REVIEW Open Access Transplantation of bone marrow Alzheimer … · Transplantation of bone marrow mesenchymal stem cells improves cognitive deficits and alleviates neuropathology

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

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* 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

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mailto:[email protected]

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


https://www.ncbi.nlm.nih.gov/pubmed/

https://www.ncbi.nlm.nih.gov/pubmed/

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


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

Jun;10

[5]:524–31

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

Mar

7;6:30

Harach,

2017

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

cedTN

Fa,IL-12p

70andIL-10.

Neurobiol

Aging

.2017

Mar;51:83–

96.

Kanamaru,

2015

Rand

omAPP/DAL101

mice,in

vivo

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

behavior

inAPP

mice.

Topreven

tne

urod

egen

erationandAβde

positio

n.BrainRes.2015

Apr

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


Table

1Transplantationof

BMMSC

sforthetreatm

entof

anim

almod

elswith

Alzhe


ords

“Alzhe

imer’sdisease”

and“stem


wereutilizedto

screen

database

PubM

ed,M

edline,andEm

base

respectively.Stud


thebo

nemarrow

mesen

chym

alstem

cells.Prim

arystud

ieswith

completedata

wereretained

inthecurren


(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,

2016

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.

CellTransplant.

2016;25[4]:687–

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.

2016

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


Table

1Transplantationof

BMMSC

sforthetreatm

entof

anim

almod

elswith

Alzhe


ords

“Alzhe

imer’sdisease”

and“stem


wereutilizedto

screen

database

PubM

ed,M

edline,andEm

base

respectively.Stud


thebo

nemarrow

mesen

chym

alstem

cells.Prim

arystud

ieswith

completedata

wereretained

inthecurren


(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


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


Table

2Gen


theinclud

edstud

iesin


nof

BMMSC

sforthetreatm

entof

anim

almod

elswith

Alzhe

imer’sdiseasewas

characterized

bysource

ofstem

cells,amou

ntof

stem


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


Table

2Gen


theinclud

edstud

iesin


nof

BMMSC

sforthetreatm

entof

anim

almod

elswith

Alzhe

imer’sdiseasewas

characterized

bysource

ofstem

cells,amou

ntof

stem


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


Table

2Gen


theinclud

edstud

iesin


nof

BMMSC

sforthetreatm

entof

anim

almod

elswith

Alzhe

imer’sdiseasewas

characterized

bysource

ofstem

cells,amou

ntof

stem


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.


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


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


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)


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


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


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


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.


https://doi.org/10.1186/s40035-020-00199-x

https://doi.org/10.1186/s40035-020-00199-x

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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