REVIEW Open Access
Transplantation of bone marrowmesenchymal stem cells improvescognitive deficits and alleviatesneuropathology in animal models ofAlzheimer’s disease: a meta-analytic reviewon potential mechanismsChuan Qin1*, Yalan Lu1, Kewei Wang1, Lin Bai1, Guiying Shi1, Yiying Huang1 and Yongning Li2
Abstract
Background: Alzheimer’s disease is a neurodegenerative disorder. Therapeutically, a transplantation of bonemarrow mesenchymal stem cells (BMMSCs) can play a beneficial role in animal models of Alzheimer’s disease.However, the relevant mechanism remains to be fully elucidated.
Main body: Subsequent to the transplantation of BMMSCs, memory loss and cognitive impairment weresignificantly improved in animal models with Alzheimer’s disease (AD). Potential mechanisms involvedneurogenesis, apoptosis, angiogenesis, inflammation, immunomodulation, etc. The above mechanisms might playdifferent roles at certain stages. It was revealed that the transplantation of BMMSCs could alter some gene levels.Moreover, the differential expression of representative genes was responsible for neuropathological phenotypes inAlzheimer’s disease, which could be used to construct gene-specific patterns.
Conclusions: Multiple signal pathways involve therapeutic mechanisms by which the transplantation of BMMSCsimproves cognitive and behavioral deficits in AD models. Gene expression profile can be utilized to establishstatistical regression model for the evaluation of therapeutic effect. The transplantation of autologous BMMSCsmaybe a prospective therapy for patients with Alzheimer’s disease.
Keywords: Alzheimer’s disease, Bone marrow mesenchymal stem cells, Meta-analysis, Amyloid β peptide, Memoryloss, Cognitive deficits, Animal model, Neuropathology
© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.
* Correspondence: [email protected] of Laboratory Animal Sciences, Chinese Academy of MedicalSciences & Comparative Medical Center, Peking Union Medical College,Beijing Engineering Research Center for Experimental Animal Models ofHuman Critical Diseases, 5 Panjiayuan Nanli St, Beijing 100021, ChinaFull list of author information is available at the end of the article
Qin et al. Translational Neurodegeneration (2020) 9:20 https://doi.org/10.1186/s40035-020-00199-x
BackgroundAlzheimer’s disease (AD) is a chronic disorder of centralnervous system. Its clinical manifestations are character-ized by memory loss, cognitive dysfunction, abnormalbehavior, etc. With the deterioration of AD, patients fallinto stupor state and usually die of exhaustion within5—10 years [1].In pathology, AD is manifested by the decreased num-
ber of neurons and synapses in cerebral regions, resultedin different degrees of memory loss and cognitive im-pairment. Amyloidal plaques, mostly insoluble depositsof amyloid β peptide (Aβ), are observed around neurons[1]. Neurofibrillary tangles, hyperphosphorylated aggre-gates of the microtubule-associated protein tau, are ac-cumulated inside the neuron [2]. As compared with thegeneral aging brain, many plaques and tangles in pa-tients with AD are discovered in specific brain regionssuch as temporal lobe and hippocampus [3, 4].Currently, there is no cure for the Alzheimer’s disease.
Therapeutic strategy in the treatment of AD is to allevi-ate symptoms through pharmacological intervention,such as an enhancement of neurotransmitter acetylcho-line [5, 6]. A few medicines can slow down the exacerba-tion and improve behavioral deficits in some patients.Two types of medication are presently used to treat cog-nitive symptoms, including (i) cholinesterase inhibitors(AChE inhibitors) such as donepezil, galantamine andrivastigmine [6]. These drugs boost levels of acetylcho-line that is decreased in the brain of Alzheimer’s disease,which may improve neuropsychiatric agitation or de-pression; (ii) memantine, an uncompetitive NMDA an-tagonist, is used to improve memory and awareness inmoderate to severe patients with AD. It works in cellcommunication network and delays the exacerbation ofsymptoms due to AD. Sometimes, the memantine is uti-lized in combination with AChE inhibitors. Antidepres-sants may be prescribed to control the behavioralsymptoms associated with Alzheimer’s disease. Thetherapeutic effect of above drugs is limited in advancedpatients with poor condition. Recent nanotechnologicaladvancements provide effective options of drug carriers[7, 8]. For instance, when the rivastigmine was assistedwith biocompatible nanoparticles (NPs), the NPs-baseddrug delivery could effectively cross the blood-brain bar-rier and improved its bioavailability [7]. The biocompat-ible NPs also showed significant effect on the kinetics ofAβ-fibrinogen [9, 10]. In addition, non-pharmacologicalapproaches such as diet, regular exercise or otherhealthy lifestyle choice are supplemented for the im-provement of patients’ life quality.Transplantation of mesenchymal stem cells (MSCs) as
a therapeutic technique has been well developed in therecent decades. It has also been explored in the treat-ment of animal models with nervous disease. The
accumulative evidence demonstrated that the trans-planted MSCs could be differentiated into cell lineagesuch as neurons and reconnected synaptic network,which played a critical role in the functional improve-ment of nervous system [11, 12]. A comparison hadbeen carried out among stem cells derived from differentresources such as brain, fat, bone marrow, umbilicalblood or fetal tissues [13–15]. Owing to ethical issue andalloimmunogenicity, stem cells from embryos and allo-genic umbilical cord may be not suitable for the treat-ment of AD. Autologous neurons from brain biopsy areconfronted with unacceptable attitude and challenge.Still, it is long way to go for the preparation of stem cellsthrough iPSc method. Therefore, autologous stem cellsfrom bone marrow or fat were additional choices. Inter-estingly, the stem cells from bone marrow had a bettertherapeutic effect as compared with that from the fattytissue based on previous studies [16, 17]. The MSCsfrom autologous bone marrow could be delivered intoAD subjects via different approaches such as intracere-bral, peripheral vein and intracerebroventricular injec-tion. The therapeutic effect of bone marrowmesenchymal stem cells (BMMSCs) was verified in sev-eral animal models. The results indicated that theBMMSCs could alleviate the memory loss, behavioraldeficits and neuropathology. Technical advantages in au-tologous BMMSCs have provided a prospective therapyfor patients with Alzheimer’s disease.The early studies demonstrated that the therapeutic ef-
fect of exogenous stem cells could improve pathologicalmanifestations in animal models with Alzheimer’s dis-ease. Furthermore, there were seldom adverse responsesfollowing a transplantation of bone marrow mesenchy-mal stem cells [17, 18]. Advantages of bone marrowmesenchymal stem cells were reflected by its efficiencyand safety. At present, the transplantation of bone mar-row mesenchymal stem cell has been optimized throughappropriate facilities as well as experimental conditions.A series of research data proved a dramatic improve-ment in cognitive deterioration and neuropathologicalsymptoms among AD-like animal models. Autologousbone marrow-derived mesenchymal stem cells may beused in the clinical treatment of Alzheimer’s disease innear future. The present study aims to explore the po-tential mechanisms by which the transplantation ofBMMSCs improves cognitive and behavioral deficits inanimal models of Alzheimer’s disease, which can lay afoundation for the clinical application of autologousBMMSCs in AD patients.
MethodsSystematical search of published literatureDatabase PubMed, Medline, and Embase were systemat-ically screened, and the time point was set at the end of
Qin et al. Translational Neurodegeneration (2020) 9:20 Page 2 of 20
February 2019. Keywords “Alzheimer’s disease” and“stem cell transplantation” were used to identify litera-ture. Total 414 references were acquired, which werenot restricted by the type of publication. The publishedwork was further scrutinized according to the integrityof data and article types.
Study selectionStudies eligible for inclusion were based on quality of re-sultant data, included randomized controlled trials andcohort-controlled trials. We excluded studies usingtherapeutic stem cells from umbilicus cord, fat andbrain. Also, the exclusion covered studies that providedincomplete data relevant to the pre-specified outcomevariables. The inclusion studies were restricted to thetransplantation of BMMSCs. Data extraction was accom-plished by two investigators independently.
Data collection and outcome measuresThe extracted data were based on general characteristicsof all included studies, such as source of reference, studydesign, animal species, surgery procedure, delivery routeof stem cells, outcome measures, etc. A primary com-parison was performed among primary data derivedfrom BMMSCs and control groups. The data analysis in-volved cognitive function, behavioral change, neurogen-esis, angiogenesis, apoptosis, inflammatory response,immunomodulation, reactive gliosis, microglial activa-tion, level of Aβ peptide, tau hyperphosphorylation andso forth. Morbidity of adverse response was calculatedby the number of animals with at least one complicationafter stem cell transplantation and mortality was com-puted by death number during or after operation due toany causes. Meta-analysis based on outcome variableswas further carried out, including Y-maze test, escape la-tency, histone H3-positive cells, expression of VEGF,TNF-α, IL-1β, Aβ level, activation of Aβ-degrading en-zyme ECE, percentage of Iba-1 positive cells, percentageof AT8 positive cells, etc.
Statistical analysisReview Manager (RevMan version: 5.3.5;Copenhagen: The Nordic Cochrane Centre, TheCochrane Collaboration, 2014) was used to pool dataand meta-analysis. For categorical variable, treatmenteffect was expressed as odds ratio (OR) with corre-sponding 95% confidence intervals (CI). Results werecompared through a random-effects model. For con-tinuous variable, treatment effect was expressed asweighted mean difference (WMD) with correspond-ing 95% CI. Chi-square (Chi2 or χ2) and I2 statisticsestimate the appropriateness of pooling individualstudy. Heterogeneity was evaluated by χ2-test withsignificance set at P value 0.10. The heterogeneity
was measured by I2 more than 50% as statistical sig-nificance. Forest plots were constructed, P values of< 0.05 as significant difference. Gene data on micro-array and high-throughput DNA sequencing were re-trieved out of Geo DataSets (https://www.ncbi.nlm.nih.gov/pubmed/). The linear relationship betweenthe two variables was measured with Pearson’s cor-relation coefficient. Principal component analysis(PCA) of gene expression data was performed basedon the correlation matrix. The number of principalcomponents would satisfy more than 80% variabilityof differential gene expression. The clusters werecombined based on similar expression profiles andenriched gene ontology (GO) categories. The clusteranalysis was performed using correlation forhierarchical clustering and Euclidean distance for K-means clustering. Difference was considered signifi-cant at p values < 0.05. Data were analyzed withsoftware SPSS 19.0 (IBM Corp., Armonk, NY, USA),JMP 13.0 software (SAS Institute Inc., Cary, NorthCarolina, USA), and R 3.5.3 for Windows.
Main textQuality assessment of the included studiesSystematic review on therapeutic effect of mesenchy-mal stem cells for Alzheimer’s disease was summa-rized according to animal species, sources ofmesenchymal stem cells, cognitive improvement, routeof delivery, position of delivery, mechanisms, and soon (Supplementary table). Original studies withcomplete data were kept in the present meta-analyticreview (Fig. 1, Table 1). General characteristics of theincluded studies in the meta-analysis were reflectedby source of transplanted stem cells, amount of trans-planted stem cells, species of recipient animals, gen-der ratio of recipients, age or body weight ofrecipients, route of delivery, position of delivery, andsustainability of transplanted stem cells (Table 2).Study quality was assessed via bias in primary studies.Potential bias in the identified studies were also eval-uated (Fig. 2). The interpretation of results wasweighed in terms of existed bias and sources of het-erogeneity. The methodology of included studies wasevaluated through random sequence generation, blind-ing of outcome assessors, incomplete outcome data,and selective reporting, etc. Priori criteria of high-quality study include (i) randomized trial; (ii) con-trolled study; (iii) adequately reported methodology ofmeasurement.
Improvement of cognitive and behavioral deficitsThe present review summarized therapeutic role ofbone marrow mesenchymal stem cells in animalmodels of Alzheimer’s disease. The therapeutic effect
Qin et al. Translational Neurodegeneration (2020) 9:20 Page 3 of 20
of the bone marrow mesenchymal stem cells wasdemonstrated via behavioral changes in experimentalsubjects. After transplantation of bone marrow mes-enchymal stem cells into Alzheimer-like animalmodels, symptom and sign were significantly allevi-ated as exhibited in APP mice, DAL mice orscopolamine-induced rats [12, 19, 20]. Benefits of thetransplanted stem cells in the behavioral changes wereconfirmed through diverse tests such as Morris watermaze test, Y-maze alternation test (Y-maze), plus-maze discriminative avoidance task, social recognitiontest and open-field evaluation (Fig. 3a, b). There wasan improvement in learning ability and spatial mem-ory performance subsequent to a transplantation ofBMMSCs. The functional improvement of modelbrains was evidenced by preventive treatment againstspatial learning and memory impairment. Of note, be-havioral measurement was not performed in all exper-iments, because some animals were too young toconduct behavioral tests in certain studies [21].Importantly, the BMMSCs treatment was beneficial in
both young and aged Alzheimer-like animals. This thera-peutic approach could reverse cognitive impairments in-duced by cerebral amyloidosis as observed in mouse ADmodels [3, 18, 21]. The treatment of transplantedBMMSCs could ameliorate spatial learning and memory
impairment. Also, the BMMSCs treatment might im-prove impaired spatial memory in APP/PS1 mice as de-tected via Morris water maze test [3]. The APP/PS1mice treated with BMMSCs had shorter escape latencythan that of PBS-treated controls. These results indi-cated that the transplantation of BMMSCs was able toreduce the cognitive impairment of spatial memory [3].Moreover, 3xTg-AD mice lost their working memory,but this impairment was improved in the transgenicmice after having received transplanted MSCs. TheBMMSCs could dramatically alleviate working memoryin the 3xTg-AD mice [22]. The transgenic DAL mice ex-press a dominant-negative mutant form of mitochon-drial aldehyde dehydrogenase 2 and exhibit AD-likephenotypes. By having employed a spontaneous Y-mazealternation test, an alternation rate of BMMSC-treatedDAL mice was significantly higher than that of vehicle-treated mice in 3 months after transplantation. Even asingle transplantation of stem cells was enough to havean effective result [12]. The cognitive decline could beameliorated and even reversed via the beneficial role ofBMMSCs in the AD animals [18].Above-mentioned improvement was associated
with input concentration of stem cells, cell viability,passage number, and delivery methods. The deliveryroutes of stem cells included (i) intravenous
Fig. 1 Transplantation of bone marrow mesenchymal stem cells could improve clinical manifestations in animal models with Alzheimer’s disease.Flow chart summarized relevant references that was identified and included in the meta-analytic review
Qin et al. Translational Neurodegeneration (2020) 9:20 Page 4 of 20
Table
1Transplantationof
BMMSC
sforthetreatm
entof
anim
almod
elswith
Alzhe
imer’sdisease.Keyw
ords
“Alzhe
imer’sdisease”
and“stem
celltransplantation”
wereutilizedto
screen
database
PubM
ed,M
edline,andEm
base
respectively.Stud
ieseligibleforinclusionwererestrictedto
thebo
nemarrow
mesen
chym
alstem
cells.Prim
arystud
ieswith
completedata
wereretained
inthecurren
tmeta-analyticreview
Stud
ies
Stud
yde
sign
Results
Mechanism
sReferences
Bae,2013
Rand
omAPP/PS1
mice,in
vivo
stud
y.Declineof
amyloid-be
tade
positsandandtheim
-provem
entof
synaptictransm
ission
Sign
ificant
decrease
inthecerebralAβde
positio
n;Expression
ofdynamin
1andSynapsin
1,keypre-
synapticproteins.
CurrAlzhe
imer
Res.2013
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Garcia,
2014
Rand
om2xTg-ADmalecong
enicmice,in
vivo
stud
y.BM
MSC
sover
expressedVEGF(hum
anVEGF165
cDNAfro
muP
-VEG
F)
Behavioralbe
nefitsinclud
edtherecovery
ofmem
ory
loss
andcogn
itive
deficits
asde
mon
stratedby
open
-field
evaluatio
n,socialrecogn
ition
test,and
plus-m
aze
discrim
inativeavoidancetask
(PM-DAT).
Mechanism
sinvolved
neovascularization,redu
ctionof
amyloid-be
taplaques,andto
decrease
astrocytes
and
microglialcells
Fron
tAging
Neurosci.2014
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Harach,
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Rand
omAPP/PS1
mice,in
vivo
stud
y.Stem
cells
were
obtained
from
Stem
edicaCellTechn
olog
ies
(SanDiego
,USA
).Thecells
areeq
uivalent
tocommerciallyavailablestem
cells
from
ThermoFishe
rScientific“StemProBM
MSC
”(partnu
mbe
rA15653)(ischem
ia-tolerantmesen
chym
alstem
cells)
Sign
ificant
redu
ctionof
cerebralAbplaquesand
neuroinflammation
Redu
cedcerebralAβplaques,increasingNPE,ID
Eand
ECEAβ-de
gradingen
zymes;redu
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Kanamaru,
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omAPP/DAL101
mice,in
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stud
y.To
confirm
preven
tiveeffect
ofBM
MSC
sagainstne
uron
alde
gene
ratio
nror
therapeutic
effect
ofBM
MCson
neuron
alde
gene
ratio
nrespectively.
Tosupp
ress
neuron
alloss
andrestoremem
ory
impairm
entof
DALmice,to
redu
ceAβd
eposition
and
improvecogn
itive
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inAPP
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tne
urod
egen
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positio
n.BrainRes.2015
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24;1605:49–
58.
Lampron
,2013
Rand
omAPP/PS1
mice,in
vivo
stud
y.Bo
nemarrow-derived
cells
(BMDC)un
derstim
ulaton
ofM-CSF
couldinfiltratetheCNSin
anim
almod
elsfor
stroke
andAlzhe
imer’sdisease.They
wereconfined
indiseased
sitesforseveralw
eeks.
Hypoxic-ischem
icinjury
sitesor
amyloidplaques
couldindu
cetheen
tryof
BMDCcells.
JCom
pNeurol.
2013
Dec
1;521
[17]:3863–76.
Lee,2010
Rand
omC57BL/6
micewereinjected
with
aggreg
ated
AβtomakeADmod
el,invivo
stud
y.The
bone
marrow
cells
werecultu
redfor1week,andthe
plastic-adh
eren
tpo
pulatio
nwas
used
forsubseq
uent
expe
rimen
ts.
Toattenu
atemem
oryim
pairm
entandto
inhibit
neuron
alapop
tosis.
Toredu
ceaβ
depo
sitio
n,stim
ulatemicroglial
activation,sw
itchthemicroglialp
heno
type
into
alternativeform
,decreasetauhype
rpho
spho
rylatio
n,anddiminishAβ-indu
cedoxidativestress
inmod
elanim
als.
CurrAlzhe
imer
Res.2010
Sep;7
[6]:540–8
Lee,2010
Rand
omAPP/PS1
mice.Thebo
nemarrow
cells
were
cultu
redfor1week,andtheplastic-adh
eren
tpo
pula-
tionwas
used
forsubseq
uent
expe
rimen
ts.
Toam
eliorate
Abe
ta-in
ducedne
urop
atho
logy
andim
-provethecogn
itive
declineassociated
with
Abe
tade
posits.
Tomod
ulateim
mun
e/inflammatoryrespon
sesandto
restorede
fectivemicroglialfun
ctioninADmice,as
eviden
cedby
increasedAbe
ta-deg
rading
factors,de
-creasedinflammatoryrespon
ses,elevationof
alterna-
tivelyactivated
microglialm
arkers,and
diminishe
dtau
hype
rpho
spho
rylatio
n.
Stem
Cells.2010
Feb;28
[2]:329–
43.
Lee,2012
Rand
omAPP/PS1-GFP
chim
ericmice,in
vivo
stud
y;Therapeutic
effect;
Alternativemicrogliaactivationto
elim
inateAbe
tade
positio
nin
theADbrain,andfurthe
rim
prove
behavior.
Theicroglialactivationandmigratio
ninto
thebrains
ofAbe
ta-dep
ositedADmiceviaelevationof
theche-
moattractivefactor,C
CL5.Nep
rilysin
andinterleukin-4
derived
from
thealternativemicrogliawereassociated
with
aredu
ctionin
Abe
tade
positio
nandmem
oryim
-pairm
entin
ADmice.
Stem
Cells.2012
Jul;30[7]:1544–
55.
Li,2011
Rand
omAPP/PS1
mice,mechanisticstud
y.System
icadministrationof
SCF+G-CSF
redu
cedbe
ta-
amyloidde
positio
nin
ADmice,andincreasedthe
numbe
rof
bone
marrow-derived
microglialcellsin
thebrain.
Decreased
β-am
yloidde
positio
n,en
hanced
microglial
Alzhe
imersRes
Ther.2011Mar
15;3[2]:8
Li,2012
Rand
omratexpe
rimen
ts,in
vivo
stud
y;Therapeutic
Toim
provespatiallearningandmem
oryability
asBM
-MSC
ccouldmigrate
throug
hthebloo
d-brain
Zhejiang
DaXu
e
Qin et al. Translational Neurodegeneration (2020) 9:20 Page 5 of 20
Table
1Transplantationof
BMMSC
sforthetreatm
entof
anim
almod
elswith
Alzhe
imer’sdisease.Keyw
ords
“Alzhe
imer’sdisease”
and“stem
celltransplantation”
wereutilizedto
screen
database
PubM
ed,M
edline,andEm
base
respectively.Stud
ieseligibleforinclusionwererestrictedto
thebo
nemarrow
mesen
chym
alstem
cells.Prim
arystud
ieswith
completedata
wereretained
inthecurren
tmeta-analyticreview
(Con
tinued)
Stud
ies
Stud
yde
sign
Results
Mechanism
sReferences
effect;
demon
stratedby
Morris
water
mazeexpe
rimen
tbarrierandsurvived
inthehipp
ocam
pusof
ADrats
XueBaoYi
Xue
Ban.2012
Nov;
41[6]:659–64
Liu,2015
Rand
omAPP/PS1
mice;Overexpressionof
as-m
iR-937
inMSC
smay
improvethetherapeutic
effectsof
MSC
son
AD
MSC
sredu
cedthede
positio
nof
amyloid-be
tape
ptide
aggreg
ates
(Aβ)
andim
proved
behavior
asproved
bysocialrecogn
ition
test(SR)
andplus-m
azediscrim
ina-
tiveavoidancetask
(PM-DAT).
MSC
ssign
ificantlyincreasedBrn-4proteinlevels,
which
redu
cedthede
positio
nof
Aβand
upregu
lated
thelevelsof
BDNFin
ADmice.
CellP
hysiol
Biochem.2015;
37[1]:321–30
Magga,
2012
Transgen
icAPd
E9mice,BM
-derived
haem
atop
oietic
stem
cells
(HSC
)HSC
-derived
mon
ocyticcells
(HSC
M)couldbe
gene
ticallymod
ified
andcontrib
uted
toAbe
taredu
ctionin
APd
E9mou
semod
elof
AD.
HSC
-derived
mon
ocyticcells
(HSC
M)up
took
Abe
taproteinandredu
cedAβb
urde
nin
ADmou
sebrain.
JCellM
olMed
.2012
May;16[5]:
1060–73
Matchynski-
Franks,
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Rand
om5xFA
Dmice;theop
timallocatio
nfor
transplantingMSC
s;Injectioninto
thelateralven
tricles
was
better
than
theinjectioninto
hipp
ocam
pus.
MSC
transplantseffectivelyredu
cedlearning
deficits
inthe5xFA
Dmou
semod
elas
demon
stratedby
radial-
arm
water
maze8-choice
mem
orytask,w
ater
t-maze
two-choice
learning
task,spo
ntaneo
usmotor
activity,
motor
coordinatio
n,andprep
ulse
inhibitio
n.
Sign
ificantlyto
decrease
thelevelo
fAbe
ta42
inthe
brains
of5xFA
Dmicesubseq
uent
totransplantation
ofMSC
s.
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703.
Naaldijk,
2017
Rand
omAPP/PS1
mice,in
vivo
stud
y.Therapeutic
effect
ofBM
MCs
MSC
smay
affect
ADpatholog
y(neuroinflammation)
viaan
immun
e-mod
ulatoryfunctio
nthat
includ
esan
effect
onmicroglialcells.
Toredu
cetheexpression
allevelsof
TNF-alph
a,IL-6,
MCP
-1,and
NGFin
MSC
recipien
ts.A
lso,to
redu
cethe
size
ofpE3-Abe
taplaquesin
thehipp
ocam
pus.
Neuropathol
App
lNeurobiol.
2017
Jun;43
[4]:
299–314.
Ruzicka,
2016
Rand
om3xTg-ADmicetreatedby
human
MSC
s.Therapeutic
effect
ofBM
MCs
Learning
Deficits
improved
;red
uced
Amyloidβ
(Aβ*56);increasedne
urog
enesis;
Clustersof
proliferatin
gcells
inthesubven
tricular
zone
;the
levelo
fglutam
inesynthe
tase;
downreg
ulationof
Abe
ta*56levelsin
theen
torhinal
cortex
IntJMol
Sci.
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Jan25;17
[2].pii:E152.
Safar,2016
Adu
ltmaleWistarrats,effectsof
bone
marrow-
derived
(BM)E
PCstransplantation,en
dothelialp
roge
ni-
torcells
(EPC
s)
Improved
thelearning
andmem
oryde
ficits,and
mitigatedthede
positio
nof
amyloidplaquesand
downreg
ulationof
p-tau.To
correctmem
oryde
ficits
andAD-like
patholog
icaldysfun
ction
Dow
nreg
ulationof
p-tauandits
upstream
glycog
ensynthase
kinase-3be
ta(GSK-3be
ta);correctedthepe
r-turbations
ofne
urotransmitter
levelsinclud
ingacetyl-
choline,do
pamine,GABA
,and
thene
uroe
xitatory
glutam
ate;to
boosttheexpression
ofvascular
endo
-thelialg
rowth
factor
(VEG
F),nerve
grow
thfactor
(NGF),b
rain-derived
neurotroph
icfactor
(BDNF)
and
itsup
stream
cAMPrespon
seelem
entbind
ing(CREB);
supp
ressionof
theproinflammatorytumor
necrosis
factor-alpha
(TNF-alph
a),interleukin-1be
ta(IL-1be
ta);
upregu
latio
nof
interleukin-10(IL-10),N
rf2andseladin-
1.
Mol
Neurobiol.
2016
Apr;53[3]:
1403–1418
Selem,
2014
Adu
ltfemaleSpragu
e–Daw
leyrats,,in
vivo
stud
y.Therapeutic
effect
ofBM
MCs
Toremovebe
ta-amyloidplaquesfro
mhipp
ocam
pus;
anti-apop
totic,neuroge
nicandim
mun
omod
ulatory
prop
erties
Proliferatin
gthenu
mbe
rof
positivecells
forcholine
acetyltransferase(ChA
T)andsurvivin
expression
,as
wellasselectiveADindicator-1(seladin-1)andne
stin
gene
expression
.Histopatholog
icalexam
inationindi-
catedtheremovalof
beta-amyloidplaquesfro
mhipp
ocam
pus.Sign
ificant
improvem
entin
thesebio-
markerswas
similarto
orbe
tter
sometim
esthan
the
referencedrug
s.
CellB
iolInt.
2014
Dec;38[12]:
1367–83
Wu,2011
Rand
omSD
ratexpe
rimen
tsviahipp
ocam
palfim
bria-
Spatiallearning-mem
oryability
ofde
men
tiaratswas
Themechanism
might
bepo
ssiblycorrelated
with
Zhon
gguo
Qin et al. Translational Neurodegeneration (2020) 9:20 Page 6 of 20
Table
1Transplantationof
BMMSC
sforthetreatm
entof
anim
almod
elswith
Alzhe
imer’sdisease.Keyw
ords
“Alzhe
imer’sdisease”
and“stem
celltransplantation”
wereutilizedto
screen
database
PubM
ed,M
edline,andEm
base
respectively.Stud
ieseligibleforinclusionwererestrictedto
thebo
nemarrow
mesen
chym
alstem
cells.Prim
arystud
ieswith
completedata
wereretained
inthecurren
tmeta-analyticreview
(Con
tinued)
Stud
ies
Stud
yde
sign
Results
Mechanism
sReferences
farnix(FF)
ampu
tatio
nmod
el,G
inseno
side
Rg1treat-
men
t,invivo
stud
y.Therapeutic
effect
ofBM
MCs
improved
asde
mon
stratedby
byMorris
water
maze
andtheescape
latencytest.
mRN
Aexpression
levelo
fNGFthat
was
up-reg
ulated
inbasalforeb
rain.
Zhon
gXi
YiJie
HeZa
Zhi.2011
Jun;31
[6]:799–
802.
Yu,2018
Rand
omexpe
rimen
ts,Sprague-Daw
leyfemalerats,
invivo
stud
y.Therapeutic
effect
ofBM
MCs
Theexpression
ofSeladin-1andne
stin
werelower
intheADgrou
pwhe
ncomparedwith
thecontrol
grou
p,whe
reas
theBM
-MSC
transplantationreversed
theirdo
wn-regu
latio
n.
BM-M
SCtransplantationen
hanced
Seladin-1andne
s-tin
expression
potentially
viaamechanism
associated
with
theactivationof
thePI3K/Akt
andERK1/2
sign
al-
ingpathways.
Oncol
Lett.2018
May;15[5]:7443–
7449.
Zhang,
2012
Spragu
e-Daw
leyrats,in
vivo
stud
y.Therapeutic
effect
ofBM
MCs
BMMSC
splus
BDNFresultedin
sign
ificant
attenu
ation
ofne
rvecelldamagein
thehipp
ocam
palC
A1region
.Tyrosine
kinase
BmRN
Aandproteinlevelswere
sign
ificantlyincreased,
andlearning
andmem
ory
ability
weresign
ificantlyim
proved
.
Increasing
thelevelsof
brain-de
rived
neurotroph
icfac-
torandtyrosine
kinase
Bin
thehipp
ocam
pus.
NeuralR
egen
Res.2012
Feb5;
7[4]:245–50
Qin et al. Translational Neurodegeneration (2020) 9:20 Page 7 of 20
Table
2Gen
eralcharacteristicsof
theinclud
edstud
iesin
thismeta-analysis.Transplantatio
nof
BMMSC
sforthetreatm
entof
anim
almod
elswith
Alzhe
imer’sdiseasewas
characterized
bysource
ofstem
cells,amou
ntof
stem
cells,animalspecies,ge
nder,age
,bod
yweigh
t,de
liverymetho
d,etc.
Stud
ies
Sourcesof
transplanted
stem
cells
Amou
ntof
transplanted
stem
cells
Speciesof
recipien
tanim
als
Gen
derratio
ofrecipien
tsAge
orbo
dyweigh
tRo
uteof
delivery
Positio
nof
delivery
Sustainabilityof
transplanted
stem
cells
Bae,2013
Tibias
andfemurswere
dissectedfro
m4-
to6-week-
oldC57BL/6
mice
1×10
6of
thecells
ina
2uLvolume
TASTPM
mice(n
=9for
each
grou
p)Femaleon
ly4mon
thsof
age.
Transplanted
bilaterally
into
hipp
ocam
pus
Thefollowingcoordinates:2
mm
posteriorto
thebreg
ma,
1.5mm
bilateraltothe
midline,and2mm
ventralto
theskullsurface.
Micewere
sacrificedat
2,3,and4
mon
thsafter
BMMSC
transplantation.
Garcia,
2014
6-week-oldC57BL/6-Tg
(ACTBEG
FP)10sb/Jtransgen
icmice
1×10
6of
thecells
ina
5uLvolume
2xTg-ADmalecong
enic
mice(APPsw
e/PS1d
E9,
B6.Cg-Tg
(APPsw
e,PSEN
1dE9)85D
bo/J)
Malecong
enicmice
(n=10/group
)6,9and12
mon
thsof
age
Lateralven
tricle
Thecoordinatesfor
stereo
taxicalinjectio
n(atlas
byPaxino
sandFranklin
2004)w
ereused
:−0.34
mm
posteriorto
breg
ma,−0.9
mm
lateraltothemidline
and2.3mm
ventraltothe
skullsurface
40days
after
transplantation
Harach,
2017
Stem
cells
wereob
tained
from
Stem
edicaCell
Techno
logies
(San
Diego
,USA
).Thecells
areeq
uivalent
tocommerciallyavailable
stem
cells
from
ThermoFishe
rScientific“StemProBM
MSC
”(partnu
mbe
rA15653).
5×10
5cells
in100uLof
LRS
APP/PS1
mice
Male:female=1:1(n
=5/grou
p)1~12.5-
mon
th-old
Sing
leintraven
ousor
weekly
intraven
ousfor
10weeks
Tailvein
10weeks
Kanamaru,
2015
C57BL/6-Tg(CAG-
EGFP)m
ice(4weeks
old,
male)
5×10
6cells
in0.25
mLof
HBSS
Tg2576
(APP)andDAL
Femaleon
ly(n
=8~
12/group
)6-mon
th-old
APP
mice/9-
mon
th-old
DALmice
Perip
heralvein
Retroo
rbitalven
ousplexus
3mon
ths/9
mon
ths
Lampron
,2013
Mou
sefemursandtib
ias
weredissected,
andtheir
bone
marrow
was
flushed
with
phosph
ate-bu
fferedsa-
line(PBS)containing
5%fetal
bovine
serum,recipient
mice
weretreatedwith
aregimen
ofmyeloablativechem
othe
r-apypriorto
receivingbo
nemarrow
cells
from
GFP1
transgen
icmice
2×10
7APP/PS1
andwild-typeC57/
BL6mice
Unkno
wn
7~8-week-
oldmice
Perip
heralvein
Tailvein
ofrecipien
tmice
2.5–10
weeks
before
they
received
any
othe
rtreatm
ent
orsurgeries.
Lee,2010
4-to
6-week-oldC57BL/6
mice
1×10
5cells
in3μl
ofthe
cell
suspen
sion
Aβindu
cedAD(Aβ,
n=20;
PBS,n=10)
Unkno
wn
4~6-week-
old
Hippo
campu
sbilaterally
Thebraincoordinates:1.6
mm
posteriorto
thebreg
ma,
1.7mm
bilateraltothe
midline,and1.2mm
ventral
totheskullsurface.
Micewere
sacrificedat
11days
afterBM
-MSC
stransplantation.
Lee,2010
4to
6-week-oldC57BL/6
mice
1×10
4pe
rmou
se/3ul
APP/PS1
mice
Malemice
7mon
ths1
weekof
age
Hippo
campu
sbilaterally
Thefollowingcoordinates:
1.6mm
posteriorto
the
At9mon
thsof
age,micewere
Qin et al. Translational Neurodegeneration (2020) 9:20 Page 8 of 20
Table
2Gen
eralcharacteristicsof
theinclud
edstud
iesin
thismeta-analysis.Transplantatio
nof
BMMSC
sforthetreatm
entof
anim
almod
elswith
Alzhe
imer’sdiseasewas
characterized
bysource
ofstem
cells,amou
ntof
stem
cells,animalspecies,ge
nder,age
,bod
yweigh
t,de
liverymetho
d,etc.(Con
tinued)
Stud
ies
Sourcesof
transplanted
stem
cells
Amou
ntof
transplanted
stem
cells
Speciesof
recipien
tanim
als
Gen
derratio
ofrecipien
tsAge
orbo
dyweigh
tRo
uteof
delivery
Positio
nof
delivery
Sustainabilityof
transplanted
stem
cells
breg
ma,1.7mm
bilateralto
themidline,and1.2mm
ventraltotheskullsurface.
killedand
evaluatedfor
change
s.
Lee,2012
Bone
marrow
ofthemice
expressing
greenfluorescent
protein(GFP)
1×10
4pe
rmou
se/3ul
APP/PS1-GFP
ChimericMice
(n=10
pergrou
p)Unkno
wn
7mon
ths2
weekof
age
Intracereb
ral
hipp
ocam
pus
Thefollowingcoordinates:
1.6mm
posteriorto
the
breg
ma,1.7mm
bilateralto
themidline,and1.2mm
ventraltotheskullsurface
Micewere
sacrificedat
3,7,and14
days
afterthelast
treatm
ent.
Li,2011
UBC
-GFP
micewith
the
gene
ticbackgrou
ndof
C57BL/6J,UBC
-GFP
mice(8
to10
weeks
old)
1×10
7cells
permou
seAPP/PS1
mice.Sixweeks
afterbo
nemarrow
transplantation,micewere
rand
omlydivide
dinto
asalinecontrolg
roup
(n=5)
andan
SCF+G-CSF-treated
grou
p(n
=5).
Unkno
wn
7-mon
th-old
APP/PS1
mice
Perip
heralvein
Tailvein
After
treatm
ent
for9mon
ths,
themicewere
sacrificed
Li,2012
The5thpassaged
human
BMMSC
slabe
ledwith
PKH26
1×10
6of
thecells
ina
1000uL
volume
SDrats
Maleon
ly(10ratspe
rgrou
p)3mon
thsof
age,~300g
Perip
heralvein
Tailvein
14days
Liu,2015
Mou
seBM
MSC
soverexpressedantisen
seof
miRNA-937
1×10
6of
thecells
ina
5uLvolume
APP/PS1
mice
Unkno
wn;n=10/
grou
p9mon
thsof
age
Bilateral
hipp
ocam
piThestereo
taxiccoordinates
wereas
follows:2mm
posteriorto
thebreg
ma,2
mm
bilateralfrom
the
midline,and2mm
ventralto
theskullsurface.
At9mon
thfor
SRandPM
-DAT
evaluatio
n
Magga,
2012
Mon
ocyticcells-derived
from
mou
seor
human
bone
marrow.
3×10
5in
1ul
ofHBSS,
2%FBS
APPsw
e/PS1d
E9(APd
E9)
mice
Unkno
wn,n=5forAD
andn=4forWTmice
2-year-old
Intrahippo
campal
(righ
thipp
ocam
pus)
Thebraincoordinates:0.25
mm
med
ial/lateral,0.27mm
anterio
r/po
sterior,0.25mm
dorsal/ven
tralfro
mbreg
ma.
After
4days
post-
transplantation,
thebrains
were
collected
Matchynski-
Franks,
2016
BMMSC
sfro
mC57BJL/6or
GFP-positive
mice
2×10
5cells/
μlin
HBSS,
4μl
per
mou
se
5xFA
DMale:female=1:1;LV
(n=8),[2]
Hipp(n
=8),
[3]LV-Hipp(n
=8),[4]
WTSham
(n=6),[5]
ADSham
(n=6),WT
surgerycontrol(n=6),
andADsurgerycontrol
(n=6)
6mon
thsof
age
Cen
tralne
rvou
ssystem
Hippo
campu
sand/or
ventricle;A
burrho
lewas
drilled
oneach
side
ofthe
skull,directlyover
thesite
ofinjectionat
−0.2anterio
r/po
steriorfro
mbreg
ma(A/P)
and±1.0med
ial/lateralfro
mbreg
ma(M
/L)into
the
ventricle,−
1.2A/P
and±1.0
M/L
into
thehipp
ocam
pus,
orallfou
rlocatio
ns.
10weeks
after
transplantation
Naaldijk,
2017
C57BL/6
mou
seas
asource
forbo
nemarrow-derived
1×10
6of
thecells
ina
APP/PS1
mice
Maleanim
al(day
7n=
3andday28
n=4),
12~15
mon
thsof
Perip
heralvein
Tailvein
7or
28days
anim
alswere
Qin et al. Translational Neurodegeneration (2020) 9:20 Page 9 of 20
Table
2Gen
eralcharacteristicsof
theinclud
edstud
iesin
thismeta-analysis.Transplantatio
nof
BMMSC
sforthetreatm
entof
anim
almod
elswith
Alzhe
imer’sdiseasewas
characterized
bysource
ofstem
cells,amou
ntof
stem
cells,animalspecies,ge
nder,age
,bod
yweigh
t,de
liverymetho
d,etc.(Con
tinued)
Stud
ies
Sourcesof
transplanted
stem
cells
Amou
ntof
transplanted
stem
cells
Speciesof
recipien
tanim
als
Gen
derratio
ofrecipien
tsAge
orbo
dyweigh
tRo
uteof
delivery
Positio
nof
delivery
Sustainabilityof
transplanted
stem
cells
MSC
.MSC
sat
passage1–2
wereused
for
transplantations
150uL
volume
femalerecipien
ts(day
28,n
=3),con
trol
mice
n=11
age
sacrificed
Ruzicka,
2016
Hum
anmesen
chym
alstem
cells
(MSC
s)6×10
4cells/
2μLof
saline
3xTg-ADmice.The3xTg-AD
mou
sestrain
(LaFerla,Irvine,
CA,U
SA),harboringthree
transgen
esofPS1(M
146V),
tau(P301L)andAPP
(SWE),
was
used
.Mice(saline-
injected
3xTg-AD,n
=14;
MSC
-injected
3xTg-AD,n
=16;and
WTcontrolswith
out
treatm
ent,n=14)
Unkno
wn
8mon
thsof
age
leftlateral
ventricle
Coo
rdinates
from
breg
ma:
anteropo
sterior=
0mm,
med
iolateraly=1mm,
dorsoven
traly=2mm
6mon
ths
Safar,2016
Bone
marrow
was
aspirated
from
thefemoraandtib
iae
ofadultmalesyng
eneic
Fisher-344
rats.The
inter-
phaselayercontaining
bone
marrowde
rived
mon
onuclear
cells
(BM-M
NCs)was
col-
lected
,and
thecells
were
washe
dtw
icewith
phosph
ate-bu
fferedsaline
(PBS)be
fore
centrifug
ationat
400gfor5min.
2×10
6cells,
BM-EPC
sAdu
ltWistarrats
Maleon
ly(12ratspe
rgrou
p)Weigh
ing
180–220g
Perip
heralvein
Tailvein
One
mon
th
Selem,
2014
Bone
marrow
was
harvested
byflushingthetib
iaeand
femursof
6-week-oldmale
Spragu
e–Daw
leyratswith
Dulbe
cco’smod
ified
Eagle’s
med
ium
(DMEM
,GIBCO/BRL,
Grand
Island
,NY,USA
)sup-
plem
entedwith
10%
fetal
bovine
serum
(GIBCO/BRL).
3×10
6 cells/
rat
Adu
ltSpragu
e–Daw
leyrats,
orallyadministeredwith
alum
inum
chlorid
eat
17mg/kg
b.wt.(Krasovskiietal.,
1979)daily
for75days
for
indu
ctionof
ADdisease.
Adu
ltfemalerats(8rats/
grou
p)Weigh
ing1
30–
150g
Intraven
ously
Tailvein
in5min
with
a27G
need
le4mon
ths
Wu,2011
Bone
marrow
was
harvested
from
Wisterrat.
1×10
5cells
in5μl/per
side
SDrats
Malerats(15ratspe
rgrou
p)3~4mon
ths
Hippo
campu
sbilaterally
Coo
rdinates:4.0mm
posteriorto
thebreg
ma,2.0
mm
bilateraltothemidline,
and3.0mm
below
thedu
ramater.
One
mon
th
Yu,2018
Thefemoralbo
neswere
harvestedfro
m4do
normale
rats.
3×10
6cells/
ratin
asing
ledo
se
Spragu
e-Daw
leyrat
Femalerats(n
=8pe
rgrou
p)Bo
dyweigh
t130-150g
Perip
heralvein
Tailvein
Unkno
wn
Zhang,
2012
Sixhe
althySpragu
e-Daw
ley
rats(usedforcellcultu
re),
5×10
6in
10μl
Arand
omized
,con
trolled,
anim
alexpe
rimen
t.Adu
ltMalerats(??ratspe
rgrou
p)Weigh
ing
280–300g
Lateralven
tricular
Stereo
taxicCoo
rdinates
describ
edby
Geo
rgePaxino
sTestswere
perfo
rmed
at
Qin et al. Translational Neurodegeneration (2020) 9:20 Page 10 of 20
Table
2Gen
eralcharacteristicsof
theinclud
edstud
iesin
thismeta-analysis.Transplantatio
nof
BMMSC
sforthetreatm
entof
anim
almod
elswith
Alzhe
imer’sdiseasewas
characterized
bysource
ofstem
cells,amou
ntof
stem
cells,animalspecies,ge
nder,age
,bod
yweigh
t,de
liverymetho
d,etc.(Con
tinued)
Stud
ies
Sourcesof
transplanted
stem
cells
Amou
ntof
transplanted
stem
cells
Speciesof
recipien
tanim
als
Gen
derratio
ofrecipien
tsAge
orbo
dyweigh
tRo
uteof
delivery
Positio
nof
delivery
Sustainabilityof
transplanted
stem
cells
aged
2–3weeks,w
eigh
ing
80–120
gSpragu
e-Daw
leyrats,
[4]:Neurobiol
Aging
.2009;30
[3]:377–387;leftventriclewas
localized
at1.0mm
posterior
toBreg
maand1.5mm
adjacent
tothemed
ian,and
4.0mm
below
thedu
ramater.
16days
and
was
completed
at20
days.
Qin et al. Translational Neurodegeneration (2020) 9:20 Page 11 of 20
delivery. Animal models might receive either a sin-gle injection or a weekly injection more than 10weeks through the tail vein [21]; (ii) intranasal ad-ministration of active factors secreted by stem cells.The animal was restrained by hand withoutanesthesia. An appropriate amount of soluble MSCfactors was placed at nares of the animal via a pip-ette until the liquid drop disappeared into the nares[21]. A repeated intranasal delivery of soluble fac-tors from cultured MSCs was enough to improvebehavioral deficits in the mice; (iii) intracerebral orintracerebroventricular injection of stem cells. Intra-cerebral transplantation of grafted cells circumventsthe prohibitive blood brain barrier and the cells canreach the discreet brain site. Benefits of mesenchy-mal stem cells on memory improvement in ADmodels had been detected [23]. However, the intra-cerebral delivery, compared to peripheral route, isan invasive procedure to implant stem cells intoparticular brain area [15]. Thus, it is a major hurdlefor clinical applications. In contrast, intravenous de-livery of transplanted stem cells is fast and easy
route, and complications are rarely observed. Todate, some preclinical studies have evaluated the im-pact of intravenous MSC injections on cerebralamyloidosis [21, 24].
Neuropathological changesRemoval of Aβ plaquesAmyloid β peptide deposits in brain tissue and formsplaques. Moreover, the Aβ plaques are accumulated inspecial areas of AD brain. Nowadays cumulative level ofAβ plaques is a hallmark of AD. It is still a long way todemonstrate the actual role of Aβ plaques in the patho-genesis of Alzheimer’s disease, but the number of Aβplaques is increased along with the deterioration of ADstage. The deposition of amyloid plaques in the form ofspots and streaks could induce neuronal cell death viaoxidative stress in the hippocampus [20, 25]. The trans-plantation of stem cells was able significantly to decreasethe number of hippocampal Aβ plaques, which wasdemonstrated in APP/PS1 model mice as early as 1 weekafter intravenous delivery (Fig. 4a). Further investigationindicated that the impact of stem cells could activate
Fig. 2 Summary of potential bias in the identified studies
Qin et al. Translational Neurodegeneration (2020) 9:20 Page 12 of 20
several Aβ-degrading enzymes such as neprilysin-degrading enzyme, insulin degrading enzyme (I),endothelin-converting enzyme, etc. Those enzymes mayplay a critical role during degradation of amyloid β pla-ques. In the aspect of feasibility, the therapeutic applica-tion of stem cells via intravenous delivery is convenientand sufficient to diminish cerebral amyloidosis [21, 25].
Neurogenesis, differentiation and integrationThe intravenous transplantation of stem cells was readilydetected in brain parenchyma, i.e. hippocampus as re-vealed in 1 h after administration [21]. The expressionof sry gene in the brain tissue of female AD modeltreated with male BMMSCs confirmed the migratoryability of the intravenously infused foreign stem cells tothe site of brain injury [25]. The BMMSCs could differ-entiate into neuron-like cells and partially express ChAT[26]. Neural cells express nestin that can be as a markerof neural precursors. Brain nestin expression was up-
regulated subsequent to the treatment of BMMSCs [27].Bone marrow cells migrate throughout the brain and dif-ferentiate into neurons and glial cells [11]. In the hippo-campus, there were different neurogenic phases such asproliferation, differentiation, migration, targeting, andintegration respectively [28]. The transplanted stem cellmay play a beneficial part in different phases of cellgrowth, although exact mechanism remains to be deter-mined. The MSCs produce various trophic factors, in-cluding BDNF, NGF, and IGF-1 [29–31]. The MSCscould upregulate the trophic factors like NGF, FGF-2and BDNF. This result could be attributed to the posi-tive expression of growth factor, chemokine and extra-cellular matrix receptors on the surface of MSCs [25].All these factors contribute to recover neurobehavioralfunction and stimulate endogenous regeneration. TheBMMSCs could significantly increase the intensity ofChAT spots as well as the number of positive cells forChAT expression in AD group. Cholinergic change is
Fig. 3 Transplantation of bone marrow mesenchymal stem cells could improve behavioral deficits in animal models of Alzheimer’s disease, whichwas generally characterized by abnormal manifestation or relationship. The beneficial change might be a temporary or permanent effect whencompared to previous behavior. a. Behavioral changes as demonstrated through Y-maze test; b. Behavioral changes by Morris water maze test
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potential mechanism for the neurogenesis subsequent toa transplantation of BMMSCs. After BMMSCs treat-ment, the improvement in these biomarkers might be at-tributed to the powerful neurogenesis, neuronaldifferentiation and integration [11, 32] (Fig. 4b).
AngiogenesisAngiogenesis is a pathophysiological process that is involvedin regeneration and tissue reconstruction. Transplantationof the BMMSCs can promote angiogenesis in brain tissue asproved by (a) the fold change of expression marker such as
VEGF; (b) interaction between VEGF and Aβ protein in ex-perimental animal study; and (c) therapeutic effects of theVEGF in the murine model of Alzheimer’s disease [33–35].The role of MSC in the cerebrovasculature had been corre-lated with angiogenesis and revascularization, mainlythrough secretion of various angiogenic factors (Fig. 4c, d).An administration of MSCs stimulated revascularization atthe site of injury via secreting VEGF, FGF-2, Ang-1 andEGF [36]. The injection of hMSC into rats would increaseangiogenesis by enhancing endogenous VEGF and VEGFR2levels in the ischemic zone [37, 38]. Moreover, transplanted
Fig. 4 Meta-analysis on potential mechanisms. The transplantation of BMMSCs could alleviate neuropathology through diverse mechanisms, suchas to decrease the number of hippocampal Aβ plaques as demonstrated in AD animal models (a). The Fig. 4a was plotted by relative ratio. Thevalue in experimental group was assigned as 1 and the same as the following figures; to stimulate neurogenesis, neuronal differentiation, andneuronal integration (b); to promote angiogenesis in brain tissue as reflected by VEGF marker (c, d); to attenuate Aβ-induced apoptotic cell deathin both primary hippocampal neurons and Aβ-injected animal models (e, f); immunomodulation and neuroprotection (g); to inhibitneuroinflammation in AD animal models (h)
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stem cells were able to differentiate into mural cells that ac-celerated the formation of peripheral vascular layers [39]. Inthe context of neurodegenerative disorders, these mesenchy-mal stem cells might contribute to neuroprotection by se-creting trophic factors such as EGF, VEGF, FGF-2, NT-3,HGF, and BNDF [40]. Further study on potential mecha-nisms in AD models will be required to understand the con-tribution of above factors to the disruption of amyloidplaques following intravenous implementation of stem cells[21]. In the brains of AD patients, the soluble VEGF concen-tration is decreased because Aβ binds to VEGF forming ag-gregate that leads to the loss of angiogenic andneuroprotective activities [41]. Therefore, provide additionalVEGF would have high therapeutic effect. An overexpress-ing VEGF in mesenchymal stem cells could promote neo-vascularization in the hippocampus and recovered thememory deficit in the 2xTg-AD animals. More interestingly,only intraperitoneal injection of VEGF could improve cogni-tive function through the hippocampal angiogenesis and de-creased Aβ deposition in the brain [35, 42].
Inhibition of apoptosisThe Aβ peptide in AD animal models could induceneuronal apoptosis via caspase pathway [13, 43, 44].The neuronal apoptosis was responsible for the mem-ory impairment in AD brain. The transplantation ofBMMSCs attenuated Aβ-induced apoptotic cell deathin primary hippocampal neurons as well as intrahip-pocampally Aβ-injected AD animal models (Fig. 4e, f).The neuroprotective mechanisms of BMMSCs may bethrough (a) to reduce Aβ deposition. The Aβ peptideinduced the stress-activated protein kinases p38 andc-jun N-terminal kinase, and upregulated p53 expres-sion, which were closely associated with apoptosis [1].Furthermore, the MSCs expressed seladin-1, which in-hibits the activation of caspase-3 and is a neuropro-tective factor. The transplantation of BMMSCs couldsignificantly increase seladin-1 gene expression in ADgroups [45]; (b) activation of the cell survival signalpathway. The BMMSCs treatment upregulated thesurvivin expression as showed by the increased num-ber of survivin-positive cells in AD models [46]. TheMSCs could inhibit P53 activation [47]. Also, theMSCs produce VEGF, BDNF, NGF, and FGF2, whichwere supposed to exert an anti-apoptotic effect [48].The BMMSCs could significantly down-regulatecaspase-3 expression, thus protecting seladin-1 fromcleavage [49]; (c) to decrease oxidative stress-inducedneurotoxicity in the hippocampus [18]. ER-oxidativestress and mitochondrial failure involve the pathogen-esis of Alzheimer’s disease. The transplantation ofstem cells led to a significant improvement of mem-ory deficits in AD mouse models via the suppressionof apoptosis and the maintenance of functional
synaptic contacts [4, 13, 50]. The MSCs could up-regulate the cellular antioxidant defense through theircapability to secrete trophic factors like NGF, FGF2and BDNF. MSCs could also attenuate oxidative dam-age by reducing ROS and increasing expression of en-dogenous antioxidants in neurons [47]. The apoptoticmechanism not only took part in neuronal cell death,but also involved survival of transplanted mesenchy-mal stem cells in brain tissue. Actually, the later alsohampered the clinical application of stem cell therapyfor Alzheimer disease [51].
ImmunomodulationHistopathological examination disclosed that immuno-modulatory property of the BMMSCs play an importantrole in therapeutic role against AD as well [25]. The in-tracerebral transplantation of BMMSCs was applied toacute AD model induced through Aβ peptide injectioninto the dentate gyrus of hippocampus of C57BL/6 mice.The activation of microglia promoted the diminution ofAβ deposits due to microglial phagocytosis. TheBMMSCs could accelerate the activation of microgliaand the removal of Aβ deposition in AD brain [52]. Invitro study demonstrated the bone marrow-derived mes-enchymal stem cells could decrease expressional levelsof pro-inflammatory genes (IL-1β, TNF-α, IL-6) in astro-cytes [53]. The MSCs regulated a series of gene expres-sion, including intermediate filaments (GFAP, vimentin),pro-inflammatory enzymes (iNOS, COX-2) and recep-tors (TLR4, CD14, mGluR3, mGluR5). Immunomodula-tory influence of MSCs may be through diverse celltypes to participate in the neuroinflammation (Fig. 4g).The observation of decreased neuroinflammation inhMSC-treated APP/PS1 mice further suggests thathMSC delivery does not elicit a major immune responsefrom the host. In addition, preclinical study demon-strated that a repeated intravenous hMSC treatmentcould safely reduce cerebral Aβ pathology in a typicalmouse model of AD.
Inhibition of inflammationThe neuroinflammation was reduced in APP/PS1 micefollowing hMSC treatment [21] (Fig. 4h). There was adramatic decline on the panel of cerebral cytokines suchas IFNγ, diverse interleukins (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-12p70), KC/GRO, and TNF-α, suggest-ing an anti-inflammatory impact of hMSCs. The hMSCtreatment significantly down-regulated cerebral IBA-1.Among multiple cell types of brain tissue, the IBA-1gene is specifically expressed in microglia. Upon activa-tion of microglia due to inflammation, expression of theIBA-1 is up-regulated, which allows the discriminationbetween surveilling and activated microglia. Microglialcoverage was examined to evaluate neuroinflammation
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changes in transgenic brains following repeated hMSCtreatment [21]. There was an overall decrease of themicroglia coverage in brains of APP/PS1 transgenic miceof both young and aged groups. A qualitative observa-tion was confirmed by quantitative image analysis ofIBA-1 immunoreactivity. TNFα and IL-12p70 were re-duced following a single hMSC intravenous injection.Interestingly, TNFα has been implicated in chronic in-flammation, cancer, and other inflammatory diseases.Notably, levels of the cytokine IL-10 were decreased fol-lowing stem cell treatment, which might be therapeutic-ally relevant for AD although this cytokine was reportedto be anti-inflammatory. Accordingly, AD patientsshowed abnormally high IL-10 signaling, whichhighlighted that blocking the IL-10 anti-inflammatoryresponse could be therapeutically relevant for AD [54].The repeated intravenous hMSC injections or even sin-gle administration reduced cerebral neuroinflammation.The anti-inflammatory role of BMMSCs was also veri-fied in a rat model of spinal cord injury [55]. Obviously,the stem cell therapy significantly inhibited the inflam-matory response.
Gene-specific patterns of Alzheimer’s diseaseIn pathology, the pathogenesis of Alzheimer’s diseasecan be classified into different stages, which involvesvarious mechanisms such as proliferation, apoptosis,angiogenesis, immunomodulation, inflammation, etc.These mechanisms are reflected by differential genelevels as compared with normal control (Fig. 5a). In re-cent decades, gene analysis based on microarray assayand high-throughput DNA sequencing has providedabundant information on gene expression profile of Alz-heimer’s disease. It is reasonable to hypothesize that theAlzheimer’s disease has gene-specific patterns by whichits progression and severity are mediated.Gene data from microarray assay and high-throughput
DNA sequencing were collected and analyzed throughcomprehensive comparison. In gene ontology and signalpathway analyses, principal components of differentialgenes were identified [56]. The guideline for the con-struction of gene-specific patterns was summarized asfollows:
1) Comparison of differential gene expression in brainsamples of patients with AD (Fig. 5b).� Quantification of hippocampal key genes, such
as BDNF, NGF, VEGF, etc.� Estimation of inflammatory cytokines, such as
TNF-α, IL-1β, IL-10, etc.� Determination of oxidative damage, e.g.,
hippocampal Nrf2 level.2) Cluster analysis of all relevant gene data (Fig. 5c).3) To screen principal variables via PCA analysis.
4) Statistical regression model. After correlation andregression analysis, a multinomial logistic equationwas obtained (Fig. 5d, e).� Based on big data analysis, a predictive model
was composed of representative gene variables inthe pathogenesis of Alzheimer’s disease.
� Logistic regression equation can classify genevariables into gene-specific patterns.
5) Pathophysiological significance of the gene-specificpatterns.� To diagnose patient based on differential gene
levels. Logistic regression model can distinguishAD patient from normal control.
� To predict progression of AD, severity, andpatient’s life expectancy.
In the context of neurodegenerative AD, the trans-plantation of BMMSCs could improve cognitive def-icits and alleviated neuropathology at variousdegrees. The grafted MSCs contributed to neuro-protection through secretion of neurotrophic factorssuch as BDNF, EGF, VEGF, FGF-2, NT-3, HGF andso forth [40]. Differential gene expression involved aseries of functional results of paracrine secretion ofneurotrophic factors and cytokines. The aforemen-tioned changes might be weighed by differentiallevels of responsible genes. In fact, therapeutic effectof the BMMSCs was determined by comprehensiverole of representative genes. As presented in thisstudy, there are gene-specific patterns in the patho-genesis of Alzheimer’s disease. The gene patternswould be an appropriate method to assess the thera-peutic effect subsequent to stem cell transplantationin AD models. Accordingly, relative levels of repre-sentative genes can be used to evaluate the progressand prognosis of the disease. Next, it is necessary toexpand the sample size of representative gene dataand further to confirm real contribution of thesekey genes to the pathogenesis of Alzheimer’sdisease.
DiscussionTherapeutic effect of the transplanted BMMSCs wasdemonstrated with the improvement of memory lossand behavioral deficits in animal models with Alzhei-mer’s disease [18, 57, 58]. Positive results have been ac-quired not only through the repeated transplantation ofBMMSCs, but also via a single injection or even solubleMSC factors over nasal mucosa. In future, it is possibleto use BMMSCs for the clinical treatment of Alzheimer’sdisease. Potential mechanisms are associated with abroad coverage of neurogenesis, differentiation, apop-tosis, angiogenesis, inflammation, immunomodulation
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and so on [17, 18, 20, 22]. However, the exact mechan-ism remains to be determined. Based on data analysis, agene-specific pattern was revealed in brain tissue of pa-tients with Alzheimer’s disease. The above gene patternswere altered with the severity of neuropathology, whichmaybe a useful tool for the molecular diagnosis andtherapeutic evaluation of Alzheimer’s disease.It is a long way to clarify the pathogenesis of Alz-
heimer’s disease. However, an investigation on its po-tential mechanisms is still an essential work, sinceany progress in clinical treatment depends on a
comprehensive understanding of the relevant mecha-nisms. Neuropathological mechanism is associatedwith differential panel of gene expression [21, 54, 56].Gene change in brain tissue can be clustered into di-verse patterns based on expressional levels and func-tional features. Therefore, a novel concept of the genepattern is proposed. The gene pattern may be utilizedas a surveillance marker for the dynamic assessmentof neuropathology. Its significance will be reflected inthe molecular diagnosis and therapeutic evaluation ofAlzheimer’s disease.
Fig. 5 Construction of gene-specific regression model. a. Differential gene expression was compared between control and samples of patientswith Alzheimer’s disease. b. Hierarchical cluster analysis based on the comparison between control and gene data from samples of patients withAlzheimer’s disease. c. Heatmap of gene data from brain samples of patients with Alzheimer’s disease. d. Sigmoid curve of gene pattern. e.Logistic regression equation for prediction of gene-specific patterns of Alzheimer’s disease
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Beneficial results of BMMSCs transplantation hadbeen observed in different animal models that were in-duced using genetic modification, Aβ protein injection,or administration of chemicals. The transplantation ofstem cells from autologous BMMSCs did not cause anyimmune response. Enormous experiment data showedtherapeutic effects of the BMMSCs, which included theimprovement in cognitive deficits and pathologicalchanges [18, 20]. It is quite possible for the BMMSCs tobe utilized in clinical treatment of AD patients in future,because (a) stem cells are easily obtained through bonemarrow aspiration; (b) peripheral vein delivery; (c) au-tologous stem cells without immunogenicity.A combination of transplanted BMMSCs with drug
therapy may be a future direction. In clinical, cholin-esterase inhibitors and NMDA antagonist have beennow used to improve memory loss and behavioral symp-tom of patients with Alzheimer’s disease [5, 6]. Thera-peutic effect had been observed in certain patients, butnot all patient community. If above-mentioned medica-tions are combined with a transplantation of BMMSCs,what will happen? So far, it is only a rational hypothesis.In addition, the soluble factors from stem cells couldalso produce positive result, which encourages furtherinvestigation using the combination of neurotransmitterdrugs with cytokines [21]. Their joint application maytrigger a synergistic effect.It seems that the stem cells from autologous bone
marrow have some advantages as compared with thosefrom allogeneic embryos and umbilical cord. However,there is still weakness in the transplantation ofBMMSCs. There are some side-effects from bone mar-row aspiration. Another drawback is from the prepar-ation of stem cells. Moreover, there are diverse subtypesof stem cells according to CD markers on the cell mem-brane [59]. They can be also classified into disparatesubgroups. Different cell subtypes may play distinct rolesduring neurogenesis and functional reconstruction. Un-fortunately, it is remains to be identified for specific sub-types to give rise to precise roles and neuroprotectivemechanisms.
ConclusionIn summary, the beneficial effect was confirmed in ani-mal models with Alzheimer’s disease subsequent to thetransplantation of bone marrow mesenchymal stem cells.The therapeutic efficacy and safety were verified throughthe improvement of behavioral deficits and the allevi-ation of neuropathology. Multiple signal pathways in-volved therapeutic mechanisms, including neurogenesis,apoptosis, angiogenesis, immunomodulation, inflamma-tion and so on. Gene expression profiles might reflectrelative importance of above mechanisms in differentstages. The transplantation of BMMSCs could alter gene
expression levels. Differential expression of representa-tive genes could be used to establish statistical regressionmodel for the evaluation of therapeutic effect and theprediction of prognosis. There is a great possibility forthe clinical application of autologous BMMSCs in pa-tients with Alzheimer’s disease.
Supplementary informationSupplementary information accompanies this paper at https://doi.org/10.1186/s40035-020-00199-x.
Additional file 1: Table 1. Stem cell transplantation for the treatmentof Alzheimer’ disease. Present study utilized keywords “Alzheimer’sdisease” and “stem cell transplantation” to identify literature. Thesupplementary table further scrutinized relevant information of stem celltransplantation in different animal models.
AbbreviationAD: Alzheimer’s disease; BMMSCs: Bone marrow mesenchymal stem cells;Aβ: Amyloid β peptide; AChE: Cholinesterase; NMDA: N-methyl-D-asparticacid; iPSc: Induced pluripotent stem cell; MSCs: Mesenchymal stem cells;VEGF: Vascular endothelial growth factor; TNF-α: Tumor necrosis factor alpha;IL-1β,: Interleukin 1 beta; ECE: Endothelin converting enzyme; Iba-1: Inductionof brown adipocytes 1; AT8: ATPase subunit 8; APP: Amyloid beta precursorprotein; Y-maze: Y-maze alternation test; APP/PS1: Amyloid beta precursorprotein/ presenilin 1; 3xTg-AD: APP/PS1/Tau transgenic AD; ChAT: Cholineacetyltransferase; BDNF: Brain-derived neurotrophic factors; NGF: Nervegrowth factor; IGF-1: Insulin-like growth factor-1; FGF-2: Fibroblast growthfactor 2; Ang-1: Angiopoietin 1; EGF: Epidermal growth factor; hMSC: Humanmesenchymal stem cells; VEGFR2,: Vascular endothelial growth factorreceptor 2; NT-3: Neurotrophin-3; HGF: Hepatocyte growth factor; 2xTg-AD,: APP/PS1 transgenic AD; p38: P38 kinase; p53: Tumor protein p53;ER: Endoplasmic reticulum; ROS: Reactive oxygen species; IL-6: Interleukin 6;GFAP: Glial fibrillary acidic protein; iNOS: Inducible nitric oxide synthase; COX-2: Prostaglandin-endoperoxide synthase 2; TLR4: Toll like receptor 4;CD14: CD14 molecule; mGluR3: Metabotropic glutamate receptor 3;mGluR5: Metabotropic glutamate receptor 5; IFNγ: Interferon gamma; IL-2: Interleukin 2; IL-4: Interleukin 4; IL-5: Interleukin 5; IL-10: Interleukin 10; KC/GRO: Cxcl1 chemokine (C-X-C motif) ligand 1; ChIP: Chromatinimmunoprecipitation; Nrf2: Nuclear factor erythroid 2-related factor 2;PCA: Principle component analysis
AcknowledgmentsNot applicable
Authors’ contributionsCQ conceived and designed the manuscript. YL and KW were responsible fordata collection and statistical analysis. Additional data were provided by LB.YL, KW, LB, GS, YH and YL supported data analysis and interpretation. KWwrote the first draft that was revised by CQ and YL. All authors approved themanuscript.
FundingThis work was supported by grants Beijing Natural Science Foundation (No.517100), National Key Research and Development Project (No.2017YFA0105200) and CAMS Innovation Fund for Medical Sciences (CIFMS)(2016-I2M-2-006).
Availability of data and materialsAll generated or analyzed data are included in this published article.
Ethics approval and consent to participateNot applicable.
Consent for publicationNot applicable.
Qin et al. Translational Neurodegeneration (2020) 9:20 Page 18 of 20
Competing interestsThe authors have nothing to disclose.
Author details1Institute of Laboratory Animal Sciences, Chinese Academy of MedicalSciences & Comparative Medical Center, Peking Union Medical College,Beijing Engineering Research Center for Experimental Animal Models ofHuman Critical Diseases, 5 Panjiayuan Nanli St, Beijing 100021, China.2Department of International Medical Service & Department of Neurosurgery,Peking Union Medical College Hospital, Chinese Academy of MedicalSciences and Peking Union Medical College, Shuaifuyuan 1, Dong ChengDistrict, Beijing 100730, China.
Received: 30 December 2019 Accepted: 10 May 2020
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