Table Of ContentAdvances in Experimental Medicine and Biology 1298
Cell Biology and Translational Medicine
Kursad Turksen Editor
Cell Biology and
Translational
Medicine,
Volume 10
Stem Cells in Tissue Regeneration
Advances in Experimental Medicine
and Biology
Cell Biology and Translational Medicine
Volume 1298
SeriesEditor
KursadTurksen
Moreinformationaboutthissubseriesathttp://www.springer.com/series/15838
Kursad Turksen (Retired)
Editor
Cell Biology and
Translational Medicine,
Volume 10
Stem Cells in Tissue Regeneration
Editor
KursadTurksen(Retired)
OttawaHospitalResearchInstitute
Ottawa,ON,Canada
ISSN0065-2598 ISSN2214-8019 (electronic)
AdvancesinExperimentalMedicineandBiology
ISSN2522-090X ISSN2522-0918 (electronic)
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ISBN978-3-030-60011-2 ISBN978-3-030-60012-9 (eBook)
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Preface
InthisnextvolumeintheCellBiologyandTranslationalMedicineseries,we
continuetoexplorethepotentialutilityofstemcellsinregenerativemedicine.
Chapters in this volume cover advances and challenges in applications of
particular stem cell populations in a variety of diseases and conditions, and
certaingovernanceandpolicyissuesandoptions.
I remain very grateful to Gonzalo Cordova, the Associate Editor of the
seriesandacknowledgehiscontinuoussupport.
I would also like to acknowledge and thank Sara Germans-Huisman,
Assistant Editor, for her outstanding efforts in helping to get this volume to
theproductionstages.
A special thank you goes to Rathika Ramkumar and Anand
Venkatachalamfortheiroutstandingeffortsintheproductionofthisvolume.
Finally,sincerethankstothecontributorsnotonlyfortheirsupportofthe
series, but also for their insight and effort to capture both the advances and
remaining obstacles in their areas of research. I trust readers will find their
contributionsasinterestingandhelpfulasIhave.
Ottawa,ON,Canada KursadTurksen
Contents
ApelinReceptorSignalingDuringMesodermDevelopment. . . . . 1
DeryaSağraç,HaticeBurcuŞişli,andAyşegülDoğan
EpidermalStemCellsinRegenerativeMedicine. . . . . . . . . . . . . . 17
SimonaMartinotti,KatiaMarconato,GregorioBonsignore,
andEliaRanzato
TheCellularandMolecularPatternsInvolvedintheNeural
DifferentiationofAdipose-DerivedStemCells. . . . . . . . . . . . . . . . 23
AidaSelaru,SorinaDinescu,andMarietaCostache
BiomatricesforHeartRegenerationandCardiacTissue
ModellingInVitro. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
I.Kulvinskiene,R.Aldonyte,R.Miksiunas,A.Mobasheri,
andDaivaBironaite
Dentin-PulpTissueRegenerationApproachesinDentistry:
AnOverviewandCurrentTrends. . . . . . . . . . . . . . . . . . . . . . . . . 79
SonerSismanogluandP{narErcal
StemCellCultureUnderSimulatedMicrogravity. . . . . . . . . . . . . 105
MugeAnil-Inevi,OykuSarigil,MelikeKizilkaya,GulistanMese,
H.CumhurTekin,andEnginOzcivici
SmartPolymericSystems:ABiomedicalViewpoint. . . . . . . . . . . 133
AfsanehAdibfar,SamanehHosseini,andMohamadrezaBaghaban
Eslaminejad
AcuteLungInjury:DiseaseModellingandtheTherapeutic
PotentialofStemCells. . . . . . . .. . . . . . . . . . .. . . . . . . . . . .. . . . 149
JieLian,JuntangLin,NorashikinZakaria,andBadrulHisham
Yahaya
COVID-19andMesenchymalStemCellTreatment;
MysteryorNot. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
TuncAkkoc
PCDH19PathogenicVariantsinMales:Expanding
thePhenotypicSpectrum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
KristyL.Kolc,RikkeS.Møller,LynetteG.Sadleir,
IngridE.Scheffer,RamanKumar,andJozefGecz
Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
AdvExpMedBiol-CellBiologyandTranslationalMedicine(2020)10:1–15
https://doi.org/10.1007/5584_2020_567
#SpringerNatureSwitzerlandAG2020
Publishedonline:10July2020
Apelin Receptor Signaling During
Mesoderm Development
Derya Sağraç, Hatice Burcu Şişli, and Ayşegül Doğan
Abstract Determination of Aplnr signaling and
underlying mechanisms during mammalian
The Apelin receptor (Aplnr) is a G-protein
development might enable understanding of
coupledreceptorwhichhasawidebodydistri-
regulatory molecular mechanisms which not
butionandvariousphysiologicalrolesinclud-
only control embryonic development process
ing homeostasis, angiogenesis, cardiovascular
but also control tissue function and disease
and neuroendocrine function. Apelin and
pathologyintheadultbody.
Elabela are two peptide components of the
Aplnrsignalingandarecleavedtogivediffer-
Keywords
ent isoforms which are active in different
tissuesandorganisms. Apelin·Apelinreceptor·Development·
Aplnr signaling is related to several Elabela·Mesoderm
pathologies including obesity, heart disases
and cancer in the adult body. However, the
developmentalroleinmammalianembryogen-
Abbreviations
esis is crucial for migration of early cardiac
progenitors and cardiac function. Aplnr and
ACTH AdrenocorticotropicHormone
peptide components have a role in prolifera-
Aplnr ApelinReceptor
tion,differentiationandmovementofendoder-
AVP ArginineVasopressinHormone
malprecursors.AlthoughexpressionofAplnr
bFGF BasicFibroblastGrowthFactor
signaling is observed in endodermal lineages,
BMP-4 BoneMorphogenicProtein-4
the main function is the control of mesoderm
CD ClusterofDifferentiation
cell movement and cardiac development.
CNS CentralNervousSystem
Mutant of the Aplnr signaling components
DNA DeoxyribonucleicAcid
results in the malformations, defects and
Ela Elabela
lethality mainly due to the deformed heart
EMT Epithelial to Mesenchymal
function. This developmental role share simi-
Transition
larity with the cardiovascular functions in the
eNOS EndothelialNitricOxideSynthase
adultbody.
FGF FibroblastGrowthFactor
FOXF-1 ForkheadBoxF-1
D.Sağraç,H.B.Şişli,andA.Doğan(*)
GATA-4 GATABindingProtein-4
DepartmentofGeneticsandBioengineering,Facultyof
Engineering,YeditepeUniversity,Istanbul,Turkey
e-mail:[email protected]
1
2 D.Sağraçetal.
HAND-1 Heart-andNeuralCrestDerivatives- acids, including a signal peptide consisting of
ExpressedProtein-1 22aminoacidsatNterminal.Followingthepro-
hESCs HumanEmbryonicStemCells cesses of proteolytic cleavage and maturation,
HIV HumanImmunodeficiencyVirus three main isoforms of Apelin among various
HUVEC Human Umbilical Vein Endothelial others were characterized as 36 amino acids
Cells long Apelin-36, 17 amino acids long Apelin-17
IFN Interferon and 13 amino acids long Apelin-13, which is
IL Interleukin known as the most active form of the peptide
IRX-3 Iroquois-class Homeodomain Pro- (Tatemoto et al. 1998; Hosoya et al. 2000;
tein-3 Mesminetal.2011;Zhenetal.2013;Shinetal.
KO KnockOut 2018). Another endogenous ligand of Aplnr,
MEOX-1 MesenchymeHomeobox-1 which was named as Elabela (Ela), also called
mESCs MouseEmbryonicStemCells as Apela or Toddler, was revealed in zebrafish
mRNA MessengerRibonucleicAcid in 2013. This peptide hormone was reported to
MYH-6 MyosinHeavyChain-6 consist of 54 amino acids, including N terminal
Nkx-2.5 NK-2Homeobox-5 signalpeptide,andmakestheactiveformsofEla
OXY Oxytocin consisting of 32 amino acids (Ela-32), 21 amino
PAX-3 PairedBox-3 acids(Ela-21)and11aminoacids(Ela-11)(Chng
PHA Phytohemagglutinin etal.2013;Paulietal.2014a).
PVN ParaventricularNucleus AftertheactivationofheterotrimericAplnrby
siRNA SmallInterferingRibonucleicAcid its ligand, the signal is delivered to downstream
SON SupraopticNucleus pathwaystoregulatecellularevents.Gα subunit,
i
TBX-5 T-boxtranscriptionfactor-5 coupled to Aplnr, activates PI3K/Akt pathway
TCF-15 TranscriptionFactor-15 and PKC/Erk pathway and inhibits adenylyn
TDGF-1 Teratocarcinoma-Derived Growth cyclase, leading to inhibition of PKA by
Factor-1 downregulating CAMP level (Hamada et al.
TGF-β TransformingGrowthFactorBeta 2008; Masri et al. 2002; O’Carroll et al. 2013).
VSMCs VascularSmoothMuscleCells Ontheotherhand,Gα subunit,coupledtoAplnr,
q
leads to activation of PKC pathway and
upregulationofintracellularCa2+levelbyinduc-
ingPLCβactivation.Also,Aplnr,activatedunder
1 Apelin Receptor Signaling
mechanical stress, transduce signal in
Pathway
non-canonical pathway via β-arrestin to down-
stream pathways, which are yet to be elucidated
1.1 Components of Apelin Receptor
(Chapmanetal.2014;Murzaetal.2016).
Signaling
In 1993, Apelin receptor (Aplnr) was introduced
1.2 Tissue Distribution of Apelin
as a member of class A rhodopsin-like guanine
Receptor Signaling
nucleotide binding (G) protein coupled receptors
and the 377 amino acids long receptor was
Since the discovery of the Aplnr, its distribution
assumedorphanduetolackofitsspecifiedligand
in various tissues have been reported including
(O’Dowd et al. 1993). Apelin, the first identified
heart, endothelium, lung, brain, kidney, adipose
endogenous ligand of Aplnr, was obtained from
tissue andplasma (Edingeretal.1998;Novakov
theextractofbovinestomachin1998(Tatemoto
etal. 2015). Rat, mouse and human tissuedistri-
etal.1998).The9698bpApelingene,makingup
bution analysis of Aplnr showed that the highest
two introns and three exons, was revealed to
similarity of Aplnr expression was observed in
encode a prepropeptide, consisting of 77 amino
centralnervoussystem(CNS).Thedistributionof
ApelinReceptorSignalingDuringMesodermDevelopment 3
Aplnr mRNA in rat brain has shown that the human placenta, Ela is mainly expressed in
highest level of mRNA expression has been cytotrophoblasts until the first trimester (Wang
shown in hypothalamus (De Mota et al. 2000). et al. 2019; Georgiadou et al. 2019), while
Similarly, mouse Aplnr mRNA expression has Aplnr and Apelin are expressed in syncytiotro-
demonstrated a wide distribution in different phoblasts, cytotrophoblasts and endothelial cells
CNS regions such as hypothalamus, pituitary, of placenta as well as fetal vessels until birth
cerebral cortex, and spinal cord (Medhurst et al. (Eberlé et al. 2019). Similarly, Ela exists in
2003;Regardetal.2008).Thedetailedinvestiga- serum of pregnant mice during E7.5 to E12.5 of
tion of Aplnr distribution in mice revealed that gestation (Ho et al. 2017). In rats, Aplnr mRNA
Aplnrwasfoundatthelowestlevelintheposte- expression level was high in the lung and the
riorpituitarybutrelativelyhigherintheCNSand heartandwasnotobservedincolon,testes,stom-
in the anterior pituitary (Pope et al. 2012). Fur- achandliver(Hosoyaetal.2000;Medhurstetal.
thermore,thecorpuscallosumandthespinalcord 2003). Besides, the rat Aplnr mRNA was
express highest Aplnr mRNA level in human expressed in the kidney and in corpora lutea of
CNS (Edinger et al. 1998; Medhurst et al. 2003; ovary(Różyckaetal.2018).Also,Medhurstand
Matsumoto et al. 1996). Moreover, Choe and colleaguesreportedthatexceptforthymus,testis
colleagues reported that the human Aplnr andbladder,almostalltissuesofmiceexpressed
mRNAwashighlyexpressedinoligodendrocytes Aplnr mRNA and heart is the source of the
and was relatively low in astrocytes (Choe et al. highest level of Aplnr mRNA (Medhurst et al.
2000). The high Apelin mRNA levels in both 2003).
human and rodent CNS sections such as spinal Immunofluorescence analysis of human heart
cord(Popeetal.2012),hippocampus(O’Donnell has shown that proapelin peptide is expressed in
et al. 2007) and olfactory system (Cheng et al. theendocardialendotheliumandcardiomyocytes.
2012) may demonstrate that Aplnr pathway However,studiesabout Apelin peptideinvascu-
contributestothedevelopmentofnervoussystem lar smooth muscle cells (VSMCs) are controver-
in both human and rodent species. All these sial. It has been reported that vascular smooth
similaritiessuggestthatAplnranditsligandsare muscle cells expressed Apelin peptide (Li et al.
preserved among the high vertebrate throughout 2008; Luo et al. 2018) whereas, Mughal and
evolutionaryprocesses. Pitkin determined separately that Apelin peptide
The general distribution of Aplnr between isabsentinVSMCsandonlyexpressedinvessels
humanandrattissuesissimilar,butthissimilarity of patients with atherosclerosis (Mughal and
wasnotseenintheperipheralorgandistribution. O’Rourke2018;Pitkinetal.2010).Ontheother
In human tissues, Aplnr mRNA level is high in hand,Aplnrisdetectednotonlyinhumanvascu-
the spleen and relatively low in the small intes- lar endothelial cells andcardiomyocytes butalso
tine,colonmucosaandovaries.Moreover,Aplnr in smooth muscle cells (Folino et al. 2015;
mRNA has not been reported in bone marrow, Kidoya and Takakura 2012; Kleinz et al. 2005).
thymus, or epididymis tissues (The Human Pro- Thus,theelevatedlevelsofAplnrtranscriptsand
teinAtlasn.d.).Also,Aplnrlocusismethylatedin proteins might be a reason why lungs and the
undifferentiated human embryonic stem cells heart have a high vascularization network as
(hESCs) and therefore it is not present on the found in the spleen and placenta. During the
surface of hESCs. On the contrary, Ela is highly mouse embryonic development (E9.5–10.5),
expressed and required for the self-renewal of Aplnr mRNA is mainly found in the endothelial
hESCs (Ho et al. 2015). Subsequent studies layer of the vessels in the cardiovascular system
have reported that placenta has high level of (Kangetal.2013)andintheretinalvesselsafter
Aplnr expression, whereas low level of Aplnr birth (Saint-Geniez et al. 2002). Inductive
mRNA expression were found in heart, lung, neovascular roles of the Aplnr signaling have
stomach, liver, pancreas, intestines and kidneys been directed scientists to investigate the Aplnr-
(Medhurstetal.2003).Ithasbeenreportedthatin cancerrelationship.Aplnrsignalingisenrichedin
