Stem Cells

416 Pages·2006·11.36 MB·English

by  H. Darr

Handbook of Experimental Pharmacology
Volume 174
Editor-in-Chief
F.Hofmann,München
EditorialBoard
J.Beavo,Seattle,WA
D.Ganten,Berlin
M.Michel,Amsterdam
C.Page,London
W.Rosenthal,Berlin
AnnaM W. obus KennethR B. oheler
(cid:127)
Editors
StemC ells
Contributors

M.R. Alison, C. Badorff, N. Benvenisty, B. Berninger, N. Beyer Nardi, A. Branzi,
M. Brittan, P. Budde, G.A. Colvin, H. Darr, C. Denning, S. Dimmeler, F. Dönmez,
M.S. Dooner, R. Enseñat-Waser, L.J. Field, M. Götz, G. Grenier, M. Hack,
R. Harris, J. Jones, T. León-Quinto, M. Lovell, C. Mummery, R. Passier, G. Paul,
P.J. Quesenberry, J.A. Reig, E. Roche, S. Rose-John, M. Rubart, M.A. Rudnicki,
H. Sauer, L. da Silva Meirelles, B. Soria, N.D. Theise, C. Ventura, M. Wartenberg,
G. Weitzer, N.A. Wright

123
Professor Kenneth R. Boheler, PhD
Anna M. Wobus, PhD Investigator
In Vitro Differentiation Group Laboratory of Cardiovascular Science
Dept. of Cytogenetics Gerontology Research Program
Leibnitz Institute of Plant Genetics National Institute on Aging, NIH
and Crop Plant Research (IPK) 5600 Nathan Shock Drive
Corrensstr. 3 Baltimore, MD 21224
D-06466 Gatersleben U SA
Germany [email protected]
[email protected]

ISBN:978-3-540-77854-7
HandbookofExperimentalPharmacologyISSN0171-2004
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(cid:1)c Springer-VerlagBerlinHeidelberg2008
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Preface
Significant advances in stem cell research and their potentials for therapeu-
tic applications have attracted the attention of the scientific community and
capturedtheimaginationofsocietyasawhole.Notsolongago,thestudyof
moststemcells,otherthanthosethatregeneratedthehaematopoieticsystem,
wasratherobscureandlimitedtoarelativelysmallnumberofresearchersand
laboratories. The uproar over stem cells really began in 1998 with the suc-
cessful derivation of pluripotent human embryonic stem (ES) cells by James
Thomsonandco-workers.Thisbreakthroughandthesubsequentgeneration
of specialized human cells in vitro led to a paradigm shift within the scien-
tificcommunity,whichtransformedthisspecializedendeavourfromatopicof
scientificinteresttoalineofinvestigationwiththepotentialtogeneratecellsca-
pableoftreatingseriousailments,includingdiabetes,cardiovasculardiseases
andneurodegenerativedisorders.Thusthedawnofregenerativemedicinehas
spawnedfromthesomewhatesotericstudyofstemcells.
Since1998,extensiveresearchendeavourshavebeendevotedtothestudyof
bothembryonicandadultstemcells.Earlyreportssuggestedthatadultstem
cellshadahigherplasticitythanpreviouslybelieved,perhapsevencomparable
withthatdemonstratedbyembryonicstemcells,butseveralobservationsof
the so-called transdifferentiation capacity and plasticity of adult stem cells
havenotbeenrepeated.Thesereports,however,encouragedon-goingdebates
about the capacity of adult versus embryonic stem cells and their potential
useinregenerativemedicine.Althoughattimescontroversial,theseresearch
effortsledtoabetter,althoughstilllimited,understandingofstemcellswith
respecttotheiridentification,isolation,anddevelopmentalcapacities.
Importantly, stem cells do not represent static entities that do not differ
between embryosand adults. In fact, embryonic stem cellsin early embryos
represent basic units of life in higher organisms, while adult stem cells in
somatic tissues represent cellular stores capable of regenerating tissue and
maintainingorganfunctions.Regardlessofthesedifferencesinpotential,all
stem cells derived from the embryo or adult are characterized by unique
propertiesthatpermitaccuratecellcopyinginvivoinaprocesstermedself-
renewal. Additionally, all stem cells retain the capacity to differentiate into
more mature cell types. It is the degree of self-renewal and differentiation
potentialthatdiffersamongthevariousstemcellpopulationsandcelllines.
VI Preface
These common traits have led to vigorous scientific and ethical debates,
whicharelikelytopersistformanyyears.Addingtothescientificandethical
dilemmassurroundingstemcellswasthesuccessfultransferofhumansomatic
nucleiintofertilizedhumanoocytesinaprocessknownasnucleartransfer(nt),
andthecreationthroughaprocessknownastherapeuticcloningofhumanntES
celllinesbySouthKoreanscientistsin2004.Thishasrecently(May2005)been
followed by the efficient generation of patient-derived ntES cell lines, which
willlikelyinfluencetheethicaldebateandgrowthofstemcellresearchinthe
future.Forthefirsttimeandasaconsequenceofthesedevelopments,stemcell
research coupled with molecular biology and tissue engineering techniques
constituteapotentialbasisforrationaltherapeuticstrategiesofregenerative
medicine.Moreover,humanES-derivedsomaticcellsmayrepresentinnovative
pharmacologicaltoolsfordrugscreening,theidentificationofnewdrugtargets
and cell-based compound delivery systems. Finally, these cells may facilitate
anunravellingofthehithertoinaccessibleparadigmsofhumandevelopment.
In2004,duringoneofthemostcontentiousperiodsofdebatewithrespect
to the scientific, ethical and legal issues of stem cell research, the Board of
Editors at the Handbook of Experimental Pharmacology approached us to
editaspecialvolumedevotedtostemcells.Theideawasattractivebecauseit
wouldgiveusthechancetosolicitandcombineinonevolumeabodyofwork
encompassingtherapidlyadvancingdevelopmentsofstemcellresearchwith
astate-of-the-artviewofstemcellbiology.Weinvitedleadingexpertsinthe
fields of embryonic and adult stem cells to submit chapters for this volume,
andalthoughitprovedimpossibleforeveryonetosubmitamanuscriptwithin
thedesignatedtimeframe,thisvolumeisacompilationoftheirandourefforts
toassembleanoverviewoftheimportantaspectsandissuessurroundingstem
cellresearch.
The first two chapters are dedicated to molecular mechanisms regulating
self-renewalanddifferentiationofhuman(DarrandBenvenisty)andmouse
(Weitzer) ES cells. In the latter, the author describes how ES cell research,
throughtheinvitrouseoftheembryoidbodymodel,reflectsearlydevelop-
mentalprocessesinvivo(Weitzer),andinthefollowingcontribution,Warten-
berg et al. demonstrate how the in vitro model system can be employed for
the study of angiogenesis and tumour-induced angiogenesis. The following
chaptersreviewthepresentstateofknowledgewithrespecttomouseandhu-
manEScell-derivedcardiac(RubartandField;Passieretal.)andpancreatic
(Roche et al.) cells and their potential application in tissue repair of heart
diseasesanddiabetes,respectively.VenturaandBranzidescribeautocrineand
intracrinesignallingpathwaysimplicatedinES-derivedcardiogenesisandhow
pharmacologicalapproachesmayfacilitatethisprocess.
Thesubsequentchaptersdealmainly,butnotexclusively,withadultstem
cells,andtheauthorsdiscussmechanismsandpotentialapplicationsofthese
cellsinregenerativemedicine.Auniqueconceptofstemcellregulationbased
onhaematopoieticstemcells(Quesenberryetal.)andadetailedoverviewthat
Preface VII
reflects the importance of markers in adult tissue-based stem cells (Alison
etal.)aretheperfectintroductiontothissetofchapters.Next,thechaptersde-
scribehowhaematopoieticstem/progenitorcells(Rose-John)ormesenchymal
stemcells(BeyerNardianddaSilvaMeirelles)isolatedfrombonemarrowmay
beisolatedandmanipulatedbyexvivoexpansionfortissueregeneration.Neo-
vascularizationandcardiacrepairbybonemarrow-derivedstemcells(Badorff
andDimmeler)andtheuseofdifferentstem/progenitorcellsformyogenictis-
suerepair(GrenierandRudnicki)arethetopicsofthefollowingcontributions.
Neuralstemcells,theirpropertiesandimplicationsforthetreatmentofneu-
rodegenerative diseases are extensively describedand criticallydiscussedby
Berninger,HackandGötz.Theexperimentalstudiesdescribedinthespecial
issuearethencomplementedbyadetaileddescriptionofthepresentstateofa
stemcelltherapywithrespecttopatientswithParkinson’sdisease(Paul).
Toendthisspecialvolume,wehaveselectedachapterdedicatedtothefuture
of stem cell research. Theise and Harris present a stimulating discussion on
how unexpected and controversial findings of adult stem cell research may
openupnewperspectivestofosterourunderstandingofcellbiology.
Wearedeeplygratefultoallthecontributorsfortheiractiveparticipation
and significant contributions to this volume. We are aware that this volume
could not and does not cover all topics and aspects of stem cell research. In
fact, and during the past few years, stem cell research has metamorphosed
intodistinctandspecializedavenuesofresearch;however,webelievethatthis
volumepresentsinasinglebookmanynovelaspectsofstemcellbiologywith
respecttoscientificendeavoursandfutureapplications.Ofparticularnoteare
the pharmacologicalissuesthat have been compiled, whichhave never been
adequatelyaddressedinthepast.
WealsowouldliketothankMrs.SusanneDathe,deskeditorbiomedicine
atSpringer,andMrs.KathrinSeiffert,IPKGatersleben,fortheirsupportand
experteditorialhelp.
Inconclusion,wehopethatthisvolumewillbevaluedbyresearchersinthe
field, and by those who are engaged in the future developments of stem cell
researchandtheapplicationsofstemcellsinregenerativemedicine.
Gatersleben,Germany, AnnaM.Wobus
Baltimore,MD, KennethR.Boheler
May2005
ListofContents
FactorsInvolvedinSelf-RenewalandPluripotency
ofEmbryonicStemCells . . . . . . . . . . . . . . . . . . . . . . . . . . 1
H.Darr,N.Benvenisty
EmbryonicStemCell-DerivedEmbryoidBodies:AnInVitroModel
ofEutherianPregastrulationDevelopmentandEarlyGastrulation . . . 21
G.Weitzer
EmbryonicStemCells:ANovelToolfortheStudyofAntiangiogenesis
andTumor-InducedAngiogenesis . . . . . . . . . . . . . . . . . . . . . 53
M.Wartenberg,F.Dönmez,P.Budde,H.Sauer
CardiacRepairbyEmbryonicStem-DerivedCells . . . . . . . . . . . . 73
M.Rubart,L.J.Field
CardiomyocytesfromHumanEmbryonicStemCells . . . . . . . . . . 101
R.Passier,C.Denning,C.Mummery
AutocrineandIntracrineSignalingforCardiogenesisinEmbryonicStem
Cells:ACluefortheDevelopmentofNovelDifferentiatingAgents . . . 123
C.Ventura,A.Branzi
TherapeuticPotentialofStemCellsinDiabetes . . . . . . . . . . . . . 147
E.Roche,R.Enseñat-Waser,J.A.Reig,J.Jones,T.León-Quinto,B.Soria
TheStemCellContinuum:ANewModelofStemCellRegulation . . . . 169
P.J.Quesenberry,G.A.Colvin,M.S.Dooner
MarkersofAdultTissue-BasedStemCells . . . . . . . . . . . . . . . . 185
M.R.Alison,M.Brittan,M.J.Lovell,N.A.Wright
DesignerCytokinesforHumanHaematopoieticProgenitorCell
Expansion:ImpactforTissueRegeneration . . . . . . . . . . . . . . . . 229
S.Rose-John
X ListofContents
MesenchymalStemCells:Isolation,InVitroExpansion
andCharacterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
N.BeyerNardi,L.daSilvaMeirelles
NeovascularizationandCardiacRepairbyBoneMarrow-DerivedStem
Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
C.Badorff,S.Dimmeler
ThePotentialUseofMyogenicStemCellsinRegenerativeMedicine . . 299
G.Grenier,M.A.Rudnicki
NeuralStemCells:OnWhereTheyHide,inWhichDisguise,andHow
WeMayLureThemOut . . . . . . . . . . . . . . . . . . . . . . . . . . 319
B.Berninger,M.A.Hack,M.Götz
CellTransplantationforPatientswithParkinson’sDisease . . . . . . . . 361
G.Paul
PostmodernBiology:(Adult)(Stem)CellsArePlastic,Stochastic,Com-
plex,andUncertain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
N.D.Theise,R.Harris
SubjectIndex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
ListofContributors
Addressesgivenatthebeginningofrespectivechapters
Alison,M.R. 185 León-Quinto,T. 147
Lovell,M. 185
Badorff,C. 283
Benvenisty,N. 1
Mummery,C. 101
Berninger,B. 319
BeyerNardi,N. 249 Passier,R. 101
Branzi,A. 123 Paul,G. 361
Brittan,M. 185
Budde,P. 53 Quesenberry,P.J. 169
Colvin,G.A. 169 Reig,J.A. 147
Roche,E. 147
Darr,H. 1
Rose-John,S. 229
Denning,C. 101
Rubart,M. 73
Dimmeler,S. 283
Rudnicki,M.A. 299
Dönmez,F. 53
Dooner,M.S. 169
Sauer,H. 53
Enseñat-Waser,R. 147 SilvaMeirelles,L.da 249
Soria,B. 147
Field,L.J. 73
Theise,N.D. 389
Götz,M. 319
Grenier,G. 299
Ventura,C. 123
Hack,M. 319
Wartenberg,M. 53
Harris,R. 389
Weitzer,G. 21
Jones,J. 147 Wright,N.A. 185