Mesenchy

mal
stem cel
l

Mesenchy
malst
em cel
l

Tr
ansmi
ssi
on 
elect
ronmi
crogr
aph 
ofamesenchy
mal
stem cel
l

di
spl
ayi
ngt
ypi
cal
 
ult
rast
ruct
ural
 
char
act
eri
sti
cs.

Det
ail
s

I
dent
if
ier
s

Lat
in Cel
l
ulamesenchy
mat
icapr
aecur
sor
ia

TH H2.
00.
01.
0.00008

Anat
omi
calt
ermsofmi
croanat
omy

[
edi
tonWi
ki
dat
a]

Mesenchy
mal st
em cell
s are mult
ipot
ent 
str
omal cel
ls 
thatcan dif
fer ent i
ate 
int
oavari
etyofcell
ty
pes,i
ncl
udi
ng osteobl
asts (bonecel
ls)
, 
chondrocyt
es (car
ti
lagecel ls) ,
 
my ocyt
es 
(musclecel
ls)
and 
adi
pocyt
es (
fatcell
swhi chgiveri
seto marr
owadi posetissue).
[1]
[2]
 Cont
ent
s

 1St
ruct
ure

o 1.
1Def
ini
ti
on

o 1.
2Mor
phol
ogy

 2Locat
ion

o 2.
1Bonemar
row

o 2.
2Cor
dcel
l
s

o 2.
3Adi
poset
issue

o 2.
4Mol
arcel
l
s

o 2.
5Amni
oti
cfl
uid

 3Funct
ion

o 3.
1Di
ff
erent
iat
ioncapaci
ty

o 3.
2Immunomodul
ator
yef
fect
s

o 3.
3Ant
imi
crobi
alpr
oper
ti
es

 4Cl
i
nical
signi
fi
cance

o 4.
1Aut
oimmunedi
sease

o 4.
2Ot
herdi
seases

o 4.
3Det
ect
ion

 5Resear
ch

 6Hi
stor
y

 7Seeal
so

 8Ref
erences

 9Ext
ernal
li
nks

St
ruct
ure[
edi
t]
Def
ini
ti
on[
edi
t]
Whil
etheter mesenchy
ms  malstem cell
 
( mar
MSC)and  r
owstromalcell
 hav
ebeenused
i
nter
changeabl
yformanyyear
s,nei
thertermissuff
ici
entl
ydescr
ipt
ive:

 Mesenchy
me 
i
s embr
yoni
c connect
ivet
issue 
thati
sder
ivedf
rom t
he 
mesoder
m andt
hat
di
ff
erenti
atesint
o hematopoi
eti
c andconnect
ivet
issue,
wher
easMSCsdonotdi
ff
erent
iat
eint
o
hematopoi
eticcel
ls.[
3]

 St
romal
cel
l
s ar
econnect
ivet
issuecel
l
sthatf
ormt
hesuppor
ti
vest
ruct
urei
nwhi
cht
he
f
unctionalcel
lsoftheti
ssuereside.Whil
ethisisanaccur
atedescr
ipt
ionf
oronef
unct
ionof
MSCs, theter
mf ai
l
st oconveytherelat
ivel
yrecent
lydi
scover
edrol
esofMSCsinther
epai
rof
t
issue.[
4]

 Thet
erm encompassesmul
ti
pot
entcel
l
sder
ivedf
rom ot
hernon-
mar
row 
ti
ssues,
such
as 
placent
a,[
5]
 
umbi
li
calcord bl
ood,
 adi
poset
issue,
adult
 muscl
e, 
cor
nealst
roma[6] 
ort
hedent
al
pul
pof  
deci
duous babyteeth.Thecell
sdonothavethecapaci
tytor
econst
itut
eanent i
reor
gan.
Mor
phol
ogy
[edi
t]

Humanbonemar
rowder
ivedMesenchy
mal
stem cel
lshowi
ngf
ibr
obl
ast
-l
ikemor
phol
ogyseenunderphase
cont
rastmi
croscope(
car
lzei
ssaxi
over
t40CFL)at63xmagni
fi
cat
ion

Mesenchy malstem cell

sar echar act er
izedmor phologicallybyasmal l cellbody 
withafewcel
l
processesthatarelongandt hi n.Thecel lbodycont ai
nsal arge,round  nucleus 
witha
prominent 
nucleolus,
whi chissur roundedbyf inelydispersed  chromat i
n  part
icl
es,gi
vingt
henucl
eus
aclearappearance.Ther emai nderoft hecel lbodycont ai
nsasmal lamountof  
Golgi
apparatus,
 r
oughendopl asmi cr et
iculum, mitochondr ia 
and  polyri
bosomes.Thecel l
s,whi
char
elong
andthin,arewidelydi
sper sedandt headj acent extr
acellularmat rix
 ispopul atedbya
few r
eticul
ar 
fi
bril
sbutisdev oidoft heothert ypesof  
col l
agen  f
ibri
ls.[
7][
8]

Locat
ion[
edi
t]
Bonemar
row[
edi
t]
Bonemar rowwast heori
ginalsourceofMSCs, andst
il
li
st hemostfr
equent
lyuti
li
zed.Thesebone
marrowstem cel l
sdonotcont ri
butetotheformati
onofbloodcell
sandsodonotexpr ess
the 
hematopoi et
icstem cel
l 
mar ker 
CD34.Theyaresometimesref
err
edtoas bonemar r
owstromal
stem cel
l
s.[9]

Cor
dcel
l
s[edi
t]
Theyoungestandmostprimit
iveMSCscanbeobt
ainedfrom umbil
i
calcordt
issue,
namely 
Wharton'
sjel
l
y andtheumbil
i
cal
 cor
dbl
ood.Howev erMSCsarefoundinmuchhigher
concent
rat
ionintheWharton’
sjel
l
ycomparedt
ocordblood,whichi
sarichsourceof 
hematopoi
eti
c
stem cel
ls.Theumbi
li
cal
cor
disavail
abl
eaf
terabir
th.I
tisnor
mal
l
ydiscardedandposesnori
skf
or
coll
ecti
on.TheseMSCsmayprov
et obeauseful
sourceofMSCsf
orcli
nicalappl
i
cat
ionsduet
o
thei
rprimiti
vepr
oper
ti
es.
Adi
poset
issue[
edi
t]
Adi
poset
issue 
i
sar
ichsour
ceofMSCs(
oradi
pose-
der
ivedmesenchy
mal
stem cel
l
s,AdMSCs)
.[
10]

Mol
arcel
l
s[edi
t]
Thedev el
opi
ngtoot hbudofthemandibularthi
rdmolari
sar i
chsourceofMSCs.Whi letheyare
descr
ibedasmul ti
potent
,iti
spossi
blethattheyareplur
ipot
ent.Theyev
entual
lyform enamel,
dent
in,
bl
oodv essel
s,dentalpul
pandnervoustissues.Thesest
em cell
sarecapableofproducing
hepat
ocy t
es.
Amni
oti
cfl
uid[
edi
t]
Stem cel
lsarepresentin amnioti
cflui
d.Asmanyas1in100cellscol
l
ect
ed
duri
ng amniocentesi
s areplur
ipotentmesenchy
malst
em cel
l
s.[
11]

Funct
ion[
edi
t]
Di
ff
erent
iat
ioncapaci
ty[
edi
t]
MSCshav eagr eatcapaci t
yf orsel f-renewal whi lemai nt
ainingt heirmul t
ipotency .Beyondt hat,t
here
i
sl it
tlethatcanbedef ini
ti
v el
ysai d.Thest andar dt esttoconf ir
m mul tipotencyi sdifferenti
ationof
thecel l
sintoost eoblasts,adipocy tesandchondr ocytesaswel lasmy ocy tesandneur ons.MSCs
hav ebeenseent oev endi f
ferent iat ei nt oneur on- l
ikecells,
[
 
12]
butther ei sli
nger i
ngdoubtwhet herthe
MSC- deri
vedneur onsar efunct ional .[
 
13]
Thedegr eetowhi cht hecul turewi lldif
ferentiatevaries
amongi ndividualsandhowdi ffer ent i
at ionisi nduced, e.g.,chemi cal vs.mechani cal;
[
 
14]
anditisnot
clearwhet hert hisvar i
ati
oni sduet oadi f
ferentamountof" t
r ue"progeni torcellsinthecul tureor
variabledifferentiat
ioncapaci tiesofi ndi v
idual s'progenitors.Thecapaci t
yofcel ls
to proli
fer
at e and di
fferentiat
e  isknownt odecr easewi ththeageoft hedonor ,aswel lasthet i
mei n
culture.Likewi se,whet herthisi sduet oadecr easei nthenumberofMSCsorachanget othe
existingMSCsi snotknown. ci
[ t
ati
onneeded]

I
mmunomodul
ator
yef
fect
s[edi
t]
MSCshaveaneffectoni nnateandspeci f
ici
mmunecel l
s.MSCspr oducemanymol eculeshavi
ng
i
mmunomodulatoryeffects.Theseincludeprostagl
andinE2( PGE2)
,[
 
15]
ni
tr
icoxi
de,
[
 
16]
indol
amin2,3-
di
oxi
genase(
IDO),IL-
6,andot hersurfacemar kers-FasL,
[
 
17]
PD-
L1/2.
MSCshav eanef fectonmacr ophages, neutrophi l
s,NKcel l
s,mastcel l
sanddendr iti
ccel l
sininnate
i
mmuni t
y.MSCsar eabletomi gratetothesi teofi njury ,wher etheypol arizet hroughPGE2
macr ophagesi nM2phenot ypewhi chischar act eri
zedbyanant i-
inflammat or yef f
ect.[
 
18]
Further
,
PGE2i nhi
bit
st heabi l
ityofmastcel l
stodegr anul ateandpr oduceTNF- α.  
[
19]
[20]
Proli
ferationand
cytotoxicactivityofNKcel lsisinhibi
tedbyPGE2andI DO.MSCsal sor educet heex pressionofNK
cellreceptors-NKG2D, NKp44andNKp30. [
MSCsi
21]
nhi bitrespi
rator yf
lareandapopt osisof
neutrophilsbypr oductionofcy tokinesIL-6andI L-8.
[
 
22]
Di f
ferent
iationandexpr essionofdendr it
iccel
l
surfacemar ker si sinhibit
edbyI L-6andPGE2ofMSCs. [
 
23]
Theimmunosuppr essiveeffect sofMSC
alsodependonI L-10,butitisnotcer t
ainwhet hertheypr oduceital one,oronl ysti
mul ateot hercell
s
topr oduceit.
[24]

MSCexpr essest headhesi onmoleculesVCAM- 1andICAM- 1,whichal lowT-ly

mphocy t
est oadhere
totheirsurface.ThenMSCcanaf fectthem bymol ecul
eswhi chhav eashorthalf-l
ifeandt hei
reff
ect
i
si ntheimmedi atevicini
tyofthecell
.[
16]
 
Theseincl
udenit
ri
coxi de,
[
 
25]
PGE2,HGF,[
 
26]
andact i
vat
ionof
receptorPD- 1.  
[27]
MSCsr educeTcellpr oli
fer
ati
onbetweenG0andG1cel lcycl
ephases[28] 
and
decreaset heexpr essionofIFNγofTh1cel l
swhil
eincr
easingtheexpr essi
onofIL- 4ofTh2
cel
ls.
[
 
29]
MSCsal soi
nhi
bitt
hepr
oli
fer
ati
onofB-
ly
mphocy
tesbet
weenG0andG1cel
lcy
cle
phases. [27]
[30]

Ant
imi
crobi
alpr
oper
ti
es[
edi
t]
MSCscanpr oduceanti
mi crobi
alpepti
des( AMPs)
.Theseincl
udehumancat hel
ici
dinLL-37,
[
 
31]
β-
defensines,  
[
32]
li
pocal
in2  
[
33]
andhepcidi
n.  
[
34]
MSCseffecti
vel
ydecreasenumberofcol oniesofboth
gram negativeandgr am positi
vebacter
iabypr oducti
onoftheseAMPs.I naddi
ti
on,thesame
anti
mi crobi
al ef
fectoft
heenzy meIDOpr oducedbyMSCswasf ound.[
35]

Cl
i
nical
signi
fi
cance[
edi
t]
Ty
pical
grossappear
anceofat
ubul
arcar
ti
lagi
nousconst
ructengi
neer
edf
rom amni
oti
cmesenchy
mal
stem
cel
l
s

Mesenchymalst
em cel
lsinthebodycanbeactivat
edand mobil
ized 
ifneeded.However,t
he
ef
fi
ciencyisl
ow.Fori
nstance,damagetomusclesheal
sv er
yslowlybutfurt
herstudyint
o
mechanismsofMSCact i
onmaypr ovi
deavenuesfori
ncreasi
ngt hei
rcapacit
yforti
ssuerepai
r.
[
36]
[37]

Aut
oimmunedi
sease[
edi
t]
Clini
cal studi esi nv esti
gatingtheef f
icacyofmesenchy malstem cell
sint reati
ngdi seasesarein
preli
mi narydev elopment ,
part
icularl
yf orunderstanding aut
oimmunedi seases, graftversushost
disease, Cr ohn' sdi sease, 
multipl
escl erosi
s,
 systemicl upuserythematosus  and systemic
sclerosis.[
38]
[
 
39]
Asof2014, nohigh-qualit
ycli
nicalresearchprovidesev i
denceofef ficacy,and
numer ousi nconsi stenciesandpr oblemsexi stinther esear
chmet hods.[
39]

Ot
herdi
seases[
edi
t]
Manyoftheear l
yclini
calsuccessesusingi ntrav
enoust r
ansplant
ati
oncamei nsyst
emi cdi
seases
suchas 
graf
tv ersushostdisease and 
sepsi s.Di
r ecti
njecti
onorplacementofcellsintoasi tein
needofr
epairmaybet hepreferr
edmet hodoft reatment,asvasculardel
i
v erysuf
fersfrom a
"pul
monaryf
irstpassef f
ect"wherei nt
ravenousi nject
edcel l
saresequesteredinthelungs.
[40]

Det
ect
ion[
edi
t]
TheInternati
onal SocietyforCel l
ularTher apy( I
SCT)haspr oposedasetofst andardstodef
ine
MSCs.Acel l
canbecl assifi
edasanMSCi fitshowspl asti
cadherentpr
oper ti
esundernormal
cul
tureconditionsandhasaf i
broblast-li
kemor phol
ogy.Infact,
somearguet hatMSCsand
fi
brobl
ast sarefunct i
onall
yi denti
cal.[
 
41]
Furt
her more,MSCscanunder goost eogenic,adi
pogeni
cand
chondrogenicdifferenti
ation exv i
vo.Thecul tur
edMSCsal soexpressonthei r
surf
ace CD73, CD90  and CD105, whi l
el ackingtheexpression
of 
CD11b,  
CD14,  
CD19,  
CD34,  CD45, CD79a  and  HLA-
DR surfacemarker
s.[
42]

Resear
ch[
edi
t]
Themaj ori
tyofmoder ncul turetechni
quesstill
takeacolony-for
mingunit-f
ibrobl
asts(CFU-F)
approach,whererawunpur i
fi
edbonemar roworf icol
l
-puri
fi
edbonemar r
ow  Mononuclearcel
l
 are
pl
ateddi r
ectl
yint
o cellculture 
platesorf
lasks.Mesenchy malstem cel
ls,butnotredbloodcell
sor
haemat opoet
icprogenitors,areadherenttoti
ssuecul t
ureplasti
cwithi
n24t o48hour s.Howev er
,at
l
eastonepubl i
cati
onhasi dentif
iedapopulationofnon-adherentMSCst hatarenotobt ai
nedbythe
di
rect-
plati
ngtechnique.[
43]

Other
 f
lowcytometr
y-basedmet hodsall
owt hesort
ingofbonemar r
owcell
sforspecif
icsurf
ace
markers,
suchas 
STRO- 1.[
 
44]
STRO-1+cel
lsaregenerall
ymorehomogenousandhav ehigherrat
esof
adher
enceandhigherratesofpr oli
fer
ati
on,buttheexactdi
ff
erencesbet
weenSTRO- 1+cell
sand
MSCsar
enotcl
ear
.[
45]

Methodsofi
mmunodepl
eti
onusi
ngsucht
echni
quesas 
MACS 
hav
eal
sobeenusedi
nthenegat
ive
sel
ecti
onofMSCs.
[
46]

Thesupplementati
onofbasalmediawi t
h fetalbov i
neser
um orhuman 
plat
eletl
ysat
e i
scommoni n
MSCculture.Pr
iortot
heuseofpl at
eletly
sat esforMSCcul t
ure,
thepat
hogeninacti
vat
ionpr
ocessis
recommendedtopr ev
entpathogentransmi ssi
on.[
47]

Hi
stor
y[edi
t]
I
n1924,Russian-bornmor phol
ogist 
AlexanderA.Maximov 
(Russi an: 
АлександрАлександрович
Максимов);usedext ensiv
ehistol
ogicalfi
ndingst
oident
if
yasi ngularty
peofprecur
sorcell
withi
n
mesenchy
met hatdev el
opsint
odi f
ferentt
ypesofbloodcel
ls.
[48]

Scienti
sts 
ErnestA.McCul l
och 
and JamesE.Til
l f
ir
str eveal
edthecl onalnat
ureofmar r
owcel l
sin
the1960s.[
49]
[
 
50]
An exvi
vo 
assayforexamini
ngthecl onogenicpotent ialofmult
ipot
entmar r
owcells
wasl at
errepor tedint
he1970sbyFr i
edenst
einandcol leagues.
[
51]
[
 
52]
Inthisassaysyst
em, str
omal
cell
swer eref erredtoascolony
-for
mingunit-
fi
broblasts(CFU-f)
.
Thefir
stclini
calt
ri
alsofMSCswer ecomplet
edi n1995whenagr oupof15pati
ent
swer ei
nject
ed
wit
hcul t
uredMSCst otestt
hesafetyoft
hetreatment.Si
ncethen,ov
er200cl
ini
calt
ri
alshavebeen
st
arted.Howev er
,mostaresti
l
linthesaf
etystageoftest
ing.
[
5]

Subsequentexper i
mentati
onrev eal edt hepl
astici
tyofmar r
owcell
sandhowt hei
rfateisdetermined
byenvir
onment alcues.Cult
uri
ngmar rowst r
omal cellsint
hepresenceofosteogenicsti
muli such
ascor
as  bicacid,i
nor
  gani
cphosphat e and dexamet hasone 
coul
dpr omotet
heirdif
ferenti
ati
on
i
nto 
osteoblasts.Incont
rast,
theaddi tionoft
 ransforminggrowt
hfactor
-bet
a (TGF-b)could
i
nduce chondrogenic 
markers.
[ci
tat
ionneeded]