E ec s o cell cul u e
condi ions on
Mesenchymal S em
Cells and s a egies o
imp o e hei
he apeu ic applica ion
Más e Uni e si a io de Biología
A anzada: In es igación y Aplicación.
T abajo Fin de Más e
Lau a Olmedo Mo eno
CURSO ACADÉMICO 2019/2020
Uni e sidad de Se illa
Depa amen o de Biología Celula
Cen o Andaluz de Biología
Molecula (CABIMER)
Depa amen o de Te apia Celula y Regene ación
1
INDEX
1. In oduc ion………………………………………………………………………2
2. Changes induced in MSCs du ing cell cul u e……..…….………………..…….6
2.1. Mo phological al e a ions…………………………………………………..7
2.2. Modi ica ions in he ma ke s p o ile………………..……………………....7
2.3. Physiological pe u ba ions………………...………………………………..8
3. Consequences o he in i o MSCs modi ica ions o hei use in cell he apy….8
4. S a egies o po en ia e he he apeu ic p ope ies o MSCs……………..…...…..10
4.1. Bioma e ials…………………………………………………………………13
4.2. Sec e ome…..………………………………………………………………...14
5. Conclusions and u u e p ospec s..……………………………………………..…15
6. Acknowledgmen …..…………………………………………………………….…16
7. Bibliog aphy……..………………………………………………….……………...17
2
E ec s o cell cul u e condi ions on
Mesenchymal S em Cells and
s a egies o imp o e hei
he apeu ic applica ion.
1. In oduc ion.
Mesenchymal S em Cells (MSCs) we e
disco e ed in 1974 by F iedens ein who isola ed
hem om bone ma ow and desc ibed hei
mo phology in i o as ib oblas -like spindle
shaped 1. MSCs a e mul ipo en cells ha can be
ob ained om a ious issues, including placen a 2,
umbilical co d 3, amnio ic luid 4, bone ma ow 5,
muscle 6, compac bone 7 , syno ial luid 8, a 9,
den al pulp 10, hai ollicles 11 and blood 12. MSCs
ha e wo p incipal cha ac e is ics: sel - enewal and
mul ilineage di e en ia ion 13,14. Sel - enewal
conce ns o he MSCs abili y o gene a e iden ical
copies o hemsel es, while mul ilineage
di e en ia ion e e s o hei capaci y o gi e ise o
cells in o he mesode mal, ec ode mal and
endode mal lineages 15. Gi en ha MSCs show
he e ogeneous quali ies depending on hei issue
sou ce, he In e na ional Socie y o Cellula
The apy (ISCT) has es ablished h ee minimal
s anda ds o de ine MSCs: hey adhe e o plas ic in
s anda d condi ions, hey exp ess speci ic ma ke s
(posi i e in an igens like CD73, CD105 and CD90
while nega i e o CD45, CD34, CD14 o CD11b,
CD79α o CD19 and HLA-DR) and hey ha e he
abili y o di e en ia e in o adipocy es,
chond ocy es, and os eoblas in speci ic cul u e
condi ions 16.
As men ioned abo e, he sel - enewal and
mul ilineage di e en ia ion p ope ies o MSCs a e
in e es ing poin s o basic and ansla ional
in es iga ion, bu also o clinical s udies on
se e al pa hologies, such as ca diology, neu ology,
The bene icial cha ac e is ics o
Mesenchymal S em Cells (MSCs) allow us o
use hem in ansla ional and clinical esea ch.
Recen s udies ha e shown bene icial e ec s
o MSCs o he ea men o se e al
pa hologies, such as e inal degene a i e
diso de s, neu odegene a i e diseases,
diabe es, myoca dial in a c ion, skin
p oblems, bone, and li e diso de s, among
o he s. These cells a e ound in a ious
issues, bu hey appea in low quan i ies,
which makes necessa y o expand MSCs in
i o be o e applica ion. Howe e , in i o
manipula ion has no iceable consequences on
MSCs mo phology, physiology and unc ion.
The exp ession p o ile o molecules and
ecep o s o MSCs unde goes d as ic changes
du ing cell cul u e. These al e a ions gi e ise
o di e en esul s when MSCs a e used in
cell-based he apies, such as di e en immune
esponse in he hos . In his o e iew, ou
main aim will be o analyze he di e en
modi ica ions o MSCs du ing cell cul u e,
and how hese changes al e hei he apeu ic
p ope ies a e ansplan a ion. In addi ion,
we will discuss po en ial s a egies o imp o e
he he apeu ic e ec s o MSCs.
3
o hopaedics, among o he s a eas 17–20, as hey
p omo e issue epai and egene a ion (Figu e 1
and Table 1) 21–23. Fo ins ance, MSC-based
he apies a e gene a ing inc easing in e es in he
cu en pandemic si ua ion wi h he Co ona i us
disease 2019 (COVID-19) caused by he se e e
acu e espi a o y synd ome co ona i us 2 (SARS-
CoV-2) in ec ion. Se e al esea ch g oups ha e
epo ed he bene icial e ec s o MSC applica ion
o pulmona y complica ions o COVID pa ien s.
She y and collabo a ion ha e demons a ed ha
in a enous applica ion o human MSCs (hMSCs)
p oduced imp o emen s in 7 pa ien s wi h COVID-
19 pneumonia o 14 days compa ed o 3 placebo-
ea ed pa ien s. I was sugges ed ha his could be
due o educed hype ac i a ion o he immune
sys em and inc eased endogenous epai due o he
pa ac ine e ec s o MSCs 24. They obse ed ha
he adminis a ion o hMSCs o igina ed changes in
in lamma o y ma ke s, such as a signi ican
inc ease in IL-10 and a dec ease in TNF-α. In
addi ion, compu ed omog aphy images showed
ha MSCs educed he lesion a ea in he lungs a
he end o he ea men in a c i ically ill pa ien
wi h COVID-19 24,25.
Fu he mo e, MSCs possess in insic
opism owa d damaged issues ha is media ed by
chemo axis signalling pa hways 13, being he C-X-
C mo i chemokine ligand 12 (CXCL12) – C-X-C
chemokine ecep o ype 4 (CXCR4) axis one o
he key playe s 26. The CXCL12 is ound in
di e en issues and is eleased in high
concen a ions du ing inju y 27. Impo an ly, i has
been demons a ed ha MSCs exp ess he CXCR4,
one o he ecep o s o which CXCL12 binds o
media e mig a ion owa ds inju y issues 28,29.
The low quan i y o MSCs in hei mul iple
sou ces c ea es he need o expand hem in i o o
ob ain su icien cells o he apeu ic applica ion 30.
MSCs cul u es a e no subjec o s anda dized
p o ocols. The e a e unequal cul u e media and
di e en me hods o isola e he cells, such as he
FIGURA 1. Rep esen a ion o some MSCs he apeu ic
applica ions. MSCs as ea men in pa hological condi ions: li e
diso de s (e.g. ci hosis), au oimmune diseases (e.g. C ohn's
disease), skin p oblems (e.g. skin ulce s), bone diso de s (e.g.
impe ec os eogenesis and os eonec osis), hea diseases (e.g.
myoca dial in a c ion and ca diac ischemia), pulmona y pa hologies
(e.g. pulmona y COVID-19 in ec ion) and neu ological damage
(e.g. Pa kinson’s disease and spinal co d inju y).
explan cul u e me hod 31,32 o he enzyma ic
me hod 32,33. In addi ion, MSCs can be expanded
4
on di e en plas ic su aces, which ha e peculia
hyd ophobici y cha ac e is ics a ec ing cell
g ow h 14,34. The lack o common ules gene a es a
huge a ie y o esul s when MSCs a e used in p e-
clinical he apies 35. I is sugges ed ha al e a ions
in he apies could be associa ed wi h modi ica ions
du ing MSC cul u e, such as dis inc mo phologies,
di e en memb ane ecep o s and modi ica ions in
hei sec e ome 30,36.
The majo goal o his e iew is o p o ide
a gene al o e iew abou he modi ica ions
occu ing in cul u ed MSCs ha may lead o in e -
labo a o y a iabili y obse ed when wo king wi h
his cell ype. In addi ion, we discuss al e na i es in
i o condi ions ha may help o ob ain mo e
e ec i e MSCs o cell-based he apies. The
signi icance o his e iew lies in he impo ance o
MSCs as he apeu ic ool o he ea men o a
wide ange o pa hologies due o hei bene i s on
issue epai and egene a ion.

5
CLINICALTRIALS
IDENTIFIER
PATHOLOGY
DISEASE NAME
TIME
N
MSC
TYPE
ADMINISTRATION
PHASE
COUNTRY
NCT0042013437
Li e
Ci hosis
24 wk
30
BM-
hMSC
In a enous
I/II
I an
NCT0122049238
Li e
Ci hosis
48 wk
45
UC-
hMSC
In a enous
I/II
China
NCT0145433639
Li e
Li e ib osis
48 wk
3
BM-
hMCS
In a enous
I
I an
NCT0159120040
Li e
Alcoholic Ci hosis
96 wk
40
BM-
hMCS
In aa e ial
II
India
NCT0115765041
Au oimmune
C ohn's disease
144 wk
15
Ad-
hMSC
Unknown
I/II
Spain
NCT0165976242
Au oimmune
C ohn’s disease
48 wk
16
BM-
hMSC
In a enous
I
EE. UU.
NCT0377833343
Au oimmune
Mul iple Scle osis
48 wk
7
BM-
hMSC
In a enous
I
Sweden
NCT0187362544
Au oimmune
Rheuma oid A h i is
48 wk
60
BM-
hMSC
In aa icula
II/III
I an
NCT0282439345
Skin
Ch onic au oimmune
u ica ia
48 wk
10
Ad-
hMSC
In a enous
I
Tu key
NCT0388720846
Skin
Cu is laxa senile and
sca s
27 wk
100
Ad-
hMSC
Subcu aneus
I/II
Poland
NCT0268572247
Skin
Skin ulce s
24 wk
20
UC-
hMSC
Topic
I
China
NCT0249165848
Skin
Vulga Pso iasis
48 wk
30
UC-
hMSC
In a enous
I/II
China
NCT0151369449
Bone
In e e eb al
Degene a i e Disc
disease
24 wk
15
BM-
hMSC
Implan a ion
I/II
Spain
NCT0160538350
Bone
Os eonec osis o he
Femo al Head
48 wk
23
BM-
hMSC
Implan a ion
I/II
Spain
NCT0217288551
Bone
Os eogenesis impe ec a
96 wk
2
MSC
In a enous
I
Spain
NCT0018691452
Bone
Os eodysplasia
Unkno
wn
8
BM-
hMCS
In a enous
I
EE. UU.
NCT0173977753
Hea
Ca diopa hy
48 wk
30
UC-
hMSC
In a enous
I/II
Chile
NCT0144903254
Hea
Ch onic myoca dial
ischemia
24 wk
60
Ad-
hMSC
In amyoca dial
II
Denma k
NCT0238772355
Hea
Se e e Hea Failu e
24 wk
10
Ad-
hMSC
In amyoca dial
I
Denma k
NCT0246738756
Hea
Non-Ischemic Hea
Failu e
64 wk
23
BM-
hMSC
In a enous
II
EE. UU.
NCT0436632357
Pulmona y
COVID-19
48 wk
26
Ad-
hMSC
In a enous
I/II
Spain
NCT0428810258
Pulmona y
COVID-19
12 wk
90
UC-
hMSC
In a enous
II
China
NCT0259483959
Pulmona y
P og essi e In e s i ial
Lung Disease
48 wk
20
BM-
hMSC
In a enous
I/II
Russia
NCT0191982760
Pulmona y
Idiopa hic pulmona y
ib osis
48 wk
17
BM-
hMSC
Endob onchial
I
Spain
NCT0266806861
Pulmona y
Pneumoconiosis
24 wk
80
UC-
hMSC
La age
I
China
NCT0105647162
Neu ological
Seconda y P og essi e
Mul iple Scle osis
48 wk
30
Ad-
hMSC
In a enous
I/II
Spain
NCT0261116763
Neu ological
damage
Idiopa hic Pa kinson’s
Disease
52 wk
20
BM-
hMSC
In a enous
I/II
EE. UU.
NCT0132510364
Neu ological
Spinal Co d Inju y
24 wk
14
BM-
hMSC
In alesional
I
B azil
NCT0224967665
Neu ological
Neu omyeli is Op ica
48 wk
15
BM-
hMSC
In a enous
II
China
*Ab e ia ions: Mesenchymal S em Cells (MSC), Bone Ma ow human Mesenchymal S em Cells (BM-hMSC), Umbilical Co d human
Mesenchymal S em Cells (UC-hMSC), Adipose de i ed human Mesenchymal S em Cells (Ad-hMSC).
TABLE 1. Clinical ials o Mesenchymal S em Cells he apy o di e en ypes o pa hologies.
6
2. Changes induced in MSCs du ing cell
cul u e.
Each s ep in cell cul u e is pa allel o MSCs
mo phological diso de s, changes in hei ma ke s
p o ile and physiological pe u ba ions.
Fu he mo e, he al e a ions a e de e mined by
many a iable condi ions such as dono age 66,
issue sou ce 67, passages numbe 68, oxygen le els
69 o medium composi ion 70 (Figu e 2). Zaim e al.
demons a ed ha dono age a ec s di e en ia ion
o bone ma ow hMSCs (BM-hMSCs). BM-
hMSCs om child en be ween 0-12 yea s old
showed mo e adipogenic, neu ogenic and
os eogenic di e en ia ion po en ial and mo e
p oli e a ion han BM-hMSCs om adul s be ween
25-50 yea s old o om elde ly o e 60 yea s old
in he same passage 66 . Ano he s udy
demons a ed ha he sou ce o MSCs a ec s la e
di e en ia ion. The use o BM-hMSCs p esen ed a
g ea e di e en ia ion po en ial o os eogenic cells,
while MSCs de i ed om adipose issue (Ad-
hMSCs) e ealed a g ea e di e en ia ion po en ial
o adipogenic cells 67. Fu he mo e, he passage
numbe o he cell cul u e is ano he signi ican
poin . Tan and co-wo ke s showed ha su ace
ma ke s o bo ine syno ial memb ane-de i ed
MSCs (SD-MSCs) change in passages (P) 4 68.
The e was an inc ease in he exp ession o CD73
be ween P1 and P2, whe eas CD73 le els had a
signi ican educ ion in P3. In his epo , hey
sugges ed ha he dec ease on CD73 exp ession
could be esponsible o he changes in mig a ion.
When hey applied a di ec cu en elec ic ield
(DC-EF), 85% o cells mo ed owa ds he posi i e
pole in P1, while a 75% o cells mig a ed owa ds
he nega i e pole in P4. This a ia ions in he
di ec ion o SD-MSCs mig a ion co ela ed wi h
he changes in CD73 exp ession 68. All hese
in es iga ions e idence how he cell cul u e
condi ions in luence SD-MSCs. Th oughou his
sec ion we will ocus on desc ibing mo phological
al e a ions, changes in he ma ke s p o ile and
physiological pe u ba ions ha MSCs unde go
du ing cul u e.
FIGURE 2. Rep esen a ion o in luencing ac o s on
mo phological and physiological cha ac e is ics, in addi ion o
su ace ma ke s. Fac o s esponsible o changes in cul u ed MSCs
include issue o igin, dono age, medium and supplemen s, passage
numbe , and incuba ion condi ions such as oxygen le els. All hese
pa ame e s cause mo phological al e a ions in MSCs, which change
om a spindle o m o a la ened o m. Mo eo e , he e a e changes
in su ace ma ke s such as highe exp ession o CD146, CD105 and
CD271 and a lowe exp ession o CD34 and CD90. Physiological
changes include he gene a ion o ee adicals ha di ec ly a ec
he amino acid p o ile and lipid pe oxida ion. Abb e ia ions: Clus e
o Di e en ia ion 146 (CD146), Clus e o Di e en ia ion 105
(CD105), Clus e o Di e en ia ion 271 (CD271), Clus e o
Di e en ia ion 34 (CD34), Clus e o Di e en ia ion 90 (CD90),
Reac i e oxygen species (ROS).
7
2.1 Mo phological al e a ions.
The MSCs no mally ha e a sphe ical o m in
i o 71. When MSCs a e seeded as adhe en cells,
hey usually acqui e spindle o m 72. Howe e , he
MSCs mo phology can change in esponse o
medium supplemen s 73,74, passage numbe 75
and/o oxygen condi ions 76. One o he mos
common supplemen s used in cell cul u e is e al
cal se um (FCS) as a nu i ion sou ce, p o ein and
g ow h ac o s 74. Chase e al., demons a ed ha
he use o FCS a ec s MSCs mo phology. Using
ligh mic oscopy, hey obse ed ha BM-hMSCs
cul u ed in a medium wi h FCS had a la ened
shape, while BM-hMSCs cul u ed in a se um- ee
medium had hei cha ac e is ic spindle
mo phology 73. Ano he in luen ial ac o a ec ing
cell mo phology is he passage numbe , which
e e s o MSC aging. A s udy g ew BM-hMSCs in
wo di e en media, Minimum Essen ial Medium
Eagle - Alpha Modi ica ion (α-MEM) and
Dulbecco's Modi ied Eagle Medium (DMEM), and
obse ed ha MSCs acqui ed a ypical and la
shapes by P6 75. In addi ion o medium supplemen s
and aging, ano he ac o o conside is he oxygen
concen a ion. Holzwa h's eam demons a ed how
low oxygen le els and dono a ec cell
mo phology. They cul u ed BM-hMSCs om 10
dono s unde wo condi ions 21% and 1% oxygen.
When examining he cells unde he ligh
mic oscope, hey obse ed ha BM-hMSCs om
mos dono s showed he same spindle mo phology
and all he cells appea ed as a monolaye a 21%
and 1% oxygen a e one o h ee weeks.
Con e sely, BM-hMSCs om 7 dono s did no
adop he ypical spindle shape and hey did no
c ea e monolaye s a 1% oxygen in he wo
measu es o ime 76. Examples such as hese
demons a e ha MSCs unde go dynamic changes.
The ques ion is, which a e he molecula
mechanisms unde lying he mo phological
al e a ions?
2.2. Modi ica ions in he ma ke s p o ile.
The e is no a se o de ini i e ma ke s
which de ine a unique pheno ype in MSCs due o
hei a iabili y (o igin, condi ions, age, isola ion
me hod). Howe e , he e a e common ecep o s o
g ow h ac o s, chemokines, cy okines, ma ix
p o eins, cell-cell ecep o s and inmuno-
modula ing ecep o s 26. Mos memb ane ma ke s
ha e been de e mined in i o, hence he e is a
limi ed knowledge o hei p ope ies in i o 77.
These an igens a e no exclusi e o MSCs as
Sch age e al. showed in hei s udy by
demons a ing ha CD46 is also an endo helial
ma ke (an ibody ME-9 1) 78. Mo eo e , MSCs can
ha e a di e en exp ession ecep o ac ion
acco ding o hei sou ce, o example S o-1
appea s in BM-hMSCs bu he e is a lack o his
an igen in Ad-hMSCs 79. As p e iously discussed,
he ISCT indica ed ha he posi i e MSCs su ace
ma ke s a e CD73, CD90 and CD105.
Fu he mo e, Maleki e al. compa ed hMSCs om
o a y, es is, hWJ-MSCs and hai ollicle, and hey
ound ha all hese hMSCs also sha ed S o-1,
CD44, CD166 and CD106 80. On he o he hand,
Ly and co-wo ke s in hei e iew added h ee
epe i i e memb ane ma ke s, e.g. S age-speci ic
8
Emb yonic An igen-4 (SSEA4), CD271 and CD46
81. Se e al in es iga ions ha e demons a ed ha
he ma ke s p o ile changes when MSCs a e
cul u ed in i o. Fo example, B aun and
collabo a ion ha e shown ha clus e s o
di e en ia ion, such as CD146, CD105 and CD271
o ad en i ial s omal cells (AST), we e o e -
exp essed a e ou days in i o. Howe e , CD34
had less exp ession be ween he ou h and
six h day 72. Ano he example o ma ke ha
changes in i o was iden i ied by Yu e al., who
demons a ed high exp ession o S o-1 in den al
pulp s em cells (DPSCs) o a and human a P9, as
compa ed o P1 82.
Mo eo e , i has been shown ha BM-
hMSCs seeded in a 3D algina e cul u e o unde
mechanical s imula ion p esen low CD90
exp ession 83,84. This p o ein is in ol ed in he
egula ion o cell-cell con ac and cell-ma ix
junc ions. The lack o his ma ke has
consequences such as impai ed cell mig a ion,
a ec ed ac in ilamen s and loss o cell-cell and
cell-ma ix junc ions, which could al e cell
mo phology 85.
2.3. Physiological pe u ba ions.
Cell cul u e condi ions, such as oxygen
concen a ion, passages, supplemen s, con ibu e o
main ain cellula homeos asis. The oxygen le els
applied in cul u e a e usually hose ha we ha e in
he a mosphe e (20%), bu his poin is
ques ionable since cells in he body a e indeed
exposed o 2-7% oxygen. This is an impo an issue
because high oxygen le els gene a e me abolism
pe u ba ions and oxida i e s ess, gene a ing one
o he mos no o ious consequences ha is he
inc ease o he adical oxida i e species (ROS)
concen a ion, one o he ypical senescence ma ks
in cul u es cells. In addi ion o he ac i a ion o he
senescence p ocess, high oxygen le els educes
cell su i al and p oli e a ion, which is a
bo leneck o use MSC in he apy 86. ROS a e small
molecules usually gene a ed in mi ochond ia and
hey can eac easily due o hei ee elec on
(supe oxide anions [O2-], hyd ogen pe oxide
[H2O2] and hyd oxyl adicals [OH-]). ROS can
coo dina e di e en cell le els because o i s abili y
o egula ing edox s a e o p o eins and lipids,
among o he s, gene a ing cellula
pe u ba ions87. Shin e al. demons a ed ha
inc eased ROS le els ela e o changes in amino
acid p o ile and lipid pe oxida ion. BM-hMSCs
wi h high ROS le els due o se um s a a ion
exhibi ed al e a ion o amino acids like lysine,
y osine, and γ-aminobu y ic acid (GABA)
accumula ion. A he same ime, he e is a gain o
lipid pe oxida ion gi ing ise o a dec eased
memb ane pe meabili y and luency 88.
3. Consequences o he in i o MSCs
modi ica ions o hei use in cell
he apy.
The changes occu ing in cul u ed MSCs,
such as mo phological al e a ions, he di e en
p o ile o su ace ma ke s and he physiological
modi ica ions, limi hei widely use in clinical
applica ion. Fo example, he inc eased size o
MSCs in i o in luences hei he apeu ic e ec
15
sec e ome induced beha iou imp o emen s in i o
h ough Ro a od and S ai case es s (Figu e 5) 146.
5. Conclusions and u u e p ospec s.
Th oughou his e iew, h ee main poin s
ha e been add essed: 1) changes induced in MSCs
du ing cell cul u e, 2) how hese changes a ec he
use o MSC-based he apies and 3) s a egies o
imp o e he he apeu ic e ec s o MSCs. MSCs
ha e g ea po en ial o cell he apy and
egene a i e medicine due o hei easy ex ac ion
om mul iple sou ces 147, hei abili y o mig a e o
damaged issues 148,149, hei mul ilineage
di e en ia ion 150,151, hei sel - enewal 152, and he
lack o e hical conce ns 153. All hese ad an ages
ein o ce he use o MSCs o ea se e al diseases,
such as myoca dial in a c ion 154,155, ca diac
ischemia 156,157, neu ological diso de s 100,158,159,
impe ec os eogenesis 160, o mo e ecen ly he
COVID-19 24,25,126,161,162.
La es ad ances in his esea ch a ea hold
p omises o he applica ions o MSCs in
egene a i e medicine. Howe e , MSC-based
he apies s ill p esen ba ie s ha need o be
o e come. In conclusion, all he p ocedu es ha a e
ca ied ou du ing cell cul u e gene a e
mo phological and physiological modi ica ions in
MSCs ha di ec ly a ec hei clinical applica ion.
Mo eo e , he lack o a unanimous p o ocol
o igina es disc epancies in he esul s ob ained by
esea che s, and, in many cases, his makes
di icul o ep oduce he expe imen s. The e o e, i
is impo an ha he in es iga o s make he e o
o uni y p o ocols o ob ain conclusions ha a e
mo e obus . On he o he hand, s a egies a e being
implemen ed o enhance he he apeu ic p ope ies
o MSCs, bu he e is s ill much po en ial o be
imp o ed. The scien i ic communi y should u he
in es iga e how o de elop s a egies ha
signi ican ly inc ease he e icacy o MSC-based
he apies in a sa e y way, allowing he ansla ion
o humans.
FIGURE 5. Mo o coo dina ion and balance, and spa ial memo y and
lea ning some beha iou al es s. On he le , i is ep esen ed wo
beha io al es s ela ed o mo o coo dina ion and balance. S ai case es .
In his es , wo s ai s a e used wi h eed in each s ep on bo h sides o he
anspa en con aine , and be ween hem a pla o m whe e he animal is
placed. I can be measu ed he e ec i eness and he dis ance eached by
o elimbs depending on he eed consumed and obse a ions. Ro a od
es . This me hodology consis s o a o a ing cylinde wi h modi iable
speed. Roden s a e place s on he od, and i can be measu ed hei
esis ance, s eng h, balance, and coo dina ion. On he igh , he e is a es
connec ed wi h spa ial memo y and lea ning. Maze Mo is es . In his
es , oden s a e placed in a con aine o wa e in which he e is a pla o m
ha can be iewed by indi iduals. A e se e al epe i ions, he pla o m
is hidden o check he memo y and lea ning o oden s. The leng h o he
ou e, he ime spen , he analysis o di e en quad an s can be measu ed.

16
As a c i ical analysis, he communica ion
be ween he di e en esea ch eams is equi ed o
he uni ica ion o p o ocols. The main obs acle o
achie e his poin is he lack o anspa ency in he
publica ions, which o en do no speci y all he
in o ma ion in a de ailed manne o e en he
ob ained esul s. A uni e sal p o ocol o cul u e
MSCs should include an e ec i e isola ion
me hod, he use o a speci ic cell cul u e essel, he
de ailed media composi ion (including eagen
e e ences) and he s anda dized cul u e condi ions,
such as oxygen le els. Fu he mo e, he ype o
MSCs mus also be aken in o accoun since i has
been shown ha MSC p ope ies may a y be ween
sou ce issues. Apa om ha , he expe imen al
s a egies o imp o e he he apeu ic p ope ies o
MSCs a e based on h ee main poin s: he
minimiza ion o he changes ha MSCs unde go in
i o, he use o bioma e ials o a o MSCs
applica ion, and he u iliza ion o MSC sec e ome.
The choice o he mos app op ia ed s a egy will
depend on he speci ic aim o he he apy. Fo
ins ance, he use o MSCs combined wi h
bioma e ials o acili a e hei eng a men and
su i al, would be an app op ia ed op ion when
doing local cell adminis a ion (e.g., in ac anial
injec ions). Howe e , when a sys emic
adminis a ion is used in allogenic he apies, he
MSC-de i ed sec e ome could be an in e es ing
choice since i has a low isk o ejec ion, as well
as a educed umo igenic po en ial, unlike li e
cells. In conclusion, he scien i ic communi y
should make e o s in syne gy o seek solu ions o
he a o emen ioned issues, b inging new
pe spec i es o a pe sonalized medicine ha will
allow us o success ully ea he speci ic
pa hological condi ion o each pa ien .
6. Acknowledgmen .
We would like o acknowledge he ‘Mas e 's
Deg ee in Ad anced Biology: Resea ch and
Applica ion’ o he Uni e si y o Se ille. The esea ch
g oup o S em Cells and T ansla ional Neu ology o
CABIMER ecei es he suppo o he Andalusian
Regional Minis y o Heal h (PI-0272-2017), he
Ins i u e o Heal h Ca los III co- unded by Fondos
FEDER (CP19/00046), and he c owd unding pla o m
PRECIPITA o he Spanish Founda ion o Science and
Technology (2018-000237).
17
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