec ion o misma ched allogeneic issue would appea o p e en he
ealisa ion o such ambi ions. In ac mesenchymal s em cells a oid allogeneic ejec ion in humans
and in animal models. These inding a e suppo ed by in i o co-cul u e s udies. Th ee b oad
mechanisms con ibu e o his e ec . Fi s ly, mesenchymal s em cells a e hypoimmunogenic, o en
lacking MHC-II and cos imula o y molecule exp ession. Secondly, hese s em cells p e en T cell
esponses indi ec ly h ough modula ion o dend i ic cells and di ec ly by dis up ing NK as well as
CD8+ and CD4+ T cell unc ion. Thi dly, mesenchymal s em cells induce a supp essi e local
mic oen i onmen h ough he p oduc ion o p os aglandins and in e leukin-10 as well as by he
exp ession o indoleamine 2,3,-dioxygenase, which deple es he local milieu o yp ophan.
Compa ison is made o ma e nal ole ance o he e al allog a , and con as ed wi h he immune
e asion mechanisms o umo cells. Mesenchymal s em cells a e a highly egula ed sel - enewing
popula ion o cells wi h po en mechanisms o a oid allogeneic ejec ion.
Re iew
In oduc ion: Wha a e S em Cells?
The e m "s em cell" can be applied o a ema kably
di e se g oup o cells. These cells, ega dless o hei
sou ce, sha e wo cha ac e is ic p ope ies. Fi s ly, hey
ha e he capaci y o p olonged o unlimi ed sel - enewal
unde con olled condi ions, and secondly hey e ain he
po en ial o di e en ia e in o a a ie y o mo e specialized
cell ypes [1,2]. The s em cells ha a ise du ing he i s
days o mammalian emb yonic de elopmen a e plu ipo-
en and a e e e ed o as emb yonic s em (ES) cells.
These a e usually de i ed om he inne cell mass o he
p e-implan a ion emb yo, a he blas ocys s age[3]. How-
e e s em cells a e no con ined o issues o ea ly de elop-
men , bu can also be ound a a ious si es in he adul
mammal. Adul s em cells a e mo e di e en ia ed hen ES
cells bu can s ill gi e ise o specialized lineages[1,2]. The
bes -desc ibed popula ions o da e a e he hema opoie ic
s em cells (HSC) o he bone ma ow ha can gene a e
a ious blood cells[4]. Howe e he bone ma ow also
con ains a popula ion o mesenchymal s em cells (MSC)
[1,2]. These cells, i s cha ac e ized by F iedens ein and
colleagues mo e han hi y yea s ago, a e mul ipo en
cells capable o di e en ia ing in o se e al lineages
including; ca ilage, bone, muscle, endon, ligamen and
adipose issue[2,5,6]. In hei undi e en ia ed s a e, MSC
Published: 26 July 2005
Jou nal o In lamma ion 2005, 2:8 doi:10.1186/1476-9255-2-8
Recei ed: 01 Ap il 2005
Accep ed: 26 July 2005
This a icle is a ailable om: h p://www.jou nal-in lamma ion.com/con en /2/1/8
© 2005 Ryan e al; licensee BioMed Cen al L d.
This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (h p://c ea i ecommons.o g/licenses/by/2.0),
which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed.
Jou nal o In lamma ion 2005, 2:8 h p://www.jou nal-in lamma ion.com/con en /2/1/8
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a e spindle-shaped and esemble ib oblas s[5,6] (Fig 1).
The e a e no cell su ace ma ke s ha speci ically and
uniquely iden i y MSC, and hei cha ac e iza ion in he
li e a u e lacks consis ency. The di e si y o cha ac e is ics
associa ed wi h MSC can be explained by di e ences in
issue o igin, isola ion me hods and cul u e condi ions
be ween labo a o ies, in addi ion he e appea o be
s ain- o-s ain di e ences in mu ine de i ed MSC[2,7-9].
Whils he e is an ob ious need o s anda diza ion
be ween esea ch g oups, some consensus can be ound
among he con lic ing da a. In b oad e ms, MSC
expanded in i o do no exp ess he hema opoie ic o
endo helial su ace ma ke s CD11b, CD14, CD31, CD34
o CD45 bu s ain posi i e o CD29, CD44, CD73,
CD105, CD106 and CD166 [2,5,10]. The non-emb yonic
sou ce o his popula ion, he educed likelihood o neo-
plasia, and he mo e limi ed di e en ia ion po en ial,
ha e made hese cells a ac i e candida es o applica ion
in cell based he apies usually e med " egene a i e med-
icine"[2]. The e is one con ounding in luence on his
app oach; whils sel de i ed MSC pose ew immunologi-
cal p oblems, in p ac ice egene a i e medicine is likely o
ely on misma ched (allogeneic) cells o epai o eplace
damaged issue. No mally, allogeneic cells a e dele ed by
hos immune esponses. The majo su p ise o Immunol-
ogis s wo king in his ield ha e been indings ha sugges
ha MSC do no obey he no mal " ules" o allogeneic
ejec ion. This e iew will su ey ecen da a, which con-
incingly indica e he mechanisms by which MSC escape
he no mal p ocess o alloan igen ecogni ion.
MSC e ade allo ejec ion
The majo limi o solid o gan g a su i al is T cell ecog-
ni ion by he ecipien o alloan igen (domina ed by, bu
no con ined o MHC/HLA an igens)[11]. The e a e wo
mechanisms media ing his powe ul ejec ion esponse;
"di ec " ecogni ion, in ol ing ecogni ion by ecipien
CD8+ o CD4+ T cells o dono MHC class I and class II
molecules; and "indi ec " mechanisms in ol ing ecogni-
ion o pep ides om he allogeneic issue[11]. Recipien
an igen p esen ing cells (APC) such as dend i ic cells
(DC) p ocess alloan igen in o pep ides and p esen hese
o nai e T cells on sel -MHC molecules [12]. Howe e
he e a e no able excep ions o hese allo ejec ion p oc-
esses; he e al allog a e ades ejec ion by he mo he
h ough a complex se ies o ac ions ( e iewed in[13]),
simila ly issue which has limi ed lympha ic d ainage is
less p one o allo ejec ion[14]. In e es ingly umo cells,
whils no allogeneic, a e in many cases bo h "al e ed-sel "
and immunogenic bu o en ac i ely modula e immune
esponsi eness o e ade immune su eillance[15]. Thus
mechanisms o umo e asion o he immune sys em may
p o ide insigh in o how allogeneic MSC a e ole a ed by
he misma ched hos .
The e is suppo ing e idence o he use o allogeneic MSC
om bo h in i o and in i o s udies ha show MSC
a oid no mal allo esponses. A small numbe o in- i o
s udies sugges ha MSC play a ole in enabling alloan i-
gen ole ance. Koc e al, showed no e idence o allo eac-
i e T cells and no incidence o g a hos disease when
allogeneic MSC we e in used in o pa ien s wi h Hu le 's
synd ome o me ach oma ic leukodys ophy[16]. In a
p e ious s udy by he same g oup, au ologous cul u e-
expanded MSC we e in used o b eas cance pa ien s o
in es iga e whe he MSC would enhance he eng a men
o pe iphe al blood s em cells a e myeloabla i e he apy
[17]. Resul s showed apid hema opoie ic eco e y and no
signs o oxici y om MSC in usion[17]. Ho wi z and col-
leagues, epo ed ha dono MSC con ibu ed o bone
emodelling a e allogeneic s em cell ansplan a ion in
h ee child en wi h os eogenesis impe ec a (OI)[18], a
a e gene ic diso de o ype I collagen. This is suppo ed
by da a om Ba holomew e al who showed ha in- i o
adminis a ion o allogeneic MSC p olonged 3 d pa y
skin g a su i al in animal models[19]. Fu he mo e,
Sai o e al, demons a ed ha MSC unde going di e en i-
a ion o a ca diac pheno ype we e ole a ed in a xenoge-
neic en i onmen , e aining hei abili y o be ec ui ed o
he inju ed myoca dium[20]. Mo e ecen wo k by Agga -
wal and Pi enge suppo ed he easibili y o MSC- ans-
plan a ion showing ha MSC al e ed he pheno ypes o
speci ic immune cell sub ypes he eby c ea ing a
ole ogenic en i onmen [21]. These epo s sugges ha
ansplan a ion o MSC could be bene icial in pa ien s
wi h a ious diso de s equi ing issue egene a ion, and
Human mesenchymal s em cells (MSC) a e spindle shaped, ib oblas -like cellsFigu e 1
Human mesenchymal s em cells (MSC) a e spindle shaped,
ib oblas -like cells. O iginal magni ica ion × 100, phase-con-
as ligh mic oscopy, scale ba ep esen s 50 µm.
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p o ide e idence suppo ing he ole ance o allogeneic
MSC by ecipien s.
Da a suppo ing he con en ion ha MSC a oid alloge-
neic esponses has also come om a la ge body o in i o
expe imen s, usually in ol ing co-cul u e o mixed lym-
phocy e eac ions (MLR). E idence om hese s udies
indica e ha he use o misma ched MSC does no p o-
oke a p oli e a i e T cell esponse in allogeneic MLR, hus
sugges ing an immunosupp essi e ole o MSC[19,22-
26]. Le Blanc e al, showed ha MSC ailed o elici p oli -
e a ion o allogeneic lymphocy es[27]. Addi ionally, hey
demons a ed ha MSC emained immunosupp essi e
e en a e IFN-γ s imula ion[27]. E idence om K ampe a
e al con i ms hese indings, hey showed ha mu ine
MSC lack MHC class II and inhibi ed T cell p oli e a-
ion[25]. Tse e al, also showed ha human MSC ail o
elici allogeneic T cell esponse in a MLR e en when MHC
class II was up egula ed[28]. Consis en wi h hese s ud-
ies, Ba holomew e al showed ha allogeneic baboon
MSC supp essed he p oli e a i e ac i i y o lymphocy es
in i o and p olonged g a su i al[19]. These indings
suppo he iew ha MSC can be ansplan ed be ween
MHC-incompa ible indi iduals. Al hough hese da a
show ha success ul use o allogeneic MSC in egene a i e
he apy is possible, such app oaches a e unlikely o be
b oadly accep able un il i is unde s ood why MSC a e no
ejec ed. This ques ion has been he subjec o in ense
ecen s udy and h ee candida e mechanisms a e eme g-
ing. MSC appea o e ade allogeneic ejec ion by a) being
hypoimmunogenic; b) modula ing T cell pheno ype and
c) c ea ing an immunosupp essi e local milieu. These
mechanisms a e in e - ela ed and will in ol e cell con ac
dependen and independen in e ac ions. The challenge
acing he ield is o un a el he con ibu ion o hese
di e se in e ac ions.
MSC a e hypoimmunogenic
The e is con o e sy su ounding he cell su ace exp es-
sion o MHC alloan igens by MSC. Al hough con lic ing
e idence exis s, mos s udies desc ibe human MSC as
MHC class I posi i e and MHC class II nega i e (Fig 2).
The da a con lic ing wi h hese indings may ep esen di -
e en s em cell lineages o be he esul o he ecen ly
desc ibed p ocess o cell-cell ans e [29-31]. The exp es-
sion o MHC class I by MSC is impo an because exp es-
sion p o ec s MSC om ce ain NK cell mechanisms o
dele ion. Fo ins ance, a majo unc ion o NK and NK-
like cells is o kill umo cells ha ha e down egula ed
class I [32]. HLA-G is an MHC-like p o ein ha is known
o p o ec he e al allog a agains NK media ed ejec-
ion[33,34]. This p o ein has been shown o bind o he
wo majo inhibi o y NK ecep o s, KIR1 and KIR2, and o
inhibi NK killing [35-37]. Howe e no s udies o HLA-G
exp ession by MSC ha e been epo ed o da e.
As MHC class II p o eins a e po en alloan igens, he
exp ession by MSC is ano he impo an ac o . Again
he e is some con o e sy o e exp ession, which may be
explained by he di e si y o models desc ibed abo e.
Howe e he e a e widesp ead obse a ions ha unde
non-in lamma o y condi ions, human MSC a e MHC-II
Human MSC cul u ed acco ding o [106, 107] a e A) MHC-I posi i e (HLA-A,B,C, an ibody W6/32-FITC), B) MHC class II nega i e (HLA-DR, an ibody LN-3-PE); C) CD14 nega i e (an ibody MEM-18-FITC), D) CD86 nega i e (an ibody IT2.2-PE); and E) CD40L/ CD154 (an ibody 24-31-FITC), F) CD95L (FasL) nega i e (an ibody NOK-1-PE)Figu e 2
Human MSC cul u ed acco ding o [106, 107] a e A) MHC-I
posi i e (HLA-A,B,C, an ibody W6/32-FITC), B) MHC class II
nega i e (HLA-DR, an ibody LN-3-PE); C) CD14 nega i e
(an ibody MEM-18-FITC), D) CD86 nega i e (an ibody IT2.2-
PE); and E) CD40L/ CD154 (an ibody 24-31-FITC), F)
CD95L (FasL) nega i e (an ibody NOK-1-PE). Iso ype
ma ched con ol an ibody labelling a e shown as unshaded
plo s, FITC conjuga es a e shown in blue, PE conjuga es
shown in pink. Flow cy ome y pe o med acco ding o
me hods p e iously desc ibed [108-110].
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nega i e, suppo ing a ole o MSC as ha ing educed
immunogenici y h ough he con ol o alloan igen
exp ession [38-40]. The absence o MHC class II gi es
MSC he po en ial o escape ecogni ion by allo eac i e
CD4+ T cells. In addi ion o being MHC II nega i e, MSC
do no appea o exp ess he co-s imula o y molecules
CD40, CD40L, CD80 o CD86 equi ed o e ec o T cell
induc ion[28,39]. The absence o co-s imula o y mole-
cules is a signi ican obse a ion. I implies ha any esid-
ual engagemen o he T cell ecep o on Th cells would
esul in ane gy and con ibu e o ole ance a he han
allogeneic esponses. Al hough his is a com o ing sce-
na io, based la gely on in i o s udies, i canno ully
explain he e asion o allo eac i i y demons a ed by
MSC. Expe imen s in ol ing allogeneic co-cul u es o
MLR ha e demons a ed ha bo h cell-cell con ac and
ac ion by soluble ac o s con ibu e o he immunomod-
ula o y unc ion o MSC[25,41-43]. Thus i is likely ha
e asion o allo eac i i y is a esul o bo h MSC hypoim-
munogenici y, modula ion o T cell immune induc ion
and he c ea ion o a supp essi e milieu a ound MSC.
Al hough he mechanisms go e ning he supp essi e
e ec a e no ully unde s ood, se e al s udies ha e gi en
indica o s o he p ocesses in ol ed.
MSC in e e e wi h DC ma u a ion and unc ion
Dend i ic cells (DC) a e he mos in luen ial APC, playing
a key ole in di ec ing cellula and humo al immune
esponses agains sel and non-sel an igens [44]. DC con-
ibu e o he es ablishmen o ole ance, especially in he
pe iphe y[45]. Imma u e DC a e no ully di e en ia ed
o ca y ou hei known oles as induce s o immu-
ni y[45]. Despi e his, imma u e DC ci cula e h ough is-
sues and he lymph sys em, cap u ing sel and non-sel
an igens[45]. Imma u e DC ha a e loaded wi h an igen
can silence T cells by dele ion o by expanding egula o y
T cell popula ions[45,46]. I has long been belie ed ha
his p ocess con ibu es o g a su i al du ing ansplan-
a ion [14]. The capaci y o DC o induce pe iphe al ole -
ance is a po en ial mechanism by which MSC could
manipula e immuni y in o de o escape T cell ecogni-
ion. Thus MSC could p e en no mal allogeneic
esponses ei he h ough modula ion o DC unc ion o
by di ec e ec s on T cells. Indica ions om di e en s ud-
ies encou age his hypo hesis. Zhang e al [24] p o ides
e idence ha MSC in e e e wi h DC ma u a ion. Co-cul-
u e expe imen s showed ha MSC down- egula e CD1a,
CD40, CD80, CD86, and HLA-DR exp ession du ing DC
ma u a ion[24]. This is also shown by Bey h e al. [42],
who sugges ha human MSC con e ed APC in o an
inhibi o y o supp esso pheno ype ia cell- o-cell con-
ac , hus locking DC in o a semi-ma u e s a e and he eby
inducing pe iphe al ole ance. Thei indings also show
educed IFN-γ, IL-12 and TNF-α in human MSC/mono-
cy e co-cul u e [42]. Simila ly Jiang e al epo ed ha
MSC main ain DC in an imma u e s a e[26] and show
ha MSC inhibi up egula ion o IL-12p70 [26]. These
esul s sugges ha MSC media e allogeneic ole ance by
di ec ing APC owa ds a supp esso o inhibi o y pheno-
ype ha esul s in an a enua ed o egula o y T cell
esponse.
MSC modula e CD4+ T cell esponses
E idence has eme ged ha MSC in e ac di ec ly wi h T
cells o supp ess allo ea i i y[25]. K ampe a e al showed
ha MSC impai T cell con ac wi h APC in a non-cogna e
bu ansien ashion[25]. This suppo ed wo k om Ba -
holomew e al showing ha he addi ion o IL-2 o MLR/
MSC co-cul u es educed MSC supp ession and es o ed T
cell p oli e a ion[19]. Taken oge he , hese esul s
s ongly suppo a ole o ei he a di ec (T cell pheno-
ype) o indi ec (DC pheno ype) mechanism o immune
modula ion di ec ed by MSC.
MSC modula ion o CD4+ T cell esponses is mo e ex en-
si e han he s aigh o wa d e ec desc ibed abo e. The
egula p ocess o an igen speci ic CD4+ T cell induc ion
equi es an igen cap u e and p ocessing by DC (o o he
amenable cells), ollowed by a p ocess o ma u a ion and
a icking o local lymph nodes[14,47-49]. The e is e i-
dence ha MSC p e en no mal allogeneic esponses by
di ec ing CD4+ T cells o a supp essi e o coun e - egula-
o y pheno ype[46,50]. Di Nicola e al, showed ha MSC
s ongly supp essed CD4+ (and CD8+) T cells in
MLR[43], indings suppo ed by Tse e al, who showed
ha MSC supp ess he p oli e a ion o T-cell subse s[28].
S udies o T cell di e en ia ion ha e shown ha in he
p esence o human MSC, Th1 cell sec e ion o IFN-γ
d opped by 50% compa ed o cul u es wi hou MSC.
Con e sely, e ec o T cells unde going Th2 di e en ia ion
when co-cul u ed wi h human MSC showed a signi ican
inc ease in IL-4 p oduc ion compa ed o con ols[21].
These indings sugges ha MSC exe a coun e egula-
o y, an i-in lamma o y ole by di ec ing cy okine-medi-
a ed immuni y[21].
A s a egy o egula ion and dele ion o speci ic T cells is
an e ec i e con ol agains unwan ed immune espon-
si eness especially a e ansplan ion[51]. Consequen ly,
eno mous in e es has ocused on he possibili y o T eg
cells as a ma ke o T cell ole ance du ing ansplan a-
ion. T eg can ac di ec ly on o he T cells o indi ec ly
h ough APC[46]. Agg awal e al, demons a ed ha
CD4+ CD25+ T eg popula ions inc eased signi ican ly in
MLR when MSC we e p esen compa ed o con ols[21].
Howe e , da a exis s showing ha human MSC-media ed
inhibi ion is no supp essed by emo ing T eg cells om
co-cul u es [25,42]. Ne e heless a ole o hese cells can
no be excluded, i is possible ha an incomple e eplica-
ion o he supp essi e mic oen i onmen in i o o
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indeed he di e si y o T eg cell popula ions mean ha
hese s udies do no ully explo e he po en ial ole o sup-
p essi e o egula o y T cells in p omo ing MSC ole ance.
MSC in luence con ol o e cell di ision cycle pa hways in
cells o immunological ele ance. Glennie e al ha e
shown ha T cells s imula ed in co-cul u es wi h MSC
exhibi an ex ensi e inhibi ion o cyclin D2 and up egula-
ion o he cyclin dependen kinase inhibi o p27kip1 [52].
As T cell inhibi ion could no be e e sed, hese cells we e
no in e p e ed as ane gic in he classical sense. The
au ho s sugges ha MSC a e mos likely inducing he
al e na i e condi ion o di isional a es ane gy in T cells,
an occu ence usually associa ed wi h CTLA-4 signal-
ling[53]. In addi ion, emo al o MSC om he sys em
only es o ed IFN-γ p oduc ion bu no T cell p oli e a-
ion[52]. This sugges s ha MSC induce a condi ion simi-
la o spli ane gy[54] o spli ole ance[55,56]. The key
poin is ha his wo k demons a es ha MSC exe e o
e ec s on T cells and i is signi ican in demons a ing ha
he mechanisms inducing MSC ole ance a e no con ined
o pa e ns o cy okine sec e ion bu ex end o di ec mod-
ula ion o T cell di ision.
MSC modula e CD8+ T cell and NK cell ac i i y
The impac o MSC on CD8+ CTL and NK cells has also
been add essed. CTL can lyse allogeneic cells a e ecog-
ni ion o cogna e alloan igen, by he elease o cy o oxic
e ec o s such as, pe o ins, se ine es e ases, IFN-γ and
TNF-α [57] whe eas NK cells do no equi e an igen
p ocessing[58]. Consequen ly bo h e ec o cells can ope -
a e in andem, wi h NK cells p o iding a i s line de ence
killing a ge cells ha escape CTL ecogni ion o show
inadequa e exp ession o sel -MHC[58]. The e is e idence
ha MSC inhibi he o ma ion o CTL and appea o
e ade NK cell a ge ing mechanisms. Djouad e al showed
ha CD8+ cells a e supp essed by MSC in MLR[41]. Ras-
musson suppo ed hese indings and u he showed ha
NK cells in co-cul u e did no ecognize MSC al hough
ly ic capabili y was s ill p esen [59]. This e ec appea ed
o be media ed by soluble ac o s[50,59]. Thus MSC in e -
ac and supp ess cell-media ed immune esponses di ec ly
and h ough soluble ac o s. The a ge s o his supp es-
sion a e DC, CD4+ Th, CD8+ CTL and NK cells; in e ec
MSC silence each aspec o he cellula ejec ion p ocess.
MSC sec e e soluble ac o s o c ea e an
immunosupp essi e milieu
The cha ac e isa ion o cy okines p oduced by MSC is s ill
p o isional and is hinde ed by he lack o s anda disa ion
in isola ion and cul u e condi ions, which ha e gi en ise
o mul iple indings and in e p e a ions. I is e iden ha
MSC do no cons i u i ely exp ess IL-2, IL-3, IL-4 and IL-
5[60,61]. Howe e some epo s show ha MSC do con-
s i u i ely exp ess mRNA o cy okines such as in e leukin
(IL)-6, -7, -8, -11, -12, -14, -15, -27, leukaemia inhibi o y
ac o , mac ophage colony-s imula ing ac o , and s em
cell ac o [62,63]. Some o hese cy okines p o ide c i ical
cell-cell in e ac ions and p omo e HSC di e en ia ion,
howe e cau ion should be exe cised be o e o e in e -
p e ing hese indings. P o ein sec e ion does no always
mi o mRNA le els and mos wo ke s in he ield would
adop a mo e conse a i e p o ile o cy okine and g ow h
ac o p oduc ion by MSC.
Despi e hese ca ea s, ce ain MSC sec e ed p oduc s such
as Hepa ocy e g ow h ac o , (HGF) a e likely o con ib-
u e o c ea ing a local immunosupp essi e en i onmen .
HGF induces mi ogenic and an iapop o ic ac i i y in di -
e en sys ems [64-66] and has a well-cha ac e ized ole in
wound epai [66-68], e ec s ha a e consis en wi h a
ole o MSC in egene a i e medicine. Al hough some
g oups do no de ec HGF in MSC co-cul u es [41] mo e
epo s sugges ha HGF is cons i u i ely exp essed by
MSC [13,43,69,70]. Indica ions ha MSC p oduce HGF
[13,43,69,70] encou age a ole o hese cells in issue
epai [70]. S udies by Chunmeng e al, demons a ed ha
a de mal de i ed "mul ipo en " cells sec e e HGF and
p omo e wound healing[68]. In e es ingly, Azuma e al,
showed ha HGF ea men p e en s ch onic allog a
neph opa hy in a s[71]. Taken oge he hese esul s sug-
ges ha HGF may con ibu e o he abili y o MSC o
a oid allo ejec ion.
IL-10 has a well-documen ed ole in T cell egula ion and
in he p omo ion o a " egula o y" o supp esso pheno-
ype. In ou hands human MSC cons i u i ely p oduce IL-
10 whe eas Rasmusson e al and Bey h e al only de ec ed
IL-10 in co-cul u e expe imen s [42,72]. In ei he case, IL-
10 is likely o be supp essing po en ial allo- esponsi e-
ness because i is a ecognized g ow h ac o o egula o y
T cells [73]. IL-10 can an agonize IL-12 du ing induc ion
o in lamma o y immune esponses [74-79]. This is sup-
po ed by s udies showing ha MSC pa ially media e
supp ession h ough IL-10 sec e ion in MLR cul-
u es[42,72]. Simila ly ans o ming g ow h ac o (TGF)-
β1 also plays a ole in T cell supp ession. This cy okine as
well as IL-10 in luences cell lineages b oade han lym-
phocy es [74,80,81]. Howe e cons i u i e exp ession o
TGF-β1 has no been de ec ed om ou own s udies on
human MSC[13]. This is in line wi h Le Blanc who ound
no di e ence in TGF-β1 concen a ion in co-cul u es wi h
o wi hou MSC [69]. In con as Bey h e al showed ha
TGF-β1 was sec e ed in media om co-cul u es o human
MSC and immune cells bu again co-cul u e did no aug-
men TGF-β1 concen a ion[42]. Al hough a numbe o
s udies sugges no ole o TGF-β1 in e asion o allogeneic
esponsi eness[42,69,72], i has been sugges ed ha HGF
in combina ion wi h TGF-β p omo es he allo-escaping
pheno ype[43]. Di Nicola e al showed ha neu alizing

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an ibodies o HGF and TGF-β es o ed he p oli e a i e
esponse in MLR, sugges ing ha hese ac o s a e a leas
pa ially esponsible[43].
MSC cons i u i ely exp ess he eicosanoid P os aglandin E
(PGE)-2 [82]. This may be up egula ed in co-cul-
u e[21,28] o down egula ed on di e en ia ion[82].
PGE-2 in luences nume ous immune unc ions including
supp ession o B cell ac i a ion[83] and induc ion o eg-
ula o y T cells[84]. Al hough he e is e idence o PGE-2
sec e ion by MSC, he e is con o e sy su ounding a ole
o PGE-2 as a media o o supp ession o allo esponses
in MLR. S udies om Tse, sugges ed ha PGE-2 is no a
signi ican componen o supp ession[28]. Suppo ing
hese indings Rasmusson e al showed ha blocking PGE-
2 p oduc ion did no es o e allogeneic MLR esponses
bu did in luence mi ogen d i en p oli e a ion[72].
Al hough he p esen opinions a e con lic ing, i should
be highligh ed ha o he possible p os aglandins and
eicosanoids could be in luencing allo esponses[85]. Anal-
ysis o hese o he immunomodula o y molecules could
p o ide u he clues as o how MSC escape he immune
sys em.
In con as o immunosupp ession h ough he sec e ion
o soluble ac o s, supp ession may be media ed by wi h-
d awal o ac o s in he mic o-en i onmen necessa y o
ac i e immune esponses. Indoleamine 2,3-dioxygenase
(IDO) is an enzyme ha ca abolizes L-T yp ophan,
he eby deple ing an essen ial amino acid om he local
en i onmen [86-89]. Recen e idence has shown ha
his mechanism is exploi ed by he mammalian e al allo-
g a o supp esses T cell ac i i y and p e en ejec ion [86-
89]. Al hough no a soluble ac o , he exp ession o IDO
may con ibu e o a ole genic en i onmen . This is o
g ea ele ance and has ob ious pa allels wi h MSC. Mei-
sel e al showed ha IDO is no cons i u i ely exp essed
by MSC bu can be induced by IFN-γ[90], he eby inhibi -
ing allogeneic T cell esponses by T yp ophan deple-
ion[90]. O he indings ha e sugges ed ha IDO-
media ed yp ophan deple ion inhibi s allogeneic T-cell
esponses by mul iple pa hways[91]. The disco e y o his
mechanism, which shows pa allels o he c ea ion o a
"T yp ophan dese " a he ma e no- e al in e ace[13],
p o ides a u he easible mechanism by which MSC
a oid allo eac i i y. Howe e , IDO exp ession is no
essen ial o he main enance o ole ance agains MSC. Tse
e al showed ha an IDO inhibi o o supplemen a y
T yp ophan addi ion o MLR did no es o e PBMC p oli -
e a ion [28].
MSC con ol su ace ma ke exp ession o exhibi a
hypoimmunogenic o ole ogenic pheno ype. MSC can
also modula e T cell induc ion di ec ly o ia DC and
sec e e a ba e y o immunosupp essi e ac o s. I is
appa en ha he ques ion acing he applica ion o egen-
e a i e medicine is no longe "how do MSC escape allo e-
ac i i y?" bu a he "wha is he hie a chy o signals ha
con ol immunosupp ession?" In his ega d, esea ch
om o he ields has been in o ma i e. We ha e p e i-
ously p oposed ha ma e nal accep ance o he e al allo-
g a p o ides indica o s o how his p ocess is
con olled[13]. Howe e , insigh could also come om
ano he a enue o inqui y. The mechanisms o umo e a-
sion may e lec he su i al mechanisms o MSC.
MSC a oidance o allo eac i i y shows pa allels o umo
e asion
Escape om immune su eillance is belie ed o be a p i-
ma y ea u e o malignan disease in humans. The
immune e ec o esponse is sub-op imal because umo s
de elop mul i ac o ial s a egies o escape immune dele-
ion[92,93]. These s a egies may p o ide clues o how
MSC p omo e ole ogenic mechanisms du ing allogeneic
eng a men (Fig. 3). Modula ion o umo an igen
exp ession, pa icula ly MHC class I and II is a pa icula ly
common componen o umo immune e asion[93]. This
is o en accompanied by poo o non-exp ession o co-
s imula o y molecules, which no only limi s clonal
expansion o umo -speci ic CD4+ T cells, bu also hin-
de s he p oduc ion o cy okines, and he de elopmen o
CTL[44,94,95]. Simila ly MSC show no exp ession o co-
s imula o y molecules (Fig. 2) [28,39]. In addi ion o
educed immunogenici y, umo cells can di ec ly modu-
la e DC and T cell unc ion. S udies om pa ien s wi h
hepa ocellula ca cinoma showed ha neoplasia induced
a de ec o DC ma u a ion[96]. This pa allels indings by
Bey h e al [42] sugges ing ha human MSCs in e e e
wi h no mal APC ma u a ion, he eby indi ec ly in luenc-
ing T-cell ac i a ion. F eshly isola ed umo -in il a ing T
cells a e usually inac i e agains au ologous cance cells
bu can be eac i a ed in- i o by he addi ion o IL-2[97].
S udies o MSC by Le Blanc e al showed s iking pa allels
o his o m o supp ession[69]. They sugges ha MSC ac
by p e en ing exp ession o CD25 (IL-2 ecep o ) he eby
limi ing T cell ac i a ion[69]. O he wo k has shown ha
exogenous IL-2 addi ion o co-cul u es con aining MSC
e e sed he supp essi e e ec [19,69]. Simila ly, an igen-
speci ic CD4+ CD25+ egula o y T cells also supp ess
umo -speci ic CD8 T cell cy o oxici y al hough his mech-
anism elies on TGF-β sec e ion by egula o y cells[98,99].
Tumo s can supp ess CD4+ T cell ac i i y and CTL umo
lysis di ec ly h ough sec e ion o immunosupp essi e
ac o s including TGF-β1 bu also PGE-2, and IL-10. Van
de Pouw K aan e al, showed ha umo -de i ed p os ag-
landins inc eased he p oduc ion o inhibi o y cy okines
such as IL-10, while supp essing IL-12[100], which is nec-
essa y o e ec i e hos -cell-media ed an i- umo immune
esponse[75,93]. Likewise, TGF-β p oduc ion has been
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epo ed om a numbe o umo s, con ibu ing o
immune e asion. In iguingly in his con ex i also inhib-
i s CTL di e en ia ion [101]. Al hough he e is li le e i-
dence ha MSC sec e e TGF-β1, he bone ma ow is ich
in his cy okine, sugges ing ha MSC eside in a compa -
men wi h immunosupp essi e quali ies.
Al hough he e a e s iking pa allels be ween MSC and
some umo cells, i is no ou con en ion ha hese cells
a e di ec ly ela ed. Indeed he e a e dis inc di e ences
be ween he popula ions (Table 1). The undamen al di -
e ence be ween he cell ypes esides in he con ol o cell
di ision and apop osis, which a e igh ly egula ed in
MSC bu dys egula ed in ans o med cells. Fu he mo e,
i is well documen ed ha some umo s exploi FasL
(CD95L) exp ession o acili a e immune escape [102-
104]. Howe e , ou own s udies show ha human MSC
do no exp ess FasL (Fig 2) and al hough he e is some e i-
dence om immo alized mini-pig de i ed MSC o indi-
ca e a ole o FasL in supp ession[105], i seems ha
di ec induc ion o apop o ic dele ion is no a ac o
in ol ed in MSC in e ac ion wi h T cells in he b oade li -
e a u e. The pa allels be ween neoplas ic cells and MSC lie
in he exp essed pheno ypes a he han in any di ec lin-
eage ela ion. I appea s ha MSC e ain ce ain aspec s o
he e al allog a ha p omo e ole ance, some o hese
mechanisms may be eac i a ed in neoplasia, he key di -
e ence being ha MSC pe o m hese unc ions in an
o de ed and con olled way whe eas umo cells do so in
a manne ha by de ini ion has escaped no mal con ols
on apop osis o cell di ision.
Conclusion
Cu en esea ch on he in e ac ion be ween MSC and T
cells suppo he po en ial use o allogeneic MSC in egen-
e a i e medicine. S udies showing enhanced MSC eng a -
men o bone, muscle, hea e c encou age he ansla ion
o ecen esea ch in o he apy. The u u e holds much
p omise o he use o allogeneic MSC and whils obs a-
cles exis , he po en ial o allo eac i i y does no seem o
be a majo p oblem. F om he esea ch s andpoin , MSC
appea o use a su p ising a ay o mechanisms o a oid
dele ion by he hos including hypoimmunogenici y,
modula ion o DC and T cell unc ion, as well as he c ea-
ion o a supp essi e mic oen i onmen . The challenge is
now o un a el he iming and con ol o hese mecha-
nisms in an in lamma o y si ua ion ypical o he ecipi-
en pa ien .
Lis o Abb e ia ions
APC, an igen p esen ing cells; DC, dend i ic cell; ES,
emb yonic s em; HGF, hepa ocy e g ow h ac o ; HSC,
hema opoie ic s em cells; IDO, indoleamine 2,3,dioxyge-
nase; KIR, kille inhibi o y ecep o ; MLR, mixed lym-
phocy e-like eac ion; MSC, mesenchymal s em cells; OI,
os eogenesis impe ec a; PBMC, pe iphe al blood mono-
nuclea cells; PGE-2, p os aglandin E2.
Compe ing in e es s
JMR and BPM ha e no compe ing in e es s. FPB and JMM
ha e ecei ed sala y om an o ganiza ion and hold s ocks
o sha es in an o ganiza ion ha may gain o lose inan-
cially om he publica ion o his manusc ip .
Au ho s' con ibu ions
FPB and BPM concei ed he e iew; JMR pe o med he
mic oscopy and low cy ome y. All au ho s p o ided
MSC and umo cells c ea e a supp essi e mic oen i onmen Figu e 3
MSC and umo cells c ea e a supp essi e mic oen i on-
men . The e a e undamen al di e ences be ween umo
cells (A) and MSC (B) wi h espec o con ol o cell di ision,
howe e many mechanisms exploi ed by he o me o e ade
immune dele ion a e also used by MSC o a oid allogeneic
ejec ion. De ails o mechanisms and associa ed e e ences
a e supplied in he body o he ex and Table 1.
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in e p e a ion o published s em cell da a, and ha e made
in ellec ual con ibu ions o he con en o he pape . All
au ho s ead and app o ed he inal manusc ip .
Addi ional ma e ial
Acknowledgemen s
This wo k was suppo ed by he Science Founda ion I eland Cen es o
Science Enginee ing and Technology (CSET) unding o he Regene a i e
Medicine Ins i u e (REMEDI). Be na d Mahon is a Wellcome T us /HRB
"New Blood" Fellow. Ms Ka en English is hanked o assis ance in p epa-
a ion o his manusc ip .
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Table 1: Compa ison o MSC and Tumo cellsa
Cha ac e is ic MSC Tumo cells Re e ences
Cell Di ision Con olled Uncon olled [5, 7, 111]
MHC I exp ession + Va iable Fig 2 & [25, 27, 28, 39, 93, 111, 112]
MHC II exp ession - Va iable Fig 2 & [2, 25, 27, 39, 93, 111, 112]
CD80 exp ession - - [25, 28, 39, 44, 94, 95]
CD86 exp ession - - Fig 2 & [25, 28, 39, 44, 94, 95]
FasL exp ession - + Fig. 2 & [102-104]
P os aglandin sec e ion + + [21, 28, 82, 100]
IDO exp ession + Va iable [28, 43, 59, 87, 90]
TGF-β sec e ion Va iable + [42, 43, 59, 101, 105]
IL-10 sec e ion + + [13, 42, 72, 100]
DC modula ion + + [24, 26, 42, 96]
Ve o e ec s on T cells + + [23, 112]
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Likewise he cha ac e is ics o neoplas ic cells will a y g ea ly be ween di e en umo s. This able lis s hose cha ac e is ics whe e a leas some
cells om each di e se popula ion show ei he compa a i e o con as ing ea u es.
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