Induced pluripotent stem cells (iPSCs) are reprogrammed from somatic cells via ectopic gene expression and, similarly to embryonic stem cells (ESCs), possess powerful abilities to self-renew and differentiate into cells of various lineages. However, the neural differentiation potency of iPSCs remains unknown. In this study, we demonstrated the neural differentiation ability of iPSCs compared with ESCs using an retinoic acid (RA) induction system. The neural differentiation efficiency of iPSCs was obviously lower than that of ESCs. Retinoic acid receptor-α (RARα) was critical in the RA-induced neural differentiation of iPSCs, and the effect of RARα was confirmed by applying a specific RARα antagonist ER50891 to ESCs. These findings indicate that iPSCs do not possess the complete properties that ESCs have.
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References
1.
AoiT., YaeK., NakagawaM., IchisakaT., OkitaK., TakahashiK., ChibaT., and YamanakaS. (2008). Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science, 321, 699–702.
2.
ArakiR., UdaM., HokiY., SunayamaM., NakamuraM., AndoS., SugiuraM., IdenoH., ShimadaA., NifujiA., and AbeM. (2013). Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature, 494, 100–104.
3.
BainG., KitchensD., YaoM., HuettnerJ.E., and GottliebD.I. (1995). Embryonic stem cells express neuronal properties in vitro. Dev. Biol., 168, 342–357.
4.
BastienJ., Rochette-EglyC. (2004). Nuclear retinoid receptors and the transcription of retinoid-target genes. Gene, 328, 1–16.
5.
ChandranS., KatoH., GerreliD., CompstonA., SvendsenC.N., and AllenN.D. (2003). FGF-dependent generation of oligodendrocytes by a hedgehog-independent pathway. Development, 130, 6599–6609.
ChiuC.P., and BlauH.M. (1985). 5-Azacytidine permits gene activation in a previously noninducible cell type. Cell, 40, 417–424.
8.
CorcoranJ., and MadenM. (1999). Nerve growth factor acts via retinoic acid synthesis to stimulate neurite outgrowth. Nat. Neurosci., 2, 307–308.
9.
CorcoranJ., ShrootB., PizzeyJ., and MadenM. (2000). The role of retinoic acid receptors in neurite outgrowth from different populations of embryonic mouse dorsal root ganglia. J. Cell Sci., 113 (Pt 14), 2567–2574.
10.
CorcoranJ., SoP.L., BarberR.D., VincentK.J., MazarakisN.D., MitrophanousK.A., KingsmanS.M., and MadenM. (2002). Retinoic acid receptor beta2 and neurite outgrowth in the adult mouse spinal cord in vitro. J. Cell Sci., 115(Pt 19), 3779–3786.
11.
DeyleD.R., KhanI.F., RenG., WangP.R, KhoJ., SchwarzeU., and RussellD.W. (2012). Normal collagen and bone production by gene-targeted human osteogenesis imperfecta iPSCs. Mol. Ther., 20, 204–213.
12.
DoiA., ParkI.H., WenB., MurakamiP., AryeeM.J., IrizarryR., HerbB., Ladd-AcostaC., RhoJ., LoewerS., MillerJ., SchlaegerT., DaleyG.Q., and FeinbergA.P. (2009). Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat. Genet., 41, 1350–1353.
13.
EdenS., HashimshonyT., KeshetI., CedarH., and ThorneA.W. (1998). DNA methylation models histone acetylation. Nature, 394, 842.
14.
EvansM.J., and KaufmanM.H. (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292, 154–156.
15.
FraichardA., ChassandeO., BilbautG., DehayC., SavatierP., and SamarutJ. (1995). In vitro differentiation of embryonic stem cells into glial cells and functional neurons. J. Cell Sci., 108 (Pt 10), 3181–3188.
16.
FreemantleS.J., KerleyJ.S., OlsenS.L., GrossR.H., and SpinellaM.J. (2002). Developmentally-related candidate retinoic acid target genes regulated early during neuronal differentiation of human embryonal carcinoma. Oncogene, 21, 2880–2889.
17.
GoncalvesM.B., BoyleJ., WebberD.J., HallS., MingerS.L., and CorcoranJ.P. (2005). Timing of the retinoid-signalling pathway determines the expression of neuronal markers in neural progenitor cells. Dev. Biol., 278, 60–70.
18.
GoncalvesM.B., AgudoM., ConnorS., McMahonS., MingerS.L., MadenM., and CorcoranJ.P. (2009). Sequential RARbeta and alpha signalling in vivo can induce adult forebrain neural progenitor cells to differentiate into neurons through Shh and FGF signalling pathways. Dev. Biol., 326, 305–313.
19.
HannaJ., WernigM., MarkoulakiS., SunC.W., MeissnerA., CassadyJ.P., BeardC., BrambrinkT., WuL.C., TownesT.M., and JaenischR. (2007). Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science, 318, 1920–1923.
20.
HuB.Y., WeickJ.P., YuJ., MaL.X., ZhangX.Q., ThomsonJ.A. and ZhangS.C. (2010). Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc. Natl. Acad. Sci. USA, 107, 4335–4340.
21.
KimK., DoiA., WenB., NgK., ZhaoR., CahanP., KimJ., AryeeM.J., JiH., EhrlichL.I., YabuuchiA., TakeuchiA., CunniffK.C., HongguangH., McKinney-FreemanS., NaveirasO., YoonT.J., IrizarryR.A., JungN., SeitaJ. H, annaP. M, urakamiR. J, aenischR. W, eisslederS. H. OrkinI. L. WeissmanJ., FeinbergA.P., and DaleyG.Q. (2010). Epigenetic memory in induced pluripotent stem cells. Nature, 467, 285–290.
22.
KunathT., Saba-El-LeilM.K., AlmousailleakhM., WrayJ., MelocheS., and SmithA. (2007). FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment. Development, 134, 2895–2902.
23.
LiZ., TheusM.H., and WeiL. (2006). Role of ERK 1/2 signaling in neuronal differentiation of cultured embryonic stem cells. Dev. Growth Differ., 48, 513–523.
MadenM. (2007). Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat. Rev. Neurosci., 8, 755–765.
26.
MaheraliN., AhfeldtT., RigamontiA., UtikalJ., CowanC., and HochedlingerK. (2008). A high-efficiency system for the generation and study of human induced pluripotent stem cells. Cell Stem Cell, 3, 340–345.
27.
McMahonA.P., and BradleyA. (1990). The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell, 62, 1073–1085.
28.
MikkelsenT.S., HannaJ., ZhangX., KuM., WernigM., SchorderetP., BernsteinB.E., JaenischR., LanderE.S., and MeissnerA. (2008). Dissecting direct reprogramming through integrative genomic analysis. Nature, 454, 49–55.
29.
MiuraK., OkadaY., AoiT., OkadaA., TakahashiK., OkitaK., NakagawaM., KoyanagiM., TanabeK., OhnukiM., OgawaD., IkedaE., OkanoH., and YamanakaS. (2009). Variation in the safety of induced pluripotent stem cell lines. Nat. Biotechnol., 27, 743–745.
30.
OkazawaH., OkamotoK., IshinoF., Ishino-KanekoT., TakedaS., ToyodaY., MuramatsuM., and HamadaH. (1991). The oct3 gene, a gene for an embryonic transcription factor, is controlled by a retinoic acid repressible enhancer. EMBO J., 10, 2997–3005.
31.
OkitaK., IchisakaT., and YamanakaS. (2007). Generation of germline-competent induced pluripotent stem cells. Nature, 448, 313–317.
32.
PikarskyE., SharirH., Ben-ShushanE., and BergmanY. (1994). Retinoic acid represses Oct-3/4 gene expression through several retinoic acid-responsive elements located in the promoter-enhancer region. Mol. Cell. Biol., 14, 1026–1038.
33.
RhinnM., and DolleP. (2012). Retinoic acid signalling during development. Development, 139, 843–858.
34.
SilvaJ., BarrandonO., NicholsJ., KawaguchiJ., TheunissenT.W., and SmithA. (2008). Promotion of reprogramming to ground state pluripotency by signal inhibition. PLoS Biol., 6, e253.
35.
StavridisM.P., LunnJ.S., CollinsB.J., and StoreyK.G. (2007). A discrete period of FGF-induced Erk1/2 signalling is required for vertebrate neural specification. Development, 134, 2889–2894.
TakahashiK., and YamanakaS. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126, 663–676.
38.
WernigM., LengnerC.J., HannaJ., LodatoM.A., SteineE., ForemanR., StaerkJ., MarkoulakiS., and JaenischR. (2008). A drug-inducible transgenic system for direct reprogramming of multiple somatic cell types. Nat. Biotechnol., 26, 916–924.
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