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Review ArticleEffects of Antioxidant Supplements on the Survival andDifferentiation of Stem Cells
Sara Shaban,1 Mostafa Wanees Ahmed El-Husseny,1,2 Abdelrahman Ibrahim Abushouk,2,3,4
Amr Muhammad Abdo Salem,2,3 Mediana Mamdouh,1 and Mohamed M. Abdel-Daim5,6
1Faculty of Medicine, Fayoum University, Cairo, Egypt2NovaMed Medical Research Association, Cairo, Egypt3Faculty of Medicine, Ain Shams University, Cairo, Egypt4Medical Research Group of Egypt, Cairo, Egypt5Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt6Department of Ophthalmology and Micro-Technology, Yokohama City University, Yokohama, Japan
Correspondence should be addressed to Mohamed M. Abdel-Daim; abdeldaim.m@vet.suez.edu.eg
Received 25 February 2017; Accepted 31 May 2017; Published 9 July 2017
Academic Editor: Andreas Daiber
Copyright © 2017 Sara Shaban et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Although physiological levels of reactive oxygen species (ROS) are required to maintain the self-renewal capacity of stem cells,elevated ROS levels can induce chromosomal aberrations, mitochondrial DNA damage, and defective stem cell differentiation.Over the past decade, several studies have shown that antioxidants can not only mitigate oxidative stress and improve stem cellsurvival but also affect the potency and differentiation of these cells. Further beneficial effects of antioxidants include increasinggenomic stability, improving the adhesion of stem cells to culture media, and enabling researchers to manipulate stem cellproliferation by using different doses of antioxidants. These findings can have several clinical implications, such as improvingneurogenesis in patients with stroke and neurodegenerative diseases, as well as improving the regeneration of infarctedmyocardial tissue and the banking of spermatogonial stem cells. This article reviews the cellular and molecular effects ofantioxidant supplementation to cultured or transplanted stem cells and draws up recommendations for further research in this area.
1. Introduction
Stem cells are undifferentiated cells, characterized by self-renewal and the ability to differentiate into several celltypes (potency) [1]. They can be totipotent (differentiatinginto embryonic and extraembryonic cell types), pluripotent(differentiating into cells of the three germ layers), or mul-tipotent (differentiating into cells of a closely related family)[2]. Stem cell research runs with an incredible speed and itsapplications are under investigation in different medicalfields [3, 4]. There are two main types of stem cells: embry-onic stem cells (ESCs) (present in the inner cell mass of theblastocyst) and adult stem cells (present in different maturetissues to replace dead cells) [5, 6].
Induced pluripotent stem cells (iPSCs) are adult cells,genetically reprogrammed to express genes and factors,required for maintaining the properties of ESCs. However,the reprogramming process itself results in oxidative stressby generating high levels of reactive oxygen species (ROS)[7, 8], which cause damage to DNA, RNA, and cell proteinsand may induce apoptosis [9–11]. However, ROS arerequired in physiological levels to maintain the self-renewalcapacity of stem cells and to fight invading microbes [11–14].
Antioxidants are biochemical supplements that protectcellular constituents from oxidative stress by neutralizingfree radicals and terminating the oxidative reaction chainin the mitochondrial membrane [15]. They can be classi-fied into enzymatic and nonenzymatic, endogenous and
HindawiOxidative Medicine and Cellular LongevityVolume 2017, Article ID 5032102, 16 pageshttps://doi.org/10.1155/2017/5032102
exogenous [16], and water-soluble (reacting with oxidantsin the cytosol or plasma) and lipid-soluble antioxidants(preventing lipid peroxidation of cell membranes) [17].
Over the past decade, several studies have shown thatantioxidants can not only mitigate oxidative stress andimprove stem cell survival but also affect the potency and dif-ferentiation of these cells. In our article, we reviewed theresults of preclinical studies that investigated the effects ofantioxidants on cultured or transplanted stem cells in anattempt to draw up recommendations for further researchin this area.
2. Induced Pluripotent Stem Cells (iPSCs)
As highlighted earlier, the reprogramming of iPSCs is associ-ated with generation of high ROS levels. Several reportsshowed that, in comparison to somatic precursor cells, iPSCsexhibit the following criteria: (1) marked protection againstnuclear and mitochondrial DNA (mtDNA) damage and (2)significantly lower levels of ROS due to upregulation ofintrinsic antioxidant enzymes [18, 19]. Dannenmann et al.found a 10-fold decrease in ROS level and a fourfold increaseof glutathione (GSH) and glutathione reductase (GR) levelsin iPSCs, compared to fibroblasts [18]. In another study bythe same authors, they showed that several glutathione S-transferases (GSTs), which act as antioxidant and detoxifyingenzymes, were upregulated in iPSCs, compared to theirsomatic precursor cells [19].
Ji and colleagues reported that mitigation of oxidativestress during cellular reprogramming by antioxidant sup-plementation protects the genome of reprogramming cellsagainst DNA damage and leads to iPSCs with fewer geno-mic aberrations [20]. In the same vein, Luo and colleagues[21] found that iPSCs grew well and “stemness” was pre-served for up to two months after the addition of a low-dose antioxidant supplement. Moreover, using comparativegenomic hybridization (CGH) analysis, they showed thatantioxidant supplementation lowered the levels of geneticaberrations in cultured iPSCs [21].
Hämäläinen and colleagues showed that the repro-gramming and self-renewal abilities of iPSCs were dimin-ished after subtle increases in ROS levels, originating frommtDNA mutagenesis. However, the addition of two differentantioxidants [N-acetyl-L-cysteine (NAC) and mitochondria-targeted ubiquinone (MitoQ)] efficiently rescued these abili-ties in mutator iPSCs [22]. N-acetyl-L-cysteine raises cellularGSH pool and promotes the processing of H2O2 in the cyto-sol [23], whereas MitoQ acts upstream to prevent superoxideproduction within the mitochondria before H2O2 generation[24]. Of note, Hämäläinen et al. highlighted that the thera-peutic window of MitoQ for iPSCs is narrow, while highconcentrations of NAC were not associated with toxic effectson iPSCs [22].
Interestingly, other reports showed no effect of antiox-idant supplementation on the expression of 53BP1 andATM proteins (two molecules involved in DNA repairpathways) [25–27]. Recently, it has been found thathigh-dose antioxidants downregulates DNA repair-relatedkinases, which conversely results in genomic instability of
iPSCs [21]. Therefore, adjusting the dose of supplementaryantioxidants is critical.
3.BoneMarrow-DerivedMesenchymal (BMSCs)and Hematopoietic Stem Cells (HSCs)
Several studies showed that the ex vivo expansion of ESCsand mesenchymal stem cells (MSCs) [28–31] and thein vitro expansion of HSCs [32] may cause genomic insta-bility. Through a serial transplantation assay, Jang andcolleagues showed that elevated ROS levels reduce theself-renewal ability of HSCs [33]. Therefore, decreasingO2 concentrations to physiological levels or adding properdosages of antioxidants can reduce in vitro, culture-stimulated aneuploidy, providing potential methods tolimit genomic alterations when expanding HSCs in vitro[32, 34, 35]. Hamid et al. conducted an in vitro study toevaluate the antioxidant effects of Hibiscus sabdariffa L.(roselle) on bone marrow-derived HSCs. They showed thatroselle supplementation increased superoxide dismutase(SOD) expression (at 125, 500, and 1000 ng/mL) andHSCs survival (at 500 and 1000ng/mL) and protectedagainst H2O2-induced DNA damage [36].
In another study by Halabian et al., treatment of BMSCswith Lipocalin-2 (Lcn2), a natural cytoprotective factor gen-erated upon exposure to stressful conditions, increased cellu-lar resistance against oxidative, hypoxic, and serumdeprivation stresses. Moreover, Lcn2-treated cells showedSOD gene upregulation, increased proliferation, maintainedpluripotency, and improved cellular adhesion to culturemedia upon H2O2 exposure, in comparison to untreated cells[37]. Similarly, Fan and colleagues studied different methodsfor isolation of BMSCs, aiming at reducing the number ofchromosomal abnormalities in isolated cells. They reportedthat culturing isolated BMSCs at a low O2 concentration(2%) or with antioxidant (NAC) supplementation increasedcellular proliferation and genomic stability, in comparisonto cultured cells at normoxic concentrations (20% O2) [38].
Another study by Choi et al. demonstrated that addingascorbic acid 2-phosphate (AAP) at different concentrationscan influence the fate of BMSCs, that is, AAP significantlyincreased osteogenic differentiation at 50mM concentration,while a significant induction of adipogenic differentiationwith oil droplet formation was noted at concentrations of250mM and higher [39].
4. Cardiomyoblasts and Vascular Progenitor Cells
According to Li and colleagues, culturing cardiac stem cellswith antioxidant increased the number and severity of cyto-genic abnormalities. This could be explained by the excessivedecrease in ROS to subphysiological levels, which may down-regulate DNA repair enzymes [40]. In another study byRodriguez-Porcel et al., modulation of the microenviron-ment, using antioxidants, leads to a higher rate of cardiomyo-blast survival, early after transplantation to the myocardiumof small animals [41]. Therefore, oxidative stress blockademay provide a favorable microenvironment for stem cells’engraftment and survival in the heart [42].
2 Oxidative Medicine and Cellular Longevity
Song and colleagues reported increased ROS productionduring differentiation of human ESCs into vascular progeni-tor cells (CD34+ cells) due to increased activity of NADPHoxidase-4 (Nox4) enzyme. They found that moderate ROSscavenging, using selenium, enhanced the vascular differenti-ation of human ESCs, while complete ROS scavenging, usingNAC, totally inhibited the vascular differentiation of thesecells. This confirms that a minimal level of ROS is requiredfor vascular stem cell differentiation to occur [43].
5. Neural Stem Cells (NSCs)
Neural stem cells are multipotent stem cells that have beensuggested as a therapeutic agent to enhance the recovery ofinjured tissues in neuroinflammatory diseases [44]. Parkand colleagues tested the effects of GV1001, a novel antioxi-dant agent, derived from human telomerase reverse tran-scriptase, on in vitro-cultured mouse NSCs. They showedthat GV1001 treatment attenuated the effects of H2O2 expo-sure, reduced lipid peroxidation and mtDNA mutation, andinduced the expression of survival-related proteins [45].Hachem et al. reported that treatment of NSCs, isolated fromthe spinal cords of transgenic mice, with brain-derived neu-rotrophic factor improved cell viability by increasing thelevels of GR and SOD enzymes; however, it had no effecton cellular proliferation [46].
Nitric oxide (NO) and nitric oxide synthase (NOS)-dependent signaling pathways have been implicated in differ-ent neurodegenerative diseases [47, 48]. Moreover, NO levelswere linked to neural precursor cell (NPC) survival and cellfate determination [49], that is, elevated levels of NO sup-press NSC proliferation and enhance differentiation of NPCsinto astrocytes [50, 51]. Melatonin is a hormone synthesizedin the pineal gland [52] with indirect antioxidant abilitiesthrough induction of antioxidant enzymes [53] and inhibit-ing NO production in glial cultures through p38 inhibition[54]. It has been shown to protect NSCs against lipopolysac-charide- (LPS-) induced inflammation [52]. Moreover, Negiet al. demonstrated that melatonin mitigates neuroinflamma-tion and oxidative stress via upregulating nuclear factor(erythroid-derived 2) (Nrf2) [55], a transcription factorwhich stimulates the PI3K-Akt survival signaling pathway[56, 57] and increases the expression of the antioxidantenzyme heme oxygenase-1 (HO-1) [55].
To test the effects of in vitro antioxidant supplementa-tion, Petro et al. divided male rats with experimentallyinduced thromboembolic stroke into four groups: normalrats, untreated rats with stroke, rats receiving tissue plasmin-ogen activator (tPA) only, and rats receiving tPA+CAT/SOD (loaded on nanoparticles) at three hours post stroke.Two days later, brain tissue samples were harvested foranalysis. Brain sections from the untreated group showedevidence of NSC migration through the rostral migratorystream (through detection of NSCs markers, such as nes-tin, GFAP, and SOX2), confirming the occurrence of neu-rogenesis following stroke. However, brain tissue samplesfrom the tPA-alone group showed reduction in NSCsmigration, indicating that tPA treatment suppresses neuro-genesis, either directly or through reperfusion-induced
ROS generation injury. Interestingly, tPA+Nano-CAT/SOD treatment restored and significantly increased NSCsmigration [58].
6. Human Adipose-Derived Stem Cells (ADSCs)
Adipose-derived stem cells are multipotent stem cells thatcan be isolated from the human adipose tissue and are capa-ble of in vitro expansion. Sun and colleagues reported thatboth hypoxia and antioxidants promoted ADSCs prolifera-tion by raising the number of cells in the S phase, but themaximal increase in cell number was produced in the pres-ence of antioxidants [59]. Hypoxia is believed to influencethe secretion of several growth factors [60, 61], such asinsulin-like growth factor and hepatocyte growth factor[62], while antioxidants increase the expression of stemnessgenes (CDK2, CDK4, and CDC2) and the differentiationpotential of ADSCs [59]. Another study by Higuchi et al.found that lentivirus-mediated NADPH oxidase-4 (Nox-4)overexpression did not increase ROS production in insulin,dexamethasone, indomethacin, and 3-isobutyl-1-methylxan-thine (IDII)-stimulated ADSCs [63]. This finding was laterexplained by the increased expression of endogenous antiox-idants, such as SOD and CAT during adipogenesis [63, 64].
Yang et al. showed that treatment of ADSCs with fullerol(a polyhydroxylated fullerene) potentiated the expression ofthe transcription factor FoxO1 and its downstream genes,such as Runx2 and SOD2. Moreover, it enhanced the osteo-genic activity of ADSCs, as evidenced by increased minerali-zation and expression of osteogenic markers (Runx2, OCN,and alkaline phosphatase) [65]. Wang and colleagues showedthat pretreatment of ADSCs with NAC (3mM) or AAP(0.2mM) for 20 hours suppressed advanced glycosylationend product- (AGE-) induced apoptosis via a microRNA-dependent mechanism by inhibiting AGE-induced overex-pression of miRNA-223: a key modulator of intracellularapoptotic signaling [66].
7. HumanPeriodontal Ligament Cells (hPDLCs)
In a recent study, Chung and colleagues showed that treatinghPDLCs with deferoxamine (DFO), an iron chelator, resultsin a dose-dependent elevation in ROS levels, 24 hours aftertreatment [67]. The same finding was reported in rabbit car-diomyocytes [68] and normal human hepatocytes [69]. How-ever, DFO has the ability to act on Nrf2, increasing its nucleartranslocation and the expression of its target genes, includingGST and glutamate cysteine ligase (GCL) [67]. Therefore,DFO has both beneficial (Nrf2-mediated antioxidant effect)and cytotoxic (increased ROS levels) effects. GSH depletion,using buthionine sulfoximine (BSO) and diethyl maleate(DEM), was shown to inhibit DFO-stimulated hPDLC differ-entiation into osteoblasts [67]. Moreover, GSH depletion wasalso reported to repress myogenic differentiation of murineskeletal muscle (C2C12) cells [70] and phorbol-12-myris-tate-13-acetate- (PMA-) stimulated differentiation of humanmyeloid cell line (HL-60) [71].
3Oxidative Medicine and Cellular Longevity
Table1:Summaryof
theresults
ofin
vitroandin
vivo
stud
ieson
treatm
entof
stem
cells
withantioxidantsupp
lements.
Stud
yID
Antioxidant
(dose)
Stem
celltype
(sou
rce)
Find
ings
Possiblemechanism
s
Jietal.[20]
N-A
cetyl-L-cysteine
(NAC)andvitamin
C.
Indu
cedpluripotentstem
cells
(iPSC
s)generatedfrom
human
neon
atalforeskin
fibroblasts.
Incells,infectedwithreprogramming
factors(retrovirusesencoding
human
OCT4,SO
X2,KLF
4,and
c-MYC),supp
lementation
ofthe
cultu
remediawithNACsignificantly
increasediPSC
ssurvivalandredu
ced
ROSgeneration
andthenu
mber
ofDNAdo
uble-strandedbreaks
inthereprogrammed
cells.
Antioxidantssignificantlyredu
ced
ROSgeneration
andthenu
mber
ofcopy-num
bervariations
(CNVs:
anindication
ofgeno
mic
aberration
s)in
treatediPSC
s,comparedto
theun
treatedcontrol
grou
p(p
<002).Treatmentwith
NAChadno
effecton
transgene
expression
,silencing,andviral
transduction
efficiency.
Luoetal.[21]
Hom
emadeantioxidant
cocktail[ascorbate,
glutathion
e,and
α-tocop
herolat20
mM,
4mM,and
1mM,resp.].
Twohu
man
celllin
esof
iPSC
s(201B7and253G
1).
(i)Measurementof
cellu
larROSlevels
show
eddiminishedROSlevelsin
cells,
cultu
redwithantioxidants,com
pared
totheun
treatedgrou
p.(ii)Moreover,theaddition
ofho
mem
ade
antioxidantcocktailredu
cedthenu
mber
ofgeno
micaberration
sin
treatedcells.
(i)The
compo
nentsof
homem
ade
cocktailexertedafree-radical
scavenging
activity
toneutralize
ROSin
treatedcells.
(ii)Fo
rtwomon
thsof
cultu
ring
withlowdo
sesof
antioxidants,
iPSC
smaintainedtheexpression
ofstem
ness-related
genes(O
ct3/4,
Nanog,SSE
A-4,and
ALP
).
Ham
idetal.[36]
Roselle(H
ibiscussabdariffaL.)
at125,500,or
1000
ng/m
L.
Bon
emarrow-derived
hematop
oieticstem
cells
(HSC
s)from
murinebone
marrow.
(i)Add
ingroselle
(at500and1000
ng/m
L)significantlyincreasedthesurvivalof
HSC
sandprotectedthem
against
H2O
2-indu
cedDNAdamage.
(ii)Rosellesupp
lementation
was
geno
protective,asevidencedby
the
nonrem
arkabledifference
onthe
percentage
oftailDNA,com
paredto
thecontrolgroup
(untreated
BMSC
s).
Com
paredto
thecontrolgroup
,roselle
enhanced
theactivity
ofSO
Din
HSC
s(at125,500,and
1000
ng/m
L)withasignificant
increase
inGSH
level(p<005).
How
ever,there
was
nodifference
inROSlevelsbetweenroselle-
treatedandcontrolgroup
s.
Ikedaetal.[77]
Poly(ethylene
glycol)-b-po
ly[4-(2,2,6,6-tetram
ethylpiperidine-
1-oxyl)amino-methylstyrene]
(PEG-b-PMNT).
Hem
atop
oieticstem
cells
(HSC
s)from
micefetalliver
cells.
Ikedaetal.d
esignedabiocom
patible
cellcultu
resurfacethat
canbe
used
during
exvivo
cultu
ring
and
expansionof
HSC
s.Thisnew
surfacehasseveraladvantages,
comparedto
thecurrently
used
oneinclud
inglowmolecular
weight
andantioxidantsupp
lementation
.ItdecreasedROSprod
uction
,inhibitedapop
tosis,andincreased
thepu
rity
ofseparatedcells.
The
antioxidantcultu
resurface
(PEG-b-PMNT)scavengednitric
oxideradicalsandredu
ced
oxidativemem
branedamage
witho
utchanging
the
mitocho
ndrialmem
brane
potentialb
ecause
itisno
tinternalized
withinthecellas
theconvention
alLM
Wsystem
s.
4 Oxidative Medicine and Cellular Longevity
Table1:Con
tinu
ed.
Stud
yID
Antioxidant
(dose)
Stem
celltype
(sou
rce)
Find
ings
Possiblemechanism
s
Liuetal.[32]
N-A
cetyl-L-cysteine
(NAC)at
0.1to
1μM.
LSKcells
(Lin−Sca-1+
c-Kit+,a
popu
lation
enriched
withHSC
s).
(i)Aneup
loidy/chromosom
alinstability
during
invitroexpansionof
HSC
sis
ROS-mediatedandcanbe
minim
ized
bymaintaining
ahypo
xiccond
ition
(3%
O2)du
ring
cellcultu
ring.
(ii)Similarly,NACadministration
significantlyredu
cedthepercentage
ofaneuploidy
inHSC
s,cultu
red
underno
rmoxiccond
itions,onlyat
lowdo
sages(0.1μM).
(i)Atop
timum
concentrations,
NACsignificantlyredu
ced
oxidativedamagedu
eto
itsROS-
scavenging
activity.
(ii)Moreover,hypo
xiccond
itions
andNACredu
cedthepercentage
ofaneuploidy
inboth
youn
gandoldaged
stem
cells.
Halabianetal.[37]
Lipo
calin
-2(Lcn2),a
natural
cytoprotective
factor,generated
withinthecellup
onexpo
sure
tostressfulcon
dition
s.
Bon
emarrow-derived
stem
cells
(BMSC
s)from
ratbone
marrow
(4–6
weeks
old).
(i)Lcn2
-expressingBMSC
sshow
eda
morepo
tent
defenseagainstH
2O2,
hypo
xia,andserum
deprivation
stresses,com
paredto
controlM
SCs
(ii)Moreover,Lcn2
expression
inMSC
sincreasedcellproliferation
and
adhesion
tocultu
remediaby
45%
onH
2O2expo
sure,com
paredto
controlM
SCs.
(iii)
Lcn2
-expressingBMSC
sshow
edno
rmalmultipo
tencyinto
different
celllin
eage
withmild
potentiation
ofadipogeniclin
eage
comparedto
thecontrolgroup
.
(i)The
antioxidanteffectof
Lcn2
expression
isdu
eto
ROS
scavenging
activity,associated
withup
regulation
ofantioxidant
enzymes’genes,suchas
SOD.
(ii)Thisantioxidanteffectis
associated
withan
antiapop
totic
prop
erty
asindicatedby
the
diminishednu
mberof
apop
totic
cells
onoxidativestressexpo
sure,
comparedto
thecontrolgroup
.
Fanetal.[38]
Alpha-phenyl-t-bu
tyln
itrone
(PBN)at
800μM
andNAC
at5mM.
Mesenchym
alstem
cells
(MSC
s)from
miceem
bryos.
(i)CulturedMSC
swithextracellular
matrixfrom
mou
seem
bryonic
fibroblast(M
EF-ECM)un
derhypo
xic
cond
itions
(2%
O2)show
edgreater
proliferation
,low
ergeneration
ofROS,andincreasedchromosom
alstability
comparedto
thecontrol
grou
p,cultu
redon
plasticplates
underno
rmoxiccond
itions.
(ii)Tofurtherdiminishchromosom
alinstability
andbasedon
theincreased
DNAdamageon
H2O
2expo
sure,
antioxidantsupp
lementation
tothe
cultu
remediasignificantlyredu
ced
thenu
mberof
DNAmicronu
cleiand
karyotypingabno
rmalities.The
use
ofboth
(antioxidantsandMEF-ECM)
intheinitialisolation
ofcells
from
the
Altho
ughauthorsdidno
tinvestigate
theun
derlying
mechanism
sfor
antioxidants’effects,theysuggested
that
theirfind
ings
canbe
attributed
totheability
ofboth
PBN
andNAC
totrap
free
radicals.M
oreover,NAC
serves
asaprecursorforglutathion
e,an
intracellularantioxidantmolecule.
5Oxidative Medicine and Cellular Longevity
Table1:Con
tinu
ed.
Stud
yID
Antioxidant
(dose)
Stem
celltype
(sou
rce)
Find
ings
Possiblemechanism
s
marrowincreasedpu
rity
andno
rmal
cellkaryotyping.
Wangetal.[78]
2-Vinyl-8-hydroxyqu
inoline
derivatives.
Mesenchym
alstem
cells
(MSC
s)from
ratbone
marrow.
Ingeneral,2-vinyl-8-hydroxyquino
line
derivativeshadapo
sitive
effecton
MSC
sproliferation
inado
se-
depend
entmanner.
2-Vinyl-8-hydroxyqu
inoline
derivativesareph
enol
compo
unds
that
perform
theirantioxidant
activity
throughreaction
oftheir
hydroxylgrou
pwithfree
radicals.
Cho
ietal.[39]and
Mekalaetal.[79]
Ascorbicacid-2-pho
sphate
(AAP)at
0,5,50
250,500mM.
Mesenchym
alstem
cells
(MSC
s)from
adulthu
man
bone
marrow
[39]
andhu
man
umbilicalcord
blood-derivedstem
cells
(hUCB-SCs)from
umbilical
vein
[79].
(i)Ascorbicacid
significantlyincreasedthe
proliferation
ofMSC
s/hU
CB-SCs,compared
tothecontrolgroup
(withthehighest
proliferation
rateat
250mM).Ithadno
effecton
cellu
larantigenicexpression
and
differentiation.
(ii)Moreover,AAPsignificantlyincreased
osteogenicdifferentiationat
50mM
(highest
calcium
depo
sition
atthisconcentration).In
contrast,a
significant
indu
ctionof
adipogenic
differentiationwithoild
ropletsform
ation
was
notedat
250mM
andhigher.
(i)AAPim
proved
theam
ount
ofcollagenprod
uction
percelland
increasedtheam
ount
ofcalcium
(at50
mM)andoild
eposition
(at≥2
50mM),enhancingMSC
s/hU
CB-SCsdifferentiation.
(ii)The
positive
effectof
AAP
oncellu
larproliferation
isdo
se-
depend
ent(highestat
250mM
anddecreaseswithhigher
doses
dueto
inhibitory
effecton
glycosam
inoglycanform
ation).
Koetal.[80]
PEG-catalase(200
μg/mL)
andNAC(1mM).
Hum
anum
bilicalcord
blood-
derivedstem
cells
(hUCB-SCs)
from
umbilicalvein.
(i)Exposureto
geno
toxicstress(H
2O2)in
cultu
remediacaused
amoresignificant
redu
ctionin
cellu
larproliferation
and
DNAsynthesisin
hUCB-SCs,compared
tocontrolcells(cancercells
andhu
man
prim
aryfibroblasts).
(ii)Moreover,hU
CB-SCsshow
edlow
resistance
tooxidativestresswithcellu
lar
senescence
andapop
tosisat
H2O
2levels
muchlower
than
thoseof
controlgroup
s.
Measuring
thecellu
larantioxidant
capacity
show
edthat
hUCB-SCs
hadalower
antioxidantcapacity
than
controlcells.T
oconfi
rmthat,
antioxidantsupp
lementation
increasedthiscapacity
and
diminishedcellu
lardamageup
onexpo
sure
tooxidativestress.
Zengetal.[81]
Edaravone
(10μM),a
clinicallyapproved
drug.
Hum
anum
bilicalcord
blood-
derivedstem
cells
(hUCB-SCs)
from
umbilicalvein.
(i)Unlikethepro-oxidant(diethyl
maleate),edaravon
esignificantly
redu
cedlip
opolysaccharide(LPS)/H
2O2-
indu
ceddamageandincreasedstem
cell
viability
(p<005).
(ii)In
diabeticmicewithsevere
combined
immun
odeficiency,onlythreemicedied
inthegrou
p,injected
with(G
al/LPSand
hUCB-SCs),com
paredto
50%
lossin
the
grou
p,injected
withGal/LPSon
ly.
(iii)
Pretreatm
entwithedaravon
erescuedall
micewithpo
tentiation
ofthehepaticcell
regenerative
power.F
urthermore,it
(i)LP
S/H
2O2challengeindu
ced
apop
tosisby
augm
entin
goxidative
stressandincreasing
Bax/Bcl2
ratio
.How
ever,pretreatm
entwith
edaravon
eabolishedthesechanges.
(ii)Moreover,edaravon
eincreased
theexpression
ofendo
geno
usantio
xidant
enzymes
(sup
eroxide
dism
utase,catalase).
6 Oxidative Medicine and Cellular Longevity
Table1:Con
tinu
ed.
Stud
yID
Antioxidant
(dose)
Stem
celltype
(sou
rce)
Find
ings
Possiblemechanism
s
diminishedthelevelsof
cellu
larinjury
and
proinfl
ammatorymarkers
intreatedmice,
comparedto
thecontrolgroup
.
Rod
riguez-Porcel
etal.[41]
Tem
pol(SO
Dmim
etic)at
0to
10mm/L
concentration.
Rat
cardiomyoblasts,transfected
byabiolum
inescencerepo
rter
gene
forin
vivo
detectionand
transplanted
into
themyocar-
dium
,guided
byhigh-resolution
ultrasou
nd.
(i)Cells,exposed
tohypo
xic/oxidativestress
cond
itions
during
invitroculturing,show
eddecreasedcellviability
withincreasedROS
prod
uction
andNADPH-oxidase-1
expression
,com
paredto
thecontrolgroup
.These
effectsweresignificantlyredu
cedafter
adding
antioxidantsin
ado
se-dependent
manner.
(ii)After
transplantationinto
ratmyocardium,
antioxidant-treatedcells
show
edsignificantly
higher
cellviabilitywithinthefirstthree
days
oftransplantation,
comparedto
untreated
cells.
Hypoxiaindu
cesoxidativestress
byincreasing
theexpression
ofNAD(P)H
oxidaseenzyme.
Interestingly,adding
antioxidant
didno
tredu
ceNAD(P)H
expression
,suggestingthat
tempo
lredu
cesoxidativestressby
neutralizingfree
radicalsrather
than
decreasing
theirprod
uction
.
Lietal.[40]
Hom
emadeantioxidant
cocktailconsisting
of100ML-ascorbate,L-glutathion
e,andα-tocop
herolacetate.
Cardiac
stem
cells
(CSC
s)from
theendo
myocardialtissueof
apatientun
dergoing
acardiacprocedure.
(i)Cells,culturedun
derhypo
xic
cond
itions
(5%
O2)hadalower
number
ofchromosom
alabno
rmalities,compared
tocells,culturedun
derno
rmoxic
cond
itions
(20%
O2).
(ii)Unexpectedly,increasedcytogenic
abno
rmalitiesin
numberandseverity
were
recorded
incells,culturedwithantioxidant
supp
lementation
.(iii)
Antioxidant
supp
lementation
,if
excessive,may
hind
ertheph
ysiological
rolesof
ROSin
stem
cells’p
roliferation
anddifferentiation,
which
raises
anew
concept[reductive
stress].
(i)Measuring
c-H2A
Xfoci
(amarkerof
DNAbreaks)show
edabiph
asicrelation
ship
between
ROSlevelsandfrequencyof
DNA
breaks,thatis,increased
DNA
damageoccursatlowantioxidant/
high
ROSlevels,w
hileexcessive
supp
ressionofROSlevelsincreases
DNAdamage.
(ii)There
isan
optim
allevelo
fROSin
stem
cells,above
which
geno
micinstability
occursdu
eto
ROS-indu
cedDNAdamageand
belowwhich
DNArepairenzymes
areno
tactivated
tomaintainthe
DNAstability.
Takahashi
etal.[82]
Ascorbicacid
(104
M/L)
incubation
for12
days.
Hum
anem
bryonicstem
cells
(ESC
s).
(i)Ascorbicacid
significantlyincreased
ESC
sdifferentiationinto
cardiacmyocytes
inado
se-dependent
manner,as
evidenced
byincreasedexpression
ofthecardiac
specificgene
(myosinheavychain(M
HC)).
(ii)Ascorbicacid,ind
ependent
ofits
antioxidativeprop
erty,ind
uced
ESC
sdifferentiationinto
cardiacmyocytes.
Thiswas
evidencedby
theabsenceof
this
effectwithotherantioxidants,suchas
NAC,T
iron
,and
vitamin
E.
Ascorbicacid
increasedthe
expression
ofcardiacmuscle
genes,such
asGATA4,Nkx2.5,
α-M
HC,β
-MHC,and
atrial
natriureticfactor
(ANF),w
ith
subsequent
cardiac-specific
proteinprod
uction
.
7Oxidative Medicine and Cellular Longevity
Table1:Con
tinu
ed.
Stud
yID
Antioxidant
(dose)
Stem
celltype
(sou
rce)
Find
ings
Possiblemechanism
s
Song
etal.[43]
Selenium
(20or
50ng/m
L)andNAC(100
μM).
Hum
anem
bryonicstem
cell-
(ESC
-)derivedvascular
progenitors.
(i)Fo
llowingvascular
differentiation
ofESC
sinto
vascular
progenitor
cells
(CD34+cells),aqu
iescentstateof
cellu
larproliferation
developedwith
41%
ofthecells
intheG0ph
ase,
upregulation
oftheG1checkp
oint
inhibitor(p21)proteinand
downregulationof
mitosis-related
genes.
(ii)Selenium
increasedcellu
larproliferation
,redu
cedp21expression
,and
decreased
thenu
mberof
cells
inG0ph
aseof
cell
cycle.Moreover,itprom
oted
thevascular
differentiationof
ESC
swithno
similar
effecton
endo
derm
alor
ectoderm
alpo
tentiality.
(iii)
Using
NACtotally
inhibitedthe
vascular
differentiationof
ESC
s.
(i)Physiologically,R
OSare
prod
uced
during
vascular
differentiationmainlyby
NADPH
oxidaseandis
respon
sibleforthisqu
iescent
state.
(ii)Selenium
throughincreasing
glutathion
eandthioredo
xin
activity
mod
eratelydiminished
ROSlevels.
(iii)
How
ever,N
AC,throu
ghcompletescavenging
ofROS,
abolishedtheirph
ysiological
rolein
vascular
differentiation.
Parketal.[45]
GV1001
[derived
from
human
telomerasereverse
transcriptasefrom
0to
100μM.
Neuralstem
cells
(NSC
s)from
miceem
bryonicbrain
(corticaltissue).
GV1001
significantlyredu
cedH
2O2
effectson
NSC
sinclud
ingdiminished
cellu
larproliferation
,migration
and
increasedapop
tosis.Interestingly,
GV1001
itselfhadno
effecton
norm
alun
treatedcells.
(i)GV1001
hasan
ROS-
scavenging
activity,p
reventing
lipid
peroxidation
andDNA
damage.
(ii)Atthemolecular
level,
GV1001
indu
cedtheexpression
ofsurvival-related
proteins
and
diminishedtheexpression
ofapop
tosis-relatedproteins.
Hachem
etal.[46]
CyclosporineA(CsA
),brain-derivedneurotroph
icfactor
(BDNF),and
thyrotropin-
releasingho
rmon
e(TRH).
Neuralstem
cells
(NSC
s)from
thespinalcord
oftransgenicadultfemale
rats(spinalcordinjury
mod
el).
(i)Pretreatm
entwithBDNFfor48
hours
(beforeH
2O2expo
sure)significantly
increasedNSC
sviability
anddecreased
intracellularROSaccumulation,
compared
tothecontrolgroup
.How
ever,C
sAand
TRH-treated
cells
show
edno
significant
changesfrom
thecontrolgroup
.(ii)Interestingly,BDNF-treatedcells
show
edno
changesin
cellu
larproliferation
and
differentiationcomparedto
thecontrol
grou
p.
The
neurop
rotectiveeffectof
BDNFisexertedthroughits
ROS-scavenging
activity
and
indu
ctionof
antioxidantenzymes,
such
asGRandSO
D.M
oreover,
significant
redu
ctions
inapop
totic
features
wereno
tedin
BDNF-
treatedcells,com
paredto
the
controlgroup
.
Song
etal.[52]
Melaton
in(100
nM).
Neuralstem
cells
(NSC
s)from
miceem
bryonic
corticaltissue.
(i)Melaton
insignificantlyredu
cedLP
S-indu
cedtoxicity
andapop
tosisof
NSC
sthroughredu
cing
nitricoxide(N
O)
prod
uction
andindu
cing
antioxidant
enzymes.
(i)Melaton
inincreasedthe
expression
ofmultiple
transcriptionalfactors,involved
inNSC
sproliferatio
n,self-renewal,
anddifferentiatio
n,such
asorph
an
8 Oxidative Medicine and Cellular Longevity
Table1:Con
tinu
ed.
Stud
yID
Antioxidant
(dose)
Stem
celltype
(sou
rce)
Find
ings
Possiblemechanism
s
(ii)Fu
rtherm
ore,itmaintainedthe
neurosph
eresize
inNSC
s,treatedwithLP
S.(iii)
Melaton
inincreasedcellsurvival
byactivating
PI3K/A
ktpathway.T
hiswas
confi
rmed
bytheaddition
ofwortm
annin
(aPI3Kinhibitor),w
hich
inhibitedNrf2
expression
andsubsequent
antioxidant
activities.
nuclearreceptor
TLX
andfibroblast
grow
thfactor
receptor-2.
(ii)Melaton
inup
regulatedthe
expression
ofnu
clearfactor-
erythroid2-relatedfactor
2(N
rf2),
respon
siblefordo
wnstream
activationof
antio
xidant
enzymes’
genes.
Sunetal.[59]
N-A
cetyl-Lcysteine
(NAC)
at2mM
andascorbicacid-
2-ph
osph
ate(A
AP)at
0.2mM
incomparisonto
theeffectof
hypo
xia.
Adipo
se-derived
stem
cells
(ADSC
s)from
human
adiposetissue.
ADSC
s,grow
nin
media,
supp
lementedby
antioxidantsor
underhypo
xiccond
itions
(5%
po2),
show
edamoresignificant
increase
incellproliferation
andadecrease
indo
ublin
gtimethan
thecontrolgroup
,supp
lementedby
fibroblastgrow
thfactor-2.M
oreover,cytometric
analysisshow
edthat
cells,cultured
inantioxidant-supp
lementedand
hypo
xicmedia,h
adagreater
prop
ortion
ofcells
inS1
phase
ofthecellcyclewithdiminished
G0/G1ph
asecells,com
pared
tothecontrolgroup
.
Inantioxidant-supp
lementedmedia,
PCRshow
eddiminishedlevelsof
cyclin-dependent
kinase
inhibitors
(CDK:impo
rtantcellcycle
regulatorsthat
controlenteringS1
phase),w
ithenhanced
expression
ofstem
ness-related
genes,
comparedto
thecontrolgroup
.
Lyub
linskayaetal.
[11]
Tem
pol(1-2mM),NAC
(5–20mM),andresveratrol
(20–40
μM).
End
ometrialstem
cells,
isolated
from
desquamated
endo
metrium
ofmenstrual
bloodandADSC
sfrom
adiposetissue.
(i)Reactiveoxygen
speciesare
impo
rtantregulatorsof
stem
cellself-
renewalandproliferation
upon
exit
ofthequ
iescentstage.
(ii)Using
asynchron
ized
cellin
G0
phase,therewas
atransientincrease
inROSlevelsup
onstim
ulationof
cell
proliferation
anddu
ring
initial
stages
ofDNAsynthesis.
(iii)
Add
ingantioxidantsto
the
medium
afterproliferation
indu
ction
andbefore
initiation
ofS1
phase
blockedS1
transition
.Antioxidant
didno
thave
thesameeffect
whenaddedafterS1
initiation
.
(i)Cells,treated
withantioxidants,
show
edexpression
ofthe
proliferative
marker(K
i-67),
which
isabsent
inthenu
cleusof
quiescentcells,ind
icatingthat
the
cellleftthequ
iescentstateand
was
arrested
inG1ph
ase.
(ii)Antioxidants,throughdo
se-
depend
entredu
ctionof
ROS
levels,can
beused
tocontrol
cellu
larproliferation
during
invitroculturing.
Yangetal.[65]
Fullerol(apo
lyhydroxylated
fullerene)at
0.1,0.3,1,3,
and10
μM.
Hum
anadipose-derived
stem
cells
(ADSC
s).
(i)Fu
llerolenh
ancedtheosteogenic
differentiationof
ADSC
s,as
indicated
byincreasedexpression
ofosteogenic
markers(Run
x2,O
CN,and
alkalin
e
Fullerolexerted
anantioxidant
effecton
ADSC
sthrough
potentiating
theexpression
ofthetranscriptionfactor
FoxO
1
9Oxidative Medicine and Cellular Longevity
Table1:Con
tinu
ed.
Stud
yID
Antioxidant
(dose)
Stem
celltype
(sou
rce)
Find
ings
Possiblemechanism
s
phosph
atase)
andmineralization.
(ii)Moreover,fullerol(at
all
concentrations)redu
cedROSlevelsin
theosteogeniccultu
remedia.
anditsdo
wnstream
genes
(Run
x2andSO
D2),w
hich
prom
oteROSscavenging
and
osteoblasticdifferentiation.
Yuetal.[83]
L-Ascorbicacid
2-ph
osph
ate
(AAP)at
250μM.
Adipo
se-derived
stem
cells
(ADSC
s)from
thesubcutaneous
adiposetissue
from
afemale
patient,un
dergoing
abdo
minop
lasty.
(i)Ascorbicacid
significantlyincreased
ADSC
sproliferation
,preserved
cellu
lar
stem
nessandincreasedthepo
tentiality
foradipogenic,h
epatic,n
euraland
osteogenicdifferentiation.
(ii)In
AAP-ind
uced
cellsheet,there
was
asignificant
increase
inthe
geneticexpression
andsecretionof
collagen,
laminin,and
fibron
ectin
proteins.
(iii)
The
AAP-ind
uced
cellsheet
improved
wou
ndhealingin
amurine
wou
ndmod
el,w
hich
indicatesthe
possibility
ofADSC
sdifferentiation
inano
n-mesenchym
allin
eage.
(i)Add
ingAAPto
ADSC
sincreased
theexpression
ofstem
ness-related
proteins.
(ii)Using
otherantioxidants,such
asNACdidno
tshow
anincrease
ofstem
ness
markers.Incontrast,
adding
acollagensynthesis
inhibitorabolished
AAP-ind
uced
overexpression
ofstem
ness
proteins,
indicating
that
theinvolved
mechanism
inAAPaction
iscollagensynthesis,no
tROS
scavenging.
Wangetal.[66]
NACandAAPat
3mM
and
0.2mM,respectively
(for
20ho
urs).
Hum
anADSC
sfrom
10differenthu
man
patients.
(i)PretreatedMSC
swithantioxidants
show
edless
apop
tosisandlower
caspase-3levelsup
onexpo
sure
toadvanced
glycosylationend-prod
ucts
(AGE),comparedto
thecontrolgroup
.(ii)The
effectsof
NACandAAPwere
significantlyam
plified
afterthe
addition
ofmiRNA-223
mim
etics
andweresignificantlyabolishedby
miRNA-223
inhibitors.
Antioxidantsredu
cedROS
generation
andapop
tosis,indu
ced
byAGE.T
hiscanbe
explainedby
theeffectof
both
onmiR-223
(aregulatorof
intracellularapop
totic
singlin
gthroughmod
ulationof
fibroblast-likegrow
thfactor
receptor-2
proteinlevels.
Drowleyetal.[72]
N-A
cetyl-Lcysteine
at10
mM
incomparisonto
the
pro-oxidant(diethylmaleate)
at50
μM.
Muscle-derivedstem
cells
(MDSC
s)from
theskeletal
muscleof
3-week-old
femalemice.
(i)In
comparisonto
controlcells,
NAC-treated
cells
show
edincreased
survivalanddifferentiationinto
myotubesup
onexpo
sure
tooxidative
(H2O
2)or
inflam
matorystress
(tum
ornecrosisfactor).
(ii)In
failedmicehearts,injection
withNAC-treated
cells
significantly
improved
systolicanddiastolic
function
onecho
cardiographicassessment,
comparedto
injectionwithun
treated
andDEM-treated
cells.M
oreover,
scar
tissue
form
ationwas
significantly
(i)IncreasedcellsurvivalafterNAC
treatm
entisprobablyrelatedto
stim
ulationof
mitogen-activated
proteinkinases(M
APK)and
extracellularsignal-regulated
kinase
(ERK),kinase
families
involved
incellu
larsurvivaland
proliferation
.(ii)Interestingly,asimilarincrease
inCD31+endothelialcellsinNAC-
treatedandun
treatedMDSC
swas
observed.
10 Oxidative Medicine and Cellular Longevity
Table1:Con
tinu
ed.
Stud
yID
Antioxidant
(dose)
Stem
celltype
(sou
rce)
Find
ings
Possiblemechanism
s
lower
inNAC-treated
cells
than
untreatedcells.
Aliakbarietal.[74]
Catalase(40mL)
and
α-tocop
herol(200mL).
Spermatogon
ialstem
cells
(SSC
s)from
neon
atal
malemicetestis.
Antioxidant
supp
lementation
ofcryopreservedSSCsredu
cedoxidative
damageto
mem
branes
andorganelles
andincreasedcellsurvivalin
ado
se-
depend
entmanner.
Catalaseandα-tocop
herolreduced
ROSgeneration
intreatedcells,
comparedto
controlcells.
Moreover,antioxidant-treated
cells
show
edan
increased
expression
oftheanti-apo
ptotic
BcL-2
gene
withdecreased
expression
ofthepro-apop
totic
BAXgene,com
paredto
the
controlgroup
.
ADSC
s:adipose-derivedstem
cells;C
AT:catalase;DEM:diethylmaleate;G
SH:glutathione;H
SCs:hematop
oieticstem
cells;iPSC
s:indu
cedpluripotentstem
cells;M
DSC
s:muscle-derivedstem
cells;N
AC:N
-acetyl
cysteine;N
SCs:neuralstem
cells;SCC:sperm
atogon
ialstem
cells;SOD:sup
eroxidedism
utase;ROS:reactive
oxygen
species.
11Oxidative Medicine and Cellular Longevity
8. Muscle-Derived Stem Cells (MDSCs)
According to Drowley and colleagues, injection of injuredskeletal muscles with NAC-treated MDSCs significantlyincreased muscle regeneration, compared to muscles injectedwith untreated or DEM-treated MDSCs. The direction ofscar tissue formation was opposite the direction of the hostmuscle regeneration [72]. Additionally, they showed animproved survival of NAC-treated MDSCs, probably due tostimulation of extracellular signal-regulated kinase (ERK)pathway, as evidenced by decreased survival of NAC treatedcells after inhibition of the ERK pathway [72, 73].
Moreover, they demonstrated that experimentallyinfarcted hearts, injected with NAC-treated MDSCs, showeda more significant reduction in the percentage area of collag-enous scar tissue than hearts injected with either untreated,DEM-treated, or phosphate buffered saline- (PBS-) treatedMDSCs. There was no difference in myocardial scar forma-tion between hearts injected with DEM-treated MDSCs andthose injected with PBS [72].
9. Spermatogonia Stem Cells (SSCs)
Cryopreservation of spermatogonial stem cells, in the pres-ence of catalase (CAT) and α-tocopherol (α-TCP), promotedcell viability and suppressed apoptosis through inducing theexpression of the antiapoptotic BcL-2 gene and inhibiting
the expression of the proapoptotic BAX gene [74]. In otherstudies, cryopreservation with antioxidants could promotecell enrichment and increase the efficiency of colony forma-tion in isolated SSCs [75, 76]. Spermatogonia-derived colo-nies showed increased SSC marker activity, enhancedexpression of self-renewal genes, such as promyelocytic leu-kemia zinc finger (Plzf) protein and DNA-binding proteininhibitor ID4, and suppressed expression of the proto-oncogene (c-kit) in both CAT and α-TCP treated groups[74]. This technique can increase the possibility of SSCsbanking for men with malignant diseases and promote theresumption of spermatogenesis in SCCs recipients. A sum-mary of the design and main findings of included studies isillustrated in Table 1.
10. Discussion
Our review highlights that antioxidants can influence stemcell activities by [1] mitigating oxidative stress through neu-tralization of free radicals and increasing the expression ofantioxidant enzymes and [2] influencing the differentiationfate of precursor stem cells. Further beneficial effects of anti-oxidant treatment include increasing genomic stability,improving the adhesion of stem cells to culture media, andenabling researchers to manipulate stem cell proliferationby using different doses of antioxidants. Figure 1 summarizesthe effects of antioxidants on different types of stem cells.
Induced pluripotent stem cells:mitigation of oxidative stressduring reprogramming and
reduction of genetic aberrations
Hematopoietic stem cells:increase cellular proliferation,
genomic stability, and SODcellular concentration and
in�uence di�erentiation fate
Cardiomyoblasts: increaseearly survival of
cardiomyoblasts andin�uence vascular
di�erentiation of embryonicstem cells
Neural stem cells: mitigateneuroin�ammation andoxidative stress, reducelipid peroxidation andmtDNA mutation, and
increase stem cellsmigration
Human periodontalligament cells: increase
GSH and GSTconcentrations through
Nrf2 activation andenhance osteoplastic
di�erentiation
Spermatogonial stemcells: enhance self-
renewal and suppressapoptosis by increasing
Bcl2/Bax ratio
Muscle-derived stemcells: improved survival by
stimulating MAPK/ERKpathway and decrease
collagen scar formation ininjured muscle
Adipose-derived stemcells: increase stemness
genes’ expression,reduce apoptosis, and
increase osteogenicactivity
Figure 1: Summarizes the effects of antioxidants on different types of stem cells.
12 Oxidative Medicine and Cellular Longevity
We also discussed that a physiological level of ROS (oxi-dative optimum) is needed for proper differentiation of stemcells, especially for proper cardiogenesis and vasculogenesis[40]. These findings can have several clinical applications,such as improving neurogenesis in patients with stroke andneurodegenerative diseases, as well as improving the regener-ation of infarcted myocardial tissue and the banking of SCCs.
Antioxidants are prevalent supplements worldwide.However, little is known about their cell-type-specificactions. It has been shown that a therapeutic dose may varybetween different cell types: a dose that rescues a pathologyin one tissue may roughly challenge the function of another[22]. Therefore, there is a need for dose-effect studies on anti-oxidants to confirm their safety as nutritional supplements ortherapeutic agents—particularly in the case of antioxidantsaccumulating in the mitochondria. Our review also showedthe potential of some endogenous molecules, such as melato-nin, BDNF, and the adipokine (lipocalin-2) in preservingstem cell viability and differentiation potential. Whetherthese compounds can be used in future clinical applicationsof stem cells and whether other endogenous molecules withproven antioxidant activities, such as adiponectin [84], canbe useful in this regard require further investigation.
11. Recommendations
(1) Multiplicity of stem cell sources within the body (dif-ferent home environments) and their variable ROSscavenging capacity make them susceptible to oxida-tive stress at different thresholds. Therefore, we triedto review each stem cell type as a separate entity andwe believe that clearing those differences on themolecular and genetic levels will optimize the clinicalapplication of stem cells in different medical fields.
(2) Most of stem cell characteristics are establishedwithinin vitro culturing environments. More in vivo studiesare required to define their interactions within thebody. Furthermore, few in vivo studies have focusedon the long-term survival of transplanted stem cells;therefore, this should be the interest of future studies.
(3) The effect of ROS level and redox state on the long-term oncogenicity of stem cells should be furtherinvestigated prior to in vivo clinical trials.
12. Conclusion
Using antioxidants can improve the viability and self-renewalcapacity of stem cells and affect their differentiation poten-tial. More research is needed on the dose-effect associationand cell-type-specific actions of antioxidant before applyingthese findings in human therapeutic trials.
Abbreviations
ADSCs: Adipose-derived stem cellsBMSCs: Bone marrow-derived mesenchymal stem cells
CAT: CatalaseDEM: DiethylmaleateDFO: DeferoxamineGSH: GlutathionehPDLCs: Human periodontal ligament cellsHSCs: Hematopoietic stem cellsiPSCs: Induced pluripotent stem cellsMDSCs: Muscle-derived stem cellsNAC: N-acetyl cysteineNSCs: Neural stem cellsPBP: Phosphate buffered salineSCCs: Spermatogonial stem cellsSOD: Superoxide dismutaseROS: Reactive oxygen species.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Authors’ Contributions
Sara Shaban, Mostafa Wanees Ahmed El-Husseny, andAbdelrahman Ibrahim Abushouk contributed equally tothis work.
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16 Oxidative Medicine and Cellular Longevity
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