the importance of leukemia inhibitory factor ( lif ) stimulated signaling in mouse embryonic stem cell ( esc ) culture in vitro has long been recognized . by activating janus kinase ( jak ) and signal transducer and activator of transcription 3 ( stat3 ) , lif plays essential roles in the generation and maintenance of mouse pluripotent embryonic stem cells which are capable of infinite self - renewal and differentiation to any cell type of the three - germ layers of an embryo . over the past two decades , much information has been obtained regarding the lif signaling pathway through studying mouse escs . however , the exact mechanism by which activated stat3 controls pluripotency still remains to be elucidated . the induced pluripotent stem cell ( ipsc ) technology provides a powerful tool to reprogram somatic cells such as skin fibroblasts to a pluripotent state , and brings us much closer to the establishment of personalized , cell - based therapy for the treatment of currently incurable diseases such as diabetes and neural degenerative diseases . in many aspects , somatic cell reprogramming represents a reversed cell differentiation process , by epigenetically resetting the cell nuclei back to a pluripotent state . a the same time reprogrammed cells turn on a cellular signal network capable of both robust cell division and fending off intra- and extra - cellular differentiation stimuli . recently , the lif - jak - stat3 axis was demonstrated by a number of studies to be essential for the nave state pluripotency establishment during somatic cell reprogramming . in addition , these studies provided important insight for further understanding of the mechanism behind lif regulated esc pluripotency . in this review , we will summarize the current knowledge on the role of lif and especially jak - stat3 signaling pathway in esc pluripotency maintenance and in somatic cell reprogramming . leukemia inhibitory factor ( lif ) is a member of the interleukin ( il)-6-type cytokine family , which includes il-6 , il-11 , il-27 , lif , ciliary neurotrophic factor ( cntf ) , cardiotropin-1 ( ct-1 ) , oncostatin m ( osm ) , and cardiotrophin - like cytokine-1/novel neurotrophin-1/b - cell stimulating factor-3 ( clc-1/nnt-1/bsf-3 ) . lif was initially discovered to be pleiotropic in different mouse leukemia cell lines , by exerting either an inhibitory or promotional role on cell proliferation . the same cytokine was also isolated from culture medium conditioned with buffalo rat liver cells , which can promote the self - renewal and sustain the pluripotency of mouse escs in the absence of fibroblast feeder cells . lif binds to the low - affinity cell surface lif receptor ( lifr ) , which stimulates the hetero - dimerization of lifr with the signal transducer glycoprotein 130 ( gp130 ) ( fig .  1 ) . this triggers the activation of gp130-associated jak kinases , and the subsequent phosphorylation of tyrosine residues in the gp130 cytoplasmic domain . these phosphor - tyrosines then serve as the docking sites to recruit the src - homology-2 ( sh2 ) domain containing stat proteins ( stat1 and 3 ) , which are phosphorylated by activated jak kinase . once phosphorylated , the stat proteins dimerize and enter the cell nucleus to regulate the expression of their target genes . although the jak kinases including jak1 , jak2 , and tyk2 can all be phosphorylated following stimulation by lif as well as other il-6-type cytokines , jak1-mediated il-6/il-11 signaling can not be substituted by jak2 and tyk2 . additionally , while rna inhibition of jak1 induces mouse esc differentiation , jak2-deficient escs are responsive to lif stimulation . it was also found that in mouse escs , the activity of stat3 , but not stat1 , is responsible for pluripotency maintenance , and artificially activated stat3 can sustain esc self - renewal in the absence of lif . these lines of evidence suggest that the prevailing  stemness  signaling is mediated by jak1 activated stat3 dimerization in mouse escs . this is followed by the activation of jak - stat3 , pi3k / akt , and erk1/2 signaling pathways . the activated stat3 leads to increased expression of socs3 , which serves as a negative feedback signal to lif stimulated activation of stat3 and erk1/2 . likewise , lifr can serve as the receptor to mediate signals of several ligands including lif , cntf , ct-1 , osm , and clc-1 ( table 1 ) . il-6-type cytokines induced gp130 homo- or heterodimerization with lifr also activates the phosphatidylinositol 3-kinase ( pi3k)/protein kinase b ( akt ) , and the sh2-domain containing tyrosine phosphatase ( shp2)/extracellular - signal - regulated kinases 1/2 ( erk1/2 ) pathways . activated gp130 recruits shp2 through its tyrosine residue ( tyr in humans , equivalent to tyr in mice ) , where shp2 is phosphorylated by jak kinases and interacts with the growth - factor receptor bound protein 2 ( grb2 ) and son of sevenless ( sos ) complex to activate erk1/2 . the activation of stat3 also triggers the expression of the suppressors of cytokine signaling 3 ( socs3 ) , which competes with shp2 for the cytoplasmic domain of gp130 phosphorylated at tyrosine residue tyr ( human ) or tyr ( mouse ) , and inhibits the jak - stat3 and erk1/2 activation ( fig .  1 ) . the negative regulation of jak kinases by socs3 involves both direct inhibition of the jak catalytic domain and the promotion of proteasomal degradation of jak . while constitutively activated akt was reported to sustain mouse esc pluripotency independent of stat3 , signaling from activated erk1/2 promotes the neural commitment of escs . as the jak - stat3 , pi3k / akt and erk1/2 pathways are simultaneously activated by lif , it obviously contributes to the pleiotropic roles that lif plays in different cell types , and complicates the understanding of lif signaling regulated pluripotency . it is well - known that jak - stat3 signaling is important in maintaining mouse esc pluripotency and propagation . unfortunately , thorough elucidation has not been achieved despite the numerous attempts made to uncover the mechanism behind jak - stat3-mediated esc self - renewal . stat3 is a transcription factor whose amino acid sequence is highly conserved across species among humans , cattle , pigs , rats , and mice . its dna binding domain recognizes the consensus sequence of ttcc(c / g)ggaa which is present in the regulatory regions of many genes . the phosphorylation of tyr of stat3 is important for stat3 homo - dimerization and nuclear translocation following gp130 activation . by mutating the stat3 binding tyrosine residues in the cytoplasmic domain of gp130 , it was shown that stat3 activity was necessary for gp130 signaling mediated mouse esc self - renewal . expressing a mutant form of stat3 ( stat3f , tyr to phenylalanine ) leads to esc differentiation even in the presence of lif , while dimerization of stat3 fused with estrogen receptor ( stat3er ) upon 4-hydroxytamoxifen ( 4-ht ) treatment promoted mouse esc self - renewal in the absence of lif . thus it became clear that stat3 is the key downstream mediator of lif stimulated pluripotent signal . these embryos can form embryonic ectoderm and visceral endoderm but not the mesoderm . in culture of wild - type escs , lif prevents their differentiation into mesoderm and endoderm but needs either serum supplement or bone morphogenetic proteins ( bmps ) to suppress the neuronal differentiation . bmp signaling induces the expression of inhibition of differentiation ( i d ) proteins , and mouse escs transfected with ids remain undifferentiated in the presence of lif without serum . microarray analysis using stat3er transfected escs identified 58 stat3 targets , among which 22 are responsible for inhibiting the differentiation of either mesoderm ( ccm4l , cyr61 , dact1 , etc . ) , endoderm ( krppel - like factor 4 [ klf4 ] , gbx2 , pim1 , pim3 , sall4 , smad7 , etc . ) , or both ( klf5 ) . interestingly , 14 of these genes , including klf4 , klf5 , pim1 , dact1 , and smad7 , are co - regulated by nanog , indicating a partially functional redundancy between stat3 and nanog in pluripotency maintenance . this is also in line with the finding that overexpression of either nanog or stat3 maintains esc self - renewal in the presence of reduced signaling from one another . in mouse escs , the global dna binding sites of 13 pluripotency- , cell cycle- , dna binding- , or reprogramming - related transcription factors were evaluated using chromatin immunoprecipitation coupled with high - throughput sequencing ( chip - seq ) . also , a total of 718 genomic loci were identified to be co - bound by stat3 and at least another 3 of the 13 factors , and stat3 clusters with nanog , oct4 ( also known as pou5f1 ) , or sex determining region y - box 2 ( sox2 ) among 56.8% of these loci , clearly demonstrating that stat3 shares many common targets with the core pluripotent oct4-sox2-nanog circuitry . interestingly , stat3 were found to co - bind with oct4 , sox2 , nanog , and smad1 to the regulatory region of key pluripotent genes which were also found to be reprogramming factors such as nanog , oct4 , sox2 , estrogen - related receptor  ( esrrb ) , klf4 , c - myc , t - box transcription factor 3 ( tbx3 ) , sall4 , etc . c - myc had been previously identified as a stat3 target and overexpression of constitutively active c - myc mutant maintains mouse esc pluripotency in the absence of lif . it was postulated that the lif / stat3 signaling promotes esc self - renewal by stimulating c - myc mrna expression , and by stabilizing c - myc protein levels through inhibiting glycogen synthase kinase 3 ( gsk3 ) mediated threonine 58 ( thr ) phosphorylation . however , mouse escs with c - myc disruption were reportedly normal in self - renewal , presumably due to the redundant function from n - myc . using chip and microarray analysis ( chip - chip ) , 948 genes and 1459 genes were found bound by stat3 and c - myc in mouse escs , respectively , of which stat3 and c - myc co - occupy the promoters of 218 genes , including n - myc , rest , stat3 , mbd3 , and jmjd3 . interestingly , it was shown that while stat3 binds to genes that are either transcriptionally activated or repressed , c - myc mainly occupies actively transcribed genes in escs . these , together with other studies described above , indicate that while stat3 functions synergistically with the oct4-sox2-nanog pluripotent circuitry and myc by co - regulating their common target gene expression , unique function by stat3 through regulating its specific targets not bound by these factors may exist for the pluripotency maintenance . similar to nanog , overexpression of klf4 or tbx3 gene confers lif - independent mouse esc self - renewal . it was elegantly demonstrated that upon lif stimulation , klf4 expression in mouse escs is preferentially stimulated by jak - stat3 activation , whereas tbx3 expression is stimulated by pi3k / akt pathway upon the inhibition of erk activities . based on their finding , proposed a model where lif regulates pluripotency maintenance by simultaneous stimulation of jak - stat3 and pi3k / akt pathways in escs . this leads to the activation of klf4 and tbx3 expression , and the subsequent expression of sox2 and nanog , respectively . sox2/nanog cooperate to maintain oct4 expression , while nanog also reinforce the established oct4-sox2-nanog pluripotency network in the absence of klf4 and tbx3 ( fig .  2 ) . schematic representation of lif regulated pluripotency circuit in escs . upon lif activation , jak - stat3 promotes the expression of the core pluripotency circuit ( green box ) together with pi3k / akt for pluripotency maintenance . this model of parallel axes by lif / jak - stat3/sox2 and lif / pi3k / nanog to maintain pluripotency are supported by multiple lines of evidences . first , selective activation of klf4 by stat3 was reported to synergize with klf2 , activated by oct4 , to ward off the differentiation stimuli to escs . stat3 was also reported to directly upregulate sox2 during neural progenitor cell differentiation from escs . second , upregulation of nanog through pi3k activation or gsk3 inhibition has been reported to contribute to esc maintenance . using pi3k inhibitor ly294002 , 646 downstream targets of pi3k pathway were identified in mouse escs by microarray analysis . these include some key pluripotent genes such as nanog , esrrb , tbx3 , and tcl-1 , as well as zscan4c , one of the zscan4 family of zinc finger proteins . interestingly , it was found that inhibition of zscan4c reduces the proportion of escs expressing high levels of nanog , and zscan4c was found to regulate telomerase elongation and chromosome stability in escs . in addition , although it is unclear why the constitutively activated akt confers mouse esc self - renewal , akt stabilizes myc by inhibiting gsk3-mediated phosphorylation and degradation , and akt also phosphorylates sox2 , thus enhancing its stability and transcriptional activity in escs . however , in addition to the pi3k / nanog axes in escs , stat3 also binds to nanog promoter with brachyury which co - activates nanog expression in early mesoderm progenitor cells derived from escs . the activation of canonical wnt pathway leads to phosphorylation and inhibition of gsk3 and the subsequent nuclear accumulation of -catenin to regulate cell fate and many other biological events . it was reported that inhibition of gsk3 using 6-bromoindirubin-3-oxime promotes mouse esc self - renewal in the absence of lif , and that activated -catenin upregulates nanog expression by interacting with oct4 . however , it was also reported that wnt signaling alone is not sufficient for the maintenance of mouse esc self - renewal but can cooperate with lif for this action . part of this synergistic effect of wnt could be through increasing stat3 mrna level in escs . a more recent study indicates that wnt regulated expression of orphan nuclear receptor nr5a2 ( also known as lrh-1 ) is significant in augmenting pi3k / akt pluripotent signaling through regulating tbx3 , nanog , and oct4 expression independent of jak - stat3 . however , unlike nanog and tbx3 , overexpression of nr5a2 can not sustain esc pluripotency in the absence of lif . the culture of mouse escs under the dual inhibition of erk and gsk3 ( 2i ) ensures esc self - renewal and pluripotency maintenance without lif . stat3 null escs can be derived under the 2i or triple inhibition of fgf receptor , erk1/2 , and gsk3 culture condition . although -catenin was found dispensable for esc self - renewal , its overexpression enhances pluripotent gene expression and delays the mouse esc differentiation . the pluripotency maintenance effect of gsk3 inhibition was recently found to be through inhibiting transcription factor 3 ( tcf3 ) protein by activated -catenin , which relieves the suppressive effect of tcf3 , leading to the expression of pluripotent gene esrrb . smith s group therefore proposed a model of esc signal network in which pluripotency is supported by the inhibition of gsk3 and the activation of stat3 which in turn activate the expression of tcf3 and klf4 , respectively , and esc is maintained by an expanded core pluripotent circuitry including oct4/sox2 , nanog , klf4 , tbx2 , and tcf3 ( fig .  2 ) . however , esrrb is also dispensable for esc maintenance in the presence of lif , which highlights the parallel compensatory capacity by the core pluripotent circuitry for esc self - renewal . a complementary model was proposed by savatier s group which describes the synergistic effect of stat3 with nanog in preventing mesoderm and endoderm differentiation , as well as stat3 s direct effect in preventing endoderm differentiation through regulating its specific target genes in mouse escs . together , these studies contribute a comprehensive depiction to our understanding of lif signal network ( fig .  2 ) . a few studies also investigated the stat3 regulated esc pluripotency and gene expression at the epigenetic level . one study discovered that in mouse escs , stat3 , and oct4 co - bind to the promoter region of embryonic ectoderm development ( eed ) gene and promote its expression . as eed is a core component of polycomb repressive complex 2 ( prc2 ) , this stabilizes the histone 3 lysine 27 tri - methylation ( h3k27me3 ) at the promoter regions of several lineage commitment genes , therefore suppresses their expression . the pluripotent cell - specific atp - dependent swi / snf chromatin remodeling helicase complex ( esbaf ) is essential for esc pluripotency and self - renewal , with brg1 ( also known as smarca4 ) as a key esbaf component . in mouse escs , brg1 was shown to be required to prepare the chromatin access for stat3 to activate many of its target genes , whose promoters are otherwise occupied by prc2 complex . other studies also demonstrated that brg1 binding to stat3 is necessary to allow stat3 to access the promoter region of inf regulatory factor 1 to control its expression , as well as the promoter of the p21waf1 gene followed by stat3-cdk9 interaction promoted transcriptional elongation . ipscs are esc - like cells reprogrammed from somatic cells by overexpression a set of reprogramming factors including oct4 , klf4 , sox2 , and c - myc ( oksm ) in the mice and humans , or oct4 , sox2 , nanog , and lin28 in humans . this technology represents a powerful way for regenerative medicine in terms of massively producing patient - specific pluripotent cells within a short time . however , many technical issues still remain unsolved , including the efficiency of reprogramming , the development of integration - free reprogramming method , the quality and safety of induced ipscs for clinical application , and lastly but probably most importantly , the understanding of the molecular mechanisms of reprogramming . such information is required to ensure a proper translation of the ipsc technology to human medicine . many major differences exist between the mouse escs / ipscs and human escs / ipscs . for example , human escs / ipscs are flat in colony morphology ; depend on fgf / activin signaling for their pluripotency maintenance ; and have completed x chromosome inactivation . they divide slowly ( 36 h doubling time ) , and survive poorly after single cell dissociationa property essential for gene targeting . on the contrary , mouse escs / ipscs are dome - shaped , depend on lif signaling for pluripotency , divide rapidly ( 16 h doubling time ) , and are amenable for single - cell colonization and gene targeting . the human escs / ipscs are in fact similar to mouse epiblast stem cells ( mepiscs ) derived from pre- or post - implantation mouse embryos which have limited in vivo differentiation capacity , and these cells are collectively referred to as being in the  primed  pluripotent state , while the mouse escs / ipscs from pre - implantation embryos are referred as in the  nave  state . so far numerous studies have focused on the role of jak - stat3 in the maintenance of the steady - state pluripotency of escs ; however , until recently little had been known whether lif signaling is essential for ipsc induction , despite that lif was preferably included in the induction medium . interestingly , withdrawing lif and supplementing the culture medium with fgf / activin a results in the transition of nave mouse escs to primed episc state . at the same time , episcs can be reprogrammed into nave mouse ipscs by overexpression of klf4 , klf2 , or nanog . using this episc - esc reprogramming system , yang et al . in smith s group studied the effect of lif signaling in the conversion of primed to nave state pluripotency . they first found that lif is necessary for episc - escs transition induced by klf4 or nanog overexpression under the 2i condition . previously a chimeric receptor was described ( gy118f ) , in which the ligand binding domain of the granulocyte colony stimulating factor ( gcsf ) receptor was fused to the trans - membrane and cytoplasmic domains of gp130 modified at residue tyr ( corresponding to the tyr of the wild - type mouse gp130 ) to phenylalanine . this ensures constitutive activation of stat3 upon gcsf stimulation . by expressing the gy118f receptor in episcs with gcsf stimulation , yang et al . discovered that activation of stat3 can convert episcs directly to nave ipscs in 2i medium . they further demonstrated that stat3 activation in episcs does not stimulate klf4 or nanog expression . rather , stat3 acts synergistically with either of them to dramatically improve the reprogramming efficiency . finally , they demonstrated that activated stat3 also improves the reprogramming of mouse neural stem cells and partially reprogrammed cells ( pre - ipscs ) to nave state ipscs induced by oct4 , klf4 , c - myc ( okm ) , or oksm , respectively . the study by smith s group for the first time demonstrated that stat3 activation is necessary for the reprogramming between mouse episcs to ipscs . a later study also demonstrated that enhanced stat3 activation can reprogram mouse episcs to nave pluripotent cells even in the presence of fgf / activin differentiation signals . thus the stat3 activity becomes essential for converting the primed state to nave state pluripotency in the mouse . however , it remained unclear whether the lif signaling is necessary for reprogramming of terminally differentiated mouse somatic cells , which bypasses the episc stage during reprogramming with lif containing medium . furthermore , the molecular mechanism of stat3 induced reprogramming remains elusive , albeit much information has been obtained by studying the steady - state pluripotency maintenance . we addressed these questions by studying the role of stat3 during the reprogramming of terminally differentiated mouse embryonic fibroblasts ( mefs ) . using stat3c , a constitutively activated stat3 mutant with two residues in its sh2 domain mutated to cysteine ( a662c and n664c ) , we discovered that enhanced stat3 activation significantly promotes the reprogramming from mef cells to ipscs by oct4 , klf4 , sox2 ( oks ) , or oksm overexpression . this result was doubly confirmed by expressing a mutant gp130 with tyr converted to phenylalanine , as well as by deprivation of lif during reprogramming . we further found that the complete mef reprogramming , as indicated by expression of gfp transgene driven by the oct4 distal enhancer , was completely blocked in the presence of jak inhibitor 1 ( jaki ) but not the pi3k inhibitor , ly294002 . however , the total number of induced colonies was not affected by the jaki treatment . these observations demonstrated that stat3 activation plays a vital role in the late - stage somatic cell reprogramming , i.e. , the activation of the endogenous oct4 gene . we also studied the role of stat3 activation in the complete reprogramming of pre - ipscs induced by okm . these cells form colonies but do not express endogenous oct4 , and can be completely reprogrammed by the expression of sox2 or the addition of repsox , an inhibitor of transforming growth factor  receptor ( tgfbr ) . again our results show that stat3 activation is necessary for sox2 or tgf-signaling pathway inhibitor promoted reprogramming of pre - ipscs . examining the promoter dna methylation status revealed that jak - stat3 inhibition prevents the demethylation of endogenous oct4 and nanog during reprogramming . this is associated with increased expression of dna methyltransferase 1 ( dnmt1 ) , class i histone deacetylases ( hdacs ) , and other chromatin - repressive genes . inhibition of dnmt1 and hdacs has been shown to significantly improve somatic cell reprogramming . in order to test whether the stat3 induced inhibition of dnmt1 and hdac expression is important for complete reprogramming , we applied inhibitors for dnmt1 and hdacs together with the inhibition of stat3 during reprogramming . indeed we found that inhibiting either dnmt1 or hdacs but not the overexpression of nanog can overcome the halted reprogramming by stat3 inactivation . during this study , we also observed that stat3 inhibition resulted in continued expression of the retroviral transgenes which are otherwise gradually silenced at late - stage reprogramming . this lack of external gene silencing is tightly associated with the diminished expression of de novo dna methyltransferase dnmt3l . it has previously been demonstrated that expression of dnmt3l in mouse escs is crucial to the activation of de novo dna methylation which silences the viral transgenes . our finding therefore reveals a new role of stat3 in regulating de novo dna methylation for epigenetic gene silencing during reprogramming . taken together , our work demonstrated that ( 1 ) jak - stat3 activation is essential for the reprogramming of murine somatic cells , ( 2 ) stat3 activity is crucial for the pluripotent gene promoter demethylation , and ( 3 ) stat3 is important for retroviral transgene silencing during the reprogramming . the discovery that stat3 activity is essential for the reprogramming from mouse episcs and somatic cells to nave ipscs , as demonstrated by others and us , respectively , is significant for the understanding of reprogramming and pluripotency . the continued high - level expression of ectopic transgenes in pre - ipscs and in reprogrammed cells caused by stat3 inhibition strongly indicates the existence of a reprogramming barrier which can not be simply overcome by a greater dosage of reprogramming factors in the absence of stat3 activity , even with the overexpression of klf4 and nanog which can sustain esc self - renewal in the absence of lif . a passive model of genomic dna demethylation as a result of inhibited methylation maintenance has been proposed to explain the somatic cell reprogramming . it was also found that transient stat3 activation poises the episcs for complete reprogramming by klf4 or nanog . these are in accordance with our finding that jak - stat3 functions epigenetically to inhibit the expression of dnmt1 and other heterochromatin - promoting genes , which in turn promotes the demethylation of pluripotent loci during reprogramming . together , our results strongly suggest a central role of stat3 during reprogramming , by orchestrating the establishment of open - chromatin to completely activate the pluripotent genes , and by promoting the de novo dna methylation activity to silence the expression of viral transgenes and possibly the lineage commitment genes , in addition to the stat3 promoted suppression through prc2 ( fig . schematic representation of stat3 regulated somatic cell reprogramming via epigenetic mechanisms . during late - stage reprogramming , stat3 orchestrates the epigenetic changes leading to complete pluripotency , by ensuring full activation of core pluripotency genes through promoting dna demethylation and open chromatin formation , while suppressing the viral transgenes and lineage commitment genes by promoting de novo dna methylation and probably prc2 mediated histone modifications . the jak - stat3 pathway has been identified as the core signaling pathway for pluripotency maintenance , and was also demonstrated recently to be essential for the complete reprogramming of mouse somatic cells . although a number of stat3 downstream target genes had been identified , a thorough understanding of the stat3 mediated reprogramming still remains unachieved . an emerging area of study on stat3 mechanism is to investigate the epigenetic roles of stat3 in the maintenance of steady - state pluripotency and during the dynamic changes of somatic cell reprogramming . special emphasis may be placed on the stat3 induced formation of euchromatin for the pluripotent gene activation , and formation of heterochromatin for lineage commitment gene silencing . interestingly , recently several groups reported the generation of nave state human ipscs , which also rely on lif signaling for their self - renewal . together , these series of studies have brought jak - stat3 to the central stage of ipscs research .
reprogramming somatic cells to pluripotency , especially by the induced pluripotent stem cell ( ipsc ) technology , has become widely used today to generate various types of stem cells for research and for regenerative medicine . 
 however the mechanism(s ) of reprogramming still need detailed elucidation , including the roles played by the leukemia inhibitory factor ( lif ) signaling pathway . 
 lif is central in maintaining the ground state pluripotency of mouse embryonic stem cells ( escs ) and ipscs by activating the janus kinase - signal transducer and activator of transcription 3 ( jak - stat3 ) pathway . characterizing and understanding this pathway holds the key to generate nave pluripotent human ipscs which will facilitate the development of patient - specific stem cell therapy . 
 here we review the historical and recent developments on how lif signaling pathway regulates esc pluripotency maintenance and somatic cell reprogramming , with a focus on jak - stat3 .