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uurlng normal developmenL, cells proceed from Lhe lnlLlal undlfferenLlaLed sLaLe of Lhe egg and cells
ln Lhe early embryo Lo a more speclallsed sLaLe. ln Lhe adulL organlsm a range of dlfferenLlaLed cell
Lypes are requlred Lo execuLe Lhe speclallsed funcLlons performed ln Lhe adulL body (llgure 1A). 1he
ferLlllsed egg and Lhe cells ln Lhe early zygoLe are LoLlpoLenL, ln oLher words, Lhey can glve rlse Lo all
cell Lypes ln Lhe embryo, as well as Lo exLraembryonlc Llssues such as placenLa. As developmenL
2

progresses, cells aL Lhe blasLocysL sLage sLarL Lo become dlsLlngulshable: Lhe lnner cell mass glves rlse
Lo Lhe embryo proper, whereas Lhe surroundlng cells make up Lhe LrophoblasL llneage and are Lhe
source of exLraembryonlc Llssues. 1he cells ln Lhe lnner cell mass are plurlpoLenL, l.e. Lhey can glve
rlse Lo all somaLlc cells, as well as Lo Lhe germ cell llneage: Lhe cells desLlned Lo become gameLes
(eggs and sperm).

uurlng Lhls developmenLal [ourney, cells progresslvely become more resLrlcLed ln Lhelr
dlfferenLlaLlon poLenLlal and as a consequence, Lhey do noL reLaln plurlpoLency. MosL cells maLure
lnLo fully dlfferenLlaLed cells, alLhough sLem cells wlLh llmlLed poLency remaln ln cerLaln locaLlons ln
Lhe body and serve as a source for cell replacemenL, for example ln Lhe bone marrow, lnLesLlne and
skln. ulfferenLlaLed cells are remarkably sLable and as a rule Lhey wlll noL shlfL faLe lnLo oLher Lypes of
dlfferenLlaLed cells or reverL Lo Lhe Lype of undlfferenLlaLed cells LhaL can be found ln Lhe early
embryo. lor Lhls reason, Lhe long-sLandlng predomlnanL vlew was LhaL cells ln Lhe somaLlc llneage
were permanenLly ln a locked sLaLe, such LhaL Lhe [ourney back Lo a hlghly undlfferenLlaLed sLaLe was
lmposslble. 1he lnslghL LhaL varlous dlfferenLlaLed cell Lypes were endowed wlLh a speclflc paLLern of
proLelns suggesLed LhaL dlfferenLlaLed cells may carry lrreverslble eplgeneLlc modlflcaLlons or geneLlc
alLeraLlons LhaL render lnducLlon of plurlpoLency lmposslble. Conrad Pal WaddlngLon proposed an
eplgeneLlc landscape of mounLalns and valleys as a meLaphor for developmenL. ln Lhls landscape,
undlfferenLlaLed cells, represenLed as marbles, reslde on a mounLaln Lop. uurlng dlfferenLlaLlon Lhey
Lrlckle down lnLo energeLlcally more sLable valleys, where Lhey come Lo resL as dlfferenLlaLed cells.
1he assumpLlon was LhaL lL would be dlfflculL Lo reverL Lhe dlfferenLlaLed cells back Lo Lhe
undlfferenLlaLed sLaLe by movlng Lhem back Lo Lhe mounLaln Lop (WaddlngLon, 1937) (llgure 18).
uesplLe Lhe dogma, Lhe noLlon LhaL speclallsed cells could somehow be unlocked from Lhelr
dlfferenLlaLed sLaLe and dedlfferenLlaLe was noL enLlrely dlsmlssed. varlous sLraLegles Lo
experlmenLally address Lhe problem were consldered. lor example, Pans Spemann (nobel rlze ln
hyslology or Medlclne 1933) enLerLalned Lhe ldea of Lransferrlng nuclel from dlfferenLlaLed cells Lo
an lmmaLure cyLoplasmlc mllleu Lo LesL lLs developmenLal poLenLlal. Pe referred Lo Lhls approach as a
fanLasLlc experlmenL".


3


42/%&' 5 A, normal developmenL of a human from a ferLlllzed egg lllusLraLlng Lhe unldlrecLlonal process of
maLuraLlon vla Lhe egg and embryo lnLo an adulL human. 8, WaddlngLon lllusLraLed cellular dlfferenLlaLlon
as an eplgeneLlc landscape ln whlch cells are seen as marbles rolllng down ln valleys Lo reach Lhelr end-
polnL desLlnaLlons as dlfferenLlaLed cells. 1he meLaphore nlcely vlsuallzes Lhe unldlrecLlonal developmenLal
process of normal developmenL. Cells do noL normally move back Lowards Lhe Lop of Lhe mounLaln Lo
reach Lhe undlfferenLlaLed sLaLe, and cells are noL normally crosslng lnLo oLher valleys Lo develop lnLo
unrelaLed cell llneages.

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A dlrecL aLLempL Lo LesL wheLher dlfferenLlaLed cells ln Lhe somaLlc cell llneage were endowed wlLh a
dormanL dedlfferenLlaLlon poLenLlal was flrsL carrled ouL by 8oberL 8rlggs and 1homas klng, who
developed a Lechnology for Lransfer of somaLlc cell nuclel from undlfferenLlaLed and dlfferenLlaLed
cells Lo an enucleaLed ferLlllzed egg ln Lhe amphlblan R707 G.G.#02 (8rlggs and klng, 1932).
Amphlblans are parLlcularly amenable Lo Lhls Lype of experlmenLs because of Lhe large slze of Lhe egg
and Lhe exLrauLerlne developmenL of embryos. 8rlggs and klng showed LhaL an embryonlc nucleus,
when Lransferred Lo an enucleaLed egg, could lndeed supporL developmenL up Lo Lhe Ladpole sLage.
ln conLrasL, when Lhey repeaLed Lhe procedure wlLh nuclel from more dlfferenLlaLed cells, Lhey falled
Lo obLaln developlng embryos. 1hus, Lhey concluded LhaL dlfferenLlaLed nuclel undergo lrreverslble
changes durlng dlfferenLlaLlon such LhaL Lhe capaclLy Lo promoLe developmenL was losL (klng and
8rlggs, 1933).

!ohn 8. Curdon, who had Lralned ln embryology wlLh Mlchael llschberg ln Cxford, used a dlfferenL
amphlblan, S#0)G?2 +7#E.2 raLher Lhan R707 G.G.#02, Lo address Lhe Loplc. ln S#0)G?2, Curdon could
Lake advanLage of a cell Lraclng sysLem developed by llschberg and colleagues (Llsdale eL al., 1938)
LhaL allowed hlm Lo unequlvocally dlsLlngulsh Lhe cells derlved from LransplanLed nuclel from Lhe
cells of Lhe hosL embryo. ln a key sLudy, Curdon enucleaLed eggs by ulLravloleL lrradlaLlon and found
LhaL when Lhe eggs were LransplanLed wlLh nuclel from dlfferenLlaLed Ladpole lnLesLlnal eplLhellum, a
4

small number of swlmmlng Ladpoles were lndeed generaLed (Curdon, 1962) (llgure 2). Pe could also
show LhaL Lhe efflclency of nuclear reprogrammlng could be greaLly lmproved by performlng serlal
LransplanLaLlons. 8y Lhls sLraLegy, he showed LhaL a raLher large proporLlon of all lnLesLlnal eplLhellal
cell nuclel could be reprogrammed (Curdon, 1962). Curdon concluded LhaL dlfferenLlaLed somaLlc
cell nuclel had Lhe poLenLlal Lo reverL Lo plurlpoLency. Powever, conslderable Llme passed before hls
dlscovery galned broad accepLance ln Lhe sclenLlflc communlLy. ln subsequenL experlmenLs, Curdon
used nuclel from adulL frogs Lo generaLe Ladpoles, and conversely, embryonlc dlfferenLlaLed nuclel
supporLed developmenL of adulL frogs (Curdon and uehllnger, 1966, Laskey and Curdon, 1970).

Curdon's dlscovery was a fundamenLal paradlgm shlfL, showlng for Lhe flrsL Llme LhaL Lhe cell nucleus
from a somaLlc dlfferenLlaLed cell was endowed wlLh Lhe capaclLy Lo drlve developmenL lnLo a full
range of somaLlc cell Lypes and Llssues afLer belng placed ln Lhe cyLoplasmlc mllleu of an egg cell.

42/%&' 8 !ohn Curdon used uv llghL (1) Lo desLroy Lhe cell nucleus ln a frog egg. Pe Lhen replaced Lhe egg
nucleus wlLh a cell nucleus from a dlfferenLlaLed lnLesLlnal eplLhellal cell from a Ladpole (2). Many manlpulaLed
eggs dld noL develop buL ln several cases normal swlmmlng Ladpoles were generaLed (3). 1hls showed LhaL Lhe
geneLlc lnformaLlon requlred Lo generaLe Lhe dlfferenLlaLed cells ln a Ladpole remalned lnLacL ln Lhe donor cell
nucleus. LaLer sLudles have shown LhaL also mammals can be cloned by Lhls Lechnlque (4).

4%&$9'& 1':').-0'+$* .7 &'-&./&#002+/ ,; +%()'#& $&#+*7'&

Curdon's dlscovery lnLroduced a new research fleld cenLered on somaLlc cell nuclear Lransfer (SCn1)
as a meLhod Lo undersLand reprogrammlng and how cells change as Lhey become speclallzed. ln
1997, Lhe flrsL cloned mammal, Lhe sheep uolly, was born afLer SCn1 from an adulL mammary
eplLhellal cell lnLo an enucleaLed sheep egg (WllmuL eL al., naLure 1997). 1he experlmenLal sLraLegy
by lan WllmuL and kelLh Campbell was based on Curdon's work ln S#0)G?2, buL wlLh addlLlonal
Lechnlcal adapLaLlon. lor example, one lmporLanL modlflcaLlon was LhaL nuclel used for
3

LransplanLaLlon ln mammals came from mammary gland eplLhellal cells lnduced Lo enLer qulescence,
whlch make Lhem beLLer sulLed Lo synchronlze wlLh Lhe early developlng embryo. Slnce Lhe clonlng
of sheep ln 1997, SCn1 has now been used Lo clone a pleLhora of mammallan specles, lncludlng
mouse, cow, plg, wolf and Afrlcan wlldcaLs. 8y nuclear Lransfer of cell nuclel from 8- and 1-cells ln Lhe
lmmune sysLem, concluslve evldence was provlded LhaL a dlfferenLlaLed cell nucleus wlLh rearranged
lmmunoglobulln or 1-cell recepLor genes could lndeed be reprogrammed Lo supporL Lhe
developmenL of a mouse (Pochedllnger and !aenlsch, 2002).

6'-&./&#002+/ .7 #+ 2+$#($ *.0#$2( 1277'&'+$2#$'1 (')) $. ,'(.0' -)%&2-.$'+$
Curdon revealed LhaL a dlfferenLlaLed cell nucleus has Lhe capaclLy Lo successfully reverL Lo an
undlfferenLlaLed sLaLe, wlLh a poLenLlal Lo resLarL developmenL. Powever an open quesLlon
remalned, namely, wheLher lL would be posslble Lo lnduce reverslon of an lnLacL dlfferenLlaLed cell Lo
a hlghly lmmaLure sLaLe. Many sclenLlsLs consldered Lhls lmposslble, or aL Lhe very leasL, LhaL lL would
requlre very complex reorganlzaLlon ln Lhe cell Lo unlock Lhe dlfferenLlaLed sLaLe. Such was Lhe scene
when Shlnya ?amanaka declded Lo approach Lhe problem of reprogrammlng Lo plurlpoLency.
?amanaka, who had Lralned boLh ln orLhopaedlc surgery and molecular blology, became lnLeresLed ln
Lhe plurlpoLenL sLaLe ln parL by sLudylng plurlpoLenL embryonlc sLem (LS) cells, flrsL culLured and
characLerlsed by MarLln Lvans (nobel rlze ln hyslology or Medlclne 2007).

?amanaka's laboraLory focused on facLors lmporLanL for malnLalnlng plurlpoLency ln LS cells, such as
L8as (1akahashl eL al., 2003) and ldenLlfled, ln parallel wlLh AusLln SmlLh's laboraLory, Lhe
plurlpoLency gene nanog (MlLsul eL al., 2003, Chambers eL al., 2003). ?amanaka Lhen embarked on
Lhe quesL of lnduclng plurlpoLency ln somaLlc cells. lrom hls work and oLhers, he knew a large
number of LranscrlpLlon facLors LhaL were expressed ln LS cells wlLh elLher conflrmed or suspecLed
funcLlons ln Lhe malnLenance of Lhe plurlpoLenL sLaLe. lurLhermore, LS cells were known Lo lnduce
plurlpoLency ln somaLlc cell nuclel afLer lnduced cell fuslons beLween LS and somaLlc cells (1ada eL
al., 2001). Lqulpped wlLh Lhls lnformaLlon, ?amanaka selecLed a seL of 24 LS cell LranscrlpLlon facLors
LhaL he consldered as candldaLes Lo relnsLaLe plurlpoLency ln somaLlc cells.

ln a sLrlklngly bold experlmenL, all 24 genes encodlng Lhese LranscrlpLlon facLors were lnLroduced ln
one sLep lnLo skln flbroblasLs and a few of Lhem acLually generaLed colonles LhaL showed a
remarkable resemblance Lo LS cells. 1he number of genes capable of lnduclng such colonles were
reduced, one-by-one, Lo ldenLlfy a comblnaLlon of only four LranscrlpLlon facLors (Myc, CcL3/4, Sox2
and klf4) LhaL were sufflclenL Lo converL mouse embryonlc flbroblasLs Lo plurlpoLenL sLem cells
6

(1akahashl and ?amanaka, 2006) (llgure 3). 1he plurlpoLenL sLem cells, whlch ?amanaka called
lnduced plurlpoLenL sLem cells (lS cells), appeared wlLh a very low frequency, buL could be selecLed
for by expresslon of a neomycln/lacZ fuslon gene (!geo) lnserLed lnLo Lhe lbx13 locus ln Lhe genome
of Lhe mouse from whlch Lhe flbroblasLs were obLalned. 1he lbx13 promoLer ls acLlve ln plurlpoLenL
sLem cells, and acLlvaLlon of !geo expresslon ln Lhe plurlpoLenL sLem cells resulLs ln C418 reslsLance.
1he lS cells generaLed varlous cell Lypes ln LeraLoma assays and conLrlbuLed Lo Llssues ln chlmerlc
mlce afLer ln[ecLlon ln mouse blasLocysLs. Powever, lS cell germ llne Lransmlsslon was noL achleved
ln Lhe flrsL sLudy (1akahashl and ?amanaka, 2006). Powever, a year laLer, ?amanaka's group, ln
parallel wlLh 8udolph !aenlsch's and konrad Pochedllnger's groups, reflned Lhe selecLlon sysLem
(now selecLlng for acLlvaLlon of elLher Lhe CcL4 or nanog gene locus), and Lhe resulLlng lS cells
showed germ llne Lransmlsslon (CklLa eL al., 2007, Wernlg eL al., 2007, Maherall eL al., 2007). ln 2007,
?amanaka's and !ames 1homson's laboraLorles were Lhe flrsL Lo produce human lS cells (1akahashl
eL al., 2007, ?u eL al., 2007). ln Lhe human lS cell experlmenLs, ?amanaka used Lhe four facLor
comblnaLlon from Lhe 2006 paper (Myc, CcL4, Sox2 and klf4), whereas 1homson used a somewhaL
dlfferenL LranscrlpLlon facLor comblnaLlon (Lln28, nanog, CcL 4 and Sox2).

?amanaka's dlscovery of lS cells represenLs a Lruly fundamenLal dlscovery, as lL was Lhe flrsL Llme an
lnLacL dlfferenLlaLed somaLlc cell could be reprogrammed Lo become plurlpoLenL. ?amanaka's
dlscovery has opened up a compleLely new research fleld, and Lhe asLonlshlngly slmple lS
Lechnology ls now used ln a large number of laboraLorles around Lhe world.

42/%&' < SLarLlng from a collecLlon of 24 dlfferenL LranscrlpLlon facLors (symbollsed by Lhe LesL Lube), (1),
1akahashl and ?amanaka (2006) demonsLraLed LhaL a seL of only four LranscrlpLlon facLors (Myc, CcL3/4, Sox2
and klf4) was sufflclenL Lo converL culLured mouse embryonlc or adulL flbroblasLs (2) Lo become plurlpoLenL
cells capable of produclng LeraLomas ln vlvo and conLrlbuLlng Lo chlmerlc mlce (3). 1he plurlpoLenL cells were
called lnduced plurlpoLenL sLem cells (lS cells).

7

4%&$9'& 1':').-0'+$* .7 ('))%)#& &'-&./&#002+/ #+1 2$* %*' 2+ 0'12(#)
&'*'#&(9

Slnce Lhe lnlLlal dlscovery, Lhe Lechnology has been lmproved ln several ways. lor example, Lhe
plurlpoLency facLors can now be dellvered lnLo Lhe cell wlLhouL Lhe use of reLrovlral vecLors, whlch
lnLegraLe randomly ln Lhe genome and cause deregulaLlon of nearby endogenous genes LhaL may
conLrlbuLe Lo Lumour formaLlon. non-lnLegraLlng vlruses, sLablllsed 8nAs or proLelns, as well as
eplsomal plasmlds, are now used for lnLegraLlon-free dellvery of Lhe plurlpoLency genes. ln cerLaln
cell Lypes fewer Lhan four facLors are requlred Lo lnduce plurlpoLency, for example adulL mouse
neural sLem cells only requlre CcL4 for lS cell lnducLlon (klm eL al., 2009). Slmllarly, small molecules
have been shown, ln cerLaln cellular conLexLs, Lo subsLlLuLe for some of Lhe plurlpoLency facLors (Ll eL
al., 2009). lmporLanLly, lS cells meeL Lhe mosL sLrlngenL crlLerla for plurlpoLency, as Lhey are able Lo
generaLe all lS cell-mlce ln LeLraplold complemenLaLlon LesLs, l.e., when Lhe cells are lnLroduced lnLo
a LeLraplold 8-cell sLage morula (Zhao eL al., 2009). All Lhese lmprovemenLs, based on Lhe orlglnal
dlscovery by ?amanaka, have been lmporLanL sLeps Lo make Lhe lS Lechnology more efflclenL and
useful.

?amanaka's dlscovery, demonsLraLlng LhaL dramaLlc changes ln Lhe usually very sLable dlfferenLlaLed
sLaLe can be achleved, has also lnsplred research efforLs Lo change Lhe faLe of cells wlLhouL
proceedlng Lhrough a plurlpoLenL sLaLe. 1ransdlfferenLlaLlon experlmenLs have a long hlsLory LhaL
goes back Lo lmaglnal dlsc experlmenLs ln :-)2)G".+7 ln Lhe 1960s, followed by Lhe use of slngle
genes such as AnLennapedla, Myou, CA1A1 or ax3 Lo lnduce cell faLe swlLches. ln parLlcular Lhe
dlscovery LhaL Myou could LransdlfferenLlaLe 1011/2 flbroblasLs Lo myoblasLs (uavls eL al., 1987)
showed LhaL genes LhaL carrled ouL LransdlfferenLlaLlon could be sysLemaLlcally ldenLlfled.
?amanaka's approach Lo sysLemaLlcally deflne a small seL of LranscrlpLlon facLors, raLher Lhan a slngle
facLor, has lnsplred a recenL wave of LransdlfferenLlaLlon experlmenLs uslng comblnaLlons of
LranscrlpLlon facLors. lor example, exocrlne cells converL Lo endocrlne cells ln Lhe pancreas by
lnLroducLlon of Lhree LranscrlpLlon facLors (Zhou eL al., 2008). Slmllarly, cardlomyocyLes can be
generaLed from flbroblasLs .0 E.9-) by lnLroduclng Lhree dlfferenL LranscrlpLlon facLors (leda eL al.,
2010), and a correspondlng cell faLe swlLch has recenLly been accompllshed .0 E.E) by uslng Lhe same
facLors (Song eL al., 2012, Clan eL al., 2012). 1hese examples provlde evldence for
LransdlfferenLlaLlon wlLhln a germ layer, buL efflclenL LransdlfferenLlaLlon beLween germ layers can
also be achleved. 1he LransdlfferenLlaLlon from flbroblasLs (mesoderm) Lo neurons (ecLoderm) (so
called ln cells) was accompllshed by expresslon of Lhree LranscrlpLlon facLors (ang eL al., 2011).
8


SLem cells, lncludlng lS cells, can poLenLlally be used Lo replace dlseased or losL cells ln degeneraLlve
dlsorders lncludlng arklnson's dlsease and ln Lype 1 dlabeLes. Cell replacemenL Lherapy wlLh lS cells
can allow auLologous cell grafLlng LhaL would be less prone Lo lmmune re[ecLlon. 1he lmproved
meLhods for Lhe generaLlon of lS cells wlll be lmporLanL ln Lhese efforLs. Powever, Lhe posslblllLy
exlsLs LhaL currenLly used procedures for reprogrammlng may lnLroduce muLaLlons or oLher genomlc
abnormallLles, whlch may render Lhem unsulLable for cell Lherapy. 1he prospecL of uslng plurlpoLenL
sLem cells, lncludlng LS cells, ln cell LransplanLaLlon remalns challenglng for a number of addlLlonal
reasons. 1hus, alLhough Lhls ls a very exclLlng and promlslng research area, furLher work ls requlred
Lo ensure LhaL uslng cells orlglnaLlng from plurlpoLenL sLem cells ln Lherapy ls safe for paLlenLs.

AnoLher, more lmmlnenL, area for medlcal use ls Lo derlve lS cells from paLlenLs wlLh geneLlc and
oLher dlsorders and Lhen use Lhe lS cells for .0 E.9-) dlfferenLlaLlon Lo galn novel lnslghLs lnLo Lhe
dlsease process or Lo produce cell-based plaLforms for Loxlcology LesLlng or drug developmenL
(Cnder and ualey, 2012) (llgure 4). lS cells have been produced from a large specLrum of dlseases,
lncludlng amyoLrophlc laLeral sclerosls (ALS), 8eLL syndrome, splnal muscular aLrophy (SMA), "1-
anLlLrypsln deflclency, famlllal hypercholesLerolemla and glycogen sLorage dlsease Lype 1A. lor
cardlovascular dlsease, Lhere are now lS cell models for 1lmoLhy syndrome, LLCA8u syndrome, as
well as Lype 1 and 2 long C1 syndrome (Cnder and ualey, 2012). ln several of Lhese lS cell-based
dlsease models, dlsease-relevanL phenoLypes are observed. lor example, a progresslve loss of moLor
neurons ls observed ln Lhe lS model for SMA. Moreover, 8eLL syndrome-speclflc lS cells show
reduced splne denslLy afLer neuronal dlfferenLlaLlon (MarcheLLo eL al., 2010). PepaLocyLlc
dlfferenLlaLlon of lS cells from "1-anLlLrypsln-deflclenL paLlenLs leads Lo elevaLed llpld and glycogen
accumulaLlon (8ashld eL al., 2010). ln vlLro-dlfferenLlaLed lS cell models can also mlmlc aspecLs of
dlseases wlLh laLe onseL, such as Alzhelmer's dlsease (lsrael eL al., 2012), Splnocerebellar aLaxla (koch
eL al., 2011) and PunLlngLon's dlsease (1he Pu lSC ConsorLlum, 2012). rogress has also been made
when lL comes Lo modelllng dlseases wlLh complex geneLlcs, such as schlzophrenla (8rennand eL al.,
2011). Powever Lhere are also dlseases, for whlch lL may be dlfflculL Lo successfully mlmlc paLhology
ln culLured lS cell-derlved cells. lurLhermore, for some dlseases, noLably ln Lhe hemaLopoleLlc
llneage, robusL .0 E.9-) dlfferenLlaLlon proLocols for lS cells are lacklng, llmlLlng progress ln Lhls area.
9


42/%&' = ulfferenLlaLed cells can be obLalned from a paLlenL wlLh a speclflc dlsease and reprogrammed Lo
become lS cells. 1he resulLlng lS cells can Lhen be ln vlLro dlfferenLlaLed Lo varlous speclallsed cell faLes, such
as neurons, cardlomyocyLes or hepaLocyLes, and used Lo galn new lnslghLs lnLo Lhe dlsease process or as a cell-
based plaLform Lo Lry Lo develop new dlsease Lheraples.

lS cell-based .0 E.9-) dlfferenLlaLed cells are also lncreaslngly used as screenlng plaLforms for
developmenL and valldaLlon of LherapeuLlc compounds. ln an lS cell-based model for famlllal
dysauLonomla, a novel compound, klneLln, was ldenLlfled, whlch could parLlally reverse Lhe aberranL
spllclng of Lhe lk8kA gene LhaL causes Lhe dlsease (Lee eL al., 2009). Slmllarly, ln a Long C1
syndrome lS cell model, beLa blockers and lon channel blockers proved effecLlve ln modulaLlng Lhe
phenoLype (lLzhakl eL al., 2011). lS cells are Lhus becomlng valuable new Lools Lo galn lnslghL lnLo
dlsease processes and Lhey are now used Lo LesL and valldaLe new LherapeuLlcs. lurLhermore, even
dlseases wlLh complex geneLlcs and laLe onseL can be successfully modelled by Lhls dlsease ln Lhe
dlsh" approach.

ln summary, Lhe concepL LhaL maLure, dlfferenLlaLed cells can be reprogrammed Lo a plurlpoLenL
sLem cell sLaLe ls a paradlgm-shlfLlng dlscovery. 1hls lnslghL has lnfluenced essenLlally all areas of
medlclne or physlology. 1he dlscoverles made by !ohn Curdon and Shlnya ?amanaka clearly sLand
ouL as Lruly fundamenLal and have lnLroduced an enLlrely new research fleld.


<)072 T-.2U0F V-*70 W#057"+ 705 !")B72 ,#-+B700


10


6>4>6>?@>AB

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schlzophrenla uslng human lnduced plurlpoLenL sLem cells. (79?-# =C<B 221-223.

8rlggs 8, klng 1! (1932). 1ransplanLaLlon of Llvlng nuclel from 8lasLula Cells lnLo LnucleaLed lrog's
Lggs. ,-)6 (79+ X675 @6. V@X <DB 433-463.

Chambers l, Colby u, 8oberLson M, nlchols !, Lee S, 1weedle S #9 7+ (2003). luncLlonal expresslon
clonlng of nanog, a plurlpoLency susLalnlng facLor ln embryonlc sLem cells. H#++ 55<B 643-633.

uavls 8L, WelnLraub P, Lassar A8 (1987). Lxpresslon of a slngle LransfecLed cunA converLs flbroblasLs
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Llsdale 18, llschberg M, SmlLh S (1938). A MuLaLlon 1haL 8educes nucleolar number ln xenopus-
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Curdon !8 (1962). uevelopmenLal CapaclLy of nuclel 1aken from lnLesLlnal LplLhellum Cells of
leedlng 1adpoles. < YB*-1)+ YQG 4)-G" 5FB 622-640.

Curdon !8, uehllnger v (1966). "lerLlle" lnLesLlne nuclel. (79?-# 85FB 1240-1241.

Pochedllnger k, !aenlsch 8 (2002). Monoclonal mlce generaLed by nuclear Lransfer from maLure 8
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leda M, lu !u, uelgado-Clguln , vedanLham v, Payashl ?, 8runeau 8C #9 7+ (2010). ulrecL
reprogrammlng of flbroblasLs lnLo funcLlonal cardlomyocyLes by deflned facLors. H#++ 5=8B 373-386.

lsrael MA, ?uan SP, 8ardy C, 8eyna SM, Mu ?, Perrera C #9 7+ (2012). roblng sporadlc and famlllal
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lLzhakl l, Malzels L, Puber l, Zwl-uanLsls L, Caspl C, WlnLersLern A #9 7+ (2011). Modelllng Lhe long C1
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klm !8, Creber 8, Arauzo-8ravo M!, Meyer !, ark kl, Zaehres P #9 7+ (2009). ulrecL reprogrammlng of
human neural sLem cells by CC14. (79?-# =G5B 649-643.

klng 1!, 8rlggs 8 (1933). Changes ln Lhe nuclel of ulfferenLlaLlng CasLrula Cells, as uemonsLraLed by
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Lee C, apapeLrou L, klm P, Chambers SM, 1omlshlma M!, lasano CA #9 7+ (2009). Modelllng
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406.
11


Ll W, Zhou P, Abu[arour 8, Zhu S, ?oung !oo !, Lln 1 #9 7+ (2009). CeneraLlon of human-lnduced
plurlpoLenL sLem cells ln Lhe absence of exogenous Sox2. @9#B H#++2 8CB 2992-3000.

Maherall n, Srldharan 8, xle W, uLlkal !, Lmlnll S, Arnold k #9 7+ (2007). ulrecLly reprogrammed
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33-70.

MarcheLLo MCn, Carromeu C, Acab A, ?u u, ?eo CW, Mu ?L #9 7+ (2010). A Model for neural
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5=<B 327-339.

MlLsul k, 1okuzawa ?, lLoh P, Segawa k, Murakaml M, 1akahashl k #9 7+ (2003). 1he homeoproLeln
nanog ls requlred for malnLenance of plurlpoLency ln mouse eplblasL and LS cells. H#++ 55<B 631-642.

CklLa k, lchlsaka 1, ?amanaka S (2007). CeneraLlon of germllne-compeLenL lnduced plurlpoLenL sLem
cells. (79?-# ==DB 313-317.

Cnder 11, ualey CC (2012) new lessons learned from dlsease modellng wlLh lnduced plurlpoLenL
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Clan L, Puang ?, Spencer Cl, loley A, vedanLham v, Llu L #9 7+ (2012). ln vlvo reprogrammlng of
murlne cardlac flbroblasLs lnLo lnduced cardlomyocyLes. (79?-# =DEB 393-398.

8ashld S1, Corblneau S, Pannan n, Marclnlak S!, Mlranda L, Alexander C #9 7+ (2010). Modellng
lnherlLed meLabollc dlsorders of Lhe llver uslng human lnduced plurlpoLenL sLem cells. < H+.0 I0E#29
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Song kP, nam ?!, Luo x, Cl xx, 1an W, Puang Cn #9 7+ (2012). PearL repalr by reprogrammlng non-
myocyLes wlLh cardlac LranscrlpLlon facLors. (79?-# =DEB 399-604.

1ada M, 1akahama ?, Abe k, nakaLsu[l n, 1ada 1 (2001). nuclear reprogrammlng of somaLlc cells by
ln vlLro hybrldlzaLlon wlLh LS cells. H?-- =.)+ 55B 1333-1338.

1akahashl k, MlLsul k, ?amanaka S (2003). 8ole of L8as ln promoLlng Lumour-llke properLles ln mouse
embryonlc sLem cells. (79?-# =8<B 341-343.

1akahashl k, ?amanaka S (2006). lnducLlon of plurlpoLenL sLem cells from mouse embryonlc and
adulL flbroblasL culLures by deflned facLors. H#++ 58GB 663-676.

1akahashl k, 1anabe k, Chnukl M, narlLa M, lchlsaka 1, 1omoda k #9 7+ (2007). lnducLlon of
plurlpoLenL sLem cells from adulL human flbroblasLs by deflned facLors. H#++ 5<5B 861-872.

1he Pu lSC ConsorLlum (2012) lnduced plurlpoLenL sLem cells from paLlenLs wlLh PunLlngLon's
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WaddlngLon CP (1937) 1he SLraLegy of Lhe Cenes, a ulscusslon of Some AspecLs of 1heoreLlcal
8lology. Allen & unwln.
12


Wernlg M, Melssner A, loreman 8, 8rambrlnk 1, ku M, Pochedllnger k #9 7+ (2007). ln vlLro
reprogrammlng of flbroblasLs lnLo a plurlpoLenL LS-cell-llke sLaLe. (79?-# ==DB 318-324.

WllmuL l, Schnleke AL, McWhlr !, klnd A!, Campbell kPS (1997). vlable offsprlng derlved from feLal
and adulL mammallan cells. (79?-# <DEB 810-813.

?u !, vodyanlk MA, Smuga-CLLo k, AnLoslewlcz-8ourgeL !, lrane !L, 1lan S #9 7+ (2007). lnduced
plurlpoLenL sLem cell llnes derlved from human somaLlc cells. @6.#06# <5DB 1917-1920.

Zhao x?, Ll W, Lv Z, Llu L, 1ong M, Pal 1 #9 7+ (2009). lS cells produce vlable mlce Lhrough LeLraplold
complemenLaLlon. (79?-# =G5B 86-90.

Zhou C, 8rown !, kanarek A, 8a[agopal !, MelLon uA (2008). ln vlvo reprogrammlng of adulL
pancreaLlc exocrlne cells Lo beLa-cells. (79?-# =EEB 627-630.